2021/10/21 更新

写真a

アサヌマ マサト
淺沼 幹人
ASANUMA Masato
所属
医歯薬学域 教授
職名
教授
外部リンク

学位

  • 博士(医学) ( 1992年3月   岡山大学 )

研究キーワード

  • 神経薬理学

  • 神経内科学

  • 神経化学

研究分野

  • ライフサイエンス / 神経科学一般

  • ライフサイエンス / 神経内科学

  • ライフサイエンス / 病態神経科学

学歴

  • 岡山大学   Graduate School of Medicine  

    1988年4月 - 1992年3月

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    国名: 日本国

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  • 岡山大学   医学部   医学科

    1982年4月 - 1988年3月

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    国名: 日本国

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経歴

  • 徳島大学薬学部 非常勤講師

    2016年 - 現在

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  • 岡山大学医歯薬学総合研究科 教授

    2014年 - 現在

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  • 国立精神・神経医療研究センター精神保健研究所 非常勤研究員

    2007年 - 現在

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  • 岡山大学医歯薬学総合研究科 准教授

    2001年 - 2014年

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  • 岡山大学医学部 助教授   Medical School

    2000年 - 2001年

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  • 岡山大学医学部 助手   Medical School

    1995年 - 2000年

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  • (財)長寿科学振興財団 リサーチレジデント

    1994年 - 1995年

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  • 岡山大学医学部 併任所員

    1992年 - 1994年

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所属学協会

  • 日本毒性学会

    2017年2月 - 現在

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  • 日本毒性学会生体金属部会(メタルバイオサイエンス研究会)

    2015年2月 - 現在

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  • 日本解剖学会

    2012年8月 - 現在

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  • 日本パーキンソン病・運動障害疾患学会(MDSJ)

    2009年8月 - 現在

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  • 日本薬理学会

    2008年1月 - 現在

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  • 国際神経化学会

    2004年7月 - 現在

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  • 日本神経精神薬理学会

    1999年4月 - 現在

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  • アメリカ神経科学会

    1997年2月 - 現在

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  • 日本神経科学学会

    1995年5月 - 現在

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  • 日本神経学会

    1989年11月 - 現在

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  • 日本神経化学会

    1989年10月 - 現在

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  • 日本薬学会

    2017年10月 - 現在

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  • 日本栄養改善学会

    2010年5月 - 2012年

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  • 神経行動薬理若手研究者の集い

    2010年3月 - 現在

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  • 国際脳研究機関(国際神経科学会)

    1995年5月 - 現在

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  • 国際脳循環代謝学会

    1993年5月 - 2014年

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  • 日本てんかん学会

    1992年11月 - 2007年

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  • 日本脳科学会

    1990年7月 - 2021年3月

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  • 日本老年医学会

    1990年 - 1995年

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  • 日本脳循環代謝学会

    1990年 - 1995年

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  • 日本内科学会

    1989年2月 - 現在

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  • 岡山脳研究セミナー

    1989年 - 現在

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委員歴

  • 日本パーキンソン病・運動障害疾患学会   評議員  

    2020年7月 - 現在   

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  • 日本薬理学会   代議員  

    2018年10月 - 現在   

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  • 日本毒性学会   評議員  

    2017年7月 - 現在   

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  • 日本神経精神薬理学会   企画委員会委員  

    2017年4月 - 現在   

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  • 日本神経精神薬理学会   先端研究推進基盤構築タスクフォース委員  

    2017年4月 - 現在   

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  • 日本毒性学会生体金属部会(メタルバイオサイエンス研究会)   常任幹事  

    2015年2月 - 現在   

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    団体区分:学協会

    メタルバイオサイエンス研究会

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  • 日本解剖学会   代議員  

    2014年8月 - 現在   

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    団体区分:学協会

    日本解剖学会

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  • 日本薬理学会   学術評議員  

    2013年4月 - 現在   

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  • 日本脳科学会   評議員  

    2006年6月 - 2021年3月   

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    団体区分:学協会

    日本脳科学会

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  • 日本神経精神薬理学会   評議員  

    2005年1月 - 現在   

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    団体区分:学協会

    日本神経精神薬理学会

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  • 岡山脳研究セミナー   事務局長  

    2000年 - 現在   

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    団体区分:学協会

    岡山脳研究セミナー

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  • 日本神経化学会   評議員  

    1999年9月 - 現在   

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    団体区分:学協会

    日本神経化学会

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論文

  • Dopaminergic neuroprotective effects of rotigotine via 5-HT1A receptors: Possibly involvement of metallothionein expression in astrocytes. 査読 国際誌

    Isooka N, Miyazaki I, Kikuoka R, Wada K, Nakayama E, Shin K, Yamamoto D, Kitamura Y, Asanuma M

    Neurochemistry international   132   104608 - 104608   2020年1月

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    担当区分:責任著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.neuint.2019.104608

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  • Effects of Enteric Environmental Modification by Coffee Components on Neurodegeneration in Rotenone-Treated Mice. 査読 国際誌

    Miyazaki I, Isooka N, Wada K, Kikuoka R, Kitamura Y, Asanuma M

    Cells   8 ( 3 )   2019年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.3390/cells8030221

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  • Region-Specific Neuroprotective Features of Astrocytes against Oxidative Stress Induced by 6-Hydroxydopamine. 査読 国際誌

    Asanuma M, Okumura-Torigoe N, Miyazaki I, Murakami S, Kitamura Y, Sendo T

    International journal of molecular sciences   20 ( 3 )   2019年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.3390/ijms20030598

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    その他リンク: http://orcid.org/0000-0002-3652-3722

  • Attenuation of Macrophage Migration Inhibitory Factor-Stimulated Signaling via S-Nitrosylation. 査読

    Nakahara K, Fujikawa K, Hiraoka H, Miyazaki I, Asanuma M, Ito A, Takasugi N, Uehara T

    Biological & pharmaceutical bulletin   42 ( 6 )   1044 - 1047   2019年

  • Application of Single Prolonged Stress Induces Post-traumatic Stress Disorder-like Characteristics in Mice. 査読

    Tanaka KI, Yagi T, Nanba T, Asanuma M

    Acta medica Okayama   72 ( 5 )   479 - 485   2018年10月

  • Involvement of 5-HT<sub>2A</sub> receptor hyperfunction in the anxiety-like behavior induced by doxorubicin and cyclophosphamide combination treatment in rats. 査読

    Nakamura Y, Kitamura Y, Sumiyoshi Y, Naito N, Kan S, Ushio S, Miyazaki I, Asanuma M, Sendo T

    Journal of pharmacological sciences   138 ( 3 )   192 - 197   2018年10月

  • Neuroprotective effect of fermented papaya preparation by activation of Nrf2 pathway in astrocytes 査読

    Shinki Murakami, Ikuko Miyazaki, Masato Asanuma

    Nutritional Neuroscience   21 ( 3 )   176 - 184   2018年3月

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    担当区分:責任著者   記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Taylor and Francis Ltd.  

    Objectives: Nuclear factor erythroid 2-related factor (Nrf2) in astrocyte plays important roles in brain homeostasis. Fermented papaya preparation (FPP) has anti-oxidative, anti-inflammatory, immunoregulatory properties. The present study investigated the effects of FPP on activation of Nrf2 and release of Nrf2-regulated neuroprotective antioxidants and detoxifying molecules. Methods: Primary cultured astrocytes from rat embryos were treated with FPP for 6 or 24 hours. The expression levels of nuclear Nrf2 and cytoplasmic Nrf2-regulated molecules were determined by western blot analysis and immunohistochemistry. Glutathione levels were measured in cells and medium. Dopaminergic neurons were exposed 6-hydroxydopamine (6-OHDA) with/without pre-treatment with FPP astrocytes. Mice were treated orally with FPP for 2 weeks. Results: FPP increased nuclear translocation of Nrf2 in striatal astrocytes, induced up-regulation of NAD(P)H quinine oxidoreductase-1, glutathione-S transferase and hemeoxygenase-1, and increased glutathione level and the percentage of metallothionein-expressing astrocytes. Moreover, FPP suppressed 6-OHDA-induced dopaminergic neuronal loss in not only neuron-astrocyte mixed culture, but also neuron-rich cultures pre-treated with glial conditioned medium. Two-week oral treatment of mice with FPP resulted in Nrf2 activation and increase in glutathione level in striatum. Discussion: The results indicated that FPP enhances the anti-oxidative capacity through activation of Nrf2 in astrocytes, suggesting it may provide neuroprotection in oxidative stress-related neurodegenerative diseases.

    DOI: 10.1080/1028415X.2016.1253171

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  • Influence of nicotine on doxorubicin and cyclophosphamide combination treatment-induced spatial cognitive impairment and anxiety-like behavior in rats 査読

    Yoshihisa Kitamura, Erika Kanemoto, Misaki Sugimoto, Ayumi Machida, Yuka Nakamura, Nanami Naito, Hirotaka Kanzaki, Ikuko Miyazaki, Masato Asanuma, Toshiaki Sendo

    NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY   390 ( 4 )   369 - 378   2017年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPRINGER  

    In the present study, we examined the effects of nicotine on cognitive impairment, anxiety-like behavior, and hippocampal cell proliferation in rats treated with a combination of doxorubicin and cyclophosphamide. Combined treatment with doxorubicin and cyclophosphamide produced cognitive impairment and anxiety-like behavior in rats. Nicotine treatment reversed the inhibition of novel location recognition induced by the combination treatment. This effect of nicotine was blocked by methyllycaconitine, a selective alpha 7 nicotinic acetylcholine receptor (nAChR) antagonist, and dihydro-beta-erythroidine, a selective alpha 4 beta 2 nAChR antagonist. In addition, nicotine normalized the amount of spontaneous alternation seen during the Y-maze task, which had been reduced by the combination treatment. This effect of nicotine was inhibited by dihydro-beta-erythroidine. In comparison, nicotine did not affect the anxiety-like behavior induced by the combination treatment. Furthermore, the combination treatment reduced the number of proliferating cells in the subgranular zone of the hippocampal dentate gyrus, and this was also prevented by nicotine. Finally, the combination of doxorubicin and cyclophosphamide significantly reduced hippocampal alpha 7 nAChR mRNA expression. These results suggest that nicotine inhibits doxorubicin and cyclophosphamide-induced cognitive impairment via alpha 7 nAChR and alpha 4 beta 2 nAChR, and also enhances hippocampal neurogenesis.

    DOI: 10.1007/s00210-016-1338-z

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  • Therapeutic strategy of targeting astrocytes for neuroprotection in parkinson’s disease 査読

    Ikuko Miyazaki, Masato Asanuma

    Current Pharmaceutical Design   23 ( 33 )   4936 - 4947   2017年

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    記述言語:英語   出版者・発行元:Bentham Science Publishers B.V.  

    Parkinson’s disease (PD) is one of common neurodegenerative diseases, which shows motor symptoms including tremor, bradykinesia, rigidity and postural instability. It also involves non-motor symptoms such as cognitive impairment, mental manifestation, autonomic disorder and sensory disturbance. Although treatments to improve the motor disability in PD are being assessed at present, the main challenge remains that is the development of neuroprotective or disease-modifying treatments. Therefore, it is desirable to find approaches that can inhibit the progression of dopaminergic neurodegeneration. Astrocytes are known to play an important role in the maintenance of the neuronal environment and exert neuroprotective effects. Additionally, astrocyte dysfunction increases the susceptibility of neurons to cytotoxicity. We have demonstrated neuroprotective approaches in parkinsonian models in various studies targeting astrocytes. In this article, we summarize the neuroprotective function of astrocytes in the brain, involvement of astrocyte dysfunction in neurodegeneration, and experimental approaches to dopaminergic neuroprotection. We review findings reported in several papers including our own studies. We also address target molecules and pivotal pathways in astrocytes for dopaminergic neuroprotection. The review discusses new promising therapeutic strategies to prevent dopaminergic neurodegeneration in PD.

    DOI: 10.2174/1381612823666170710163731

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  • Identification of transcription factors activated by methylmercury in mouse brain.

    Kim, M.S, Takahashi, T, Lee, J.Y, Miura, N, Asanuma, M, Hwang, G.W, Naganuma, A

    Fundam. Toxicol. Sci.   4 ( 1 )   37 - 39   2017年

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  • Effect of alteration of glutathione content on cell viability in a-synuclein-transfected SH-SY5Y cells.

    Tanaka, K, Sonoda, K, Asanuma, M

    Advances in Parkinson's Disease   6   93 - 100   2017年

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  • L-Theanine protects against excess dopamine-induced neurotoxicity in the presence of astrocytes

    Mika Takeshima, Ikuko Miyazaki, Shinki Murakami, Taizo Kita, Masato Asanuma

    JOURNAL OF CLINICAL BIOCHEMISTRY AND NUTRITION   59 ( 2 )   93 - 99   2016年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:JOURNAL CLINICAL BIOCHEMISTRY & NUTRITION  

    L-Theanine (gamma-glutamylethylamide), a component of green tea, is considered to have regulatory and neuroprotective roles in the brain. The present study was designed to determine the effect of L-theanine on excess dopamine-induced neurotoxicity in both cell culture and animal experiments. The primary cultured mesencephalic neurons or co-cultures of mesencephalic neurons and striatal astrocytes were pretreated with L-theanine for 72 h, and then treated with excess dopamine for further 24 h. The cell viability of dopamine neurons and levels of glutathione were evaluated. Excess dopamine-induced neurotoxicity was significantly attenuated by 72 h preincubation with L-theanine in neuron-astrocyte co-cultures but not in neuron-rich cultures. Exposure to L-theanine increased the levels of glutathione in both astrocytes and glial conditioned medium. The glial conditioned medium from L-theanine-pretreated striatal astrocytes attenuated dopamine-induced neurotoxicity and quinoprotein formation in mesencephalic neurons. In addition, replacement of L-glutamate with L-theanine in an in vitro cell-free glutathione-synthesis system produced glutathione-like thiol compounds. Furthermore, L-theanine administration (4 mg/kg, p.o.) for 14 days significantly increased glutathione levels in the striatum of mice. The results suggest that L-theanine provides neuroprotection against oxidative stress-induced neuronal damage by humoral molecules released from astrocytes, probably including glutathione.

    DOI: 10.3164/jcbn.16-15

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  • 3-O-Methyldopa inhibits astrocyte-mediated dopaminergic neuroprotective effects of L-DOPA

    Masato Asanuma, Ikuko Miyazaki

    BMC NEUROSCIENCE   17   52   2016年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:BIOMED CENTRAL LTD  

    Background: We evaluated the effects of 3-O-methyldopa (3-OMD), a metabolite of L-DOPA which is formed by catechol-O-methyltransferase (COMT), on the uptake, metabolism, and neuroprotective effects of L-DOPA in striatal astrocytes. We examined changes in the numbers of dopaminergic neurons after treatment with L-DOPA and 3-OMD or entacapone, a peripheral COMT inhibitor, using primary cultured mesencephalic neurons and striatal astrocytes.
    Results: The number of tyrosine hydroxylase-positive dopaminergic neurons was not affected by L-DOPA treatment in mesencephalic neurons alone. However, the increase in viability of dopaminergic neurons in the presence of astrocytes was further enhanced after methyl-L-DOPA treatment (25 mu M) in mixed cultured mesencephalic neurons and striatal astrocytes. The neuroprotective effect of 25 mu M L-DOPA was almost completely inhibited by simultaneous treatment with 3-OMD (10 or 100 mu M), and was enhanced by concomitant treatment with entacapone (0.3 mu M). The uptake of L-DOPA into and the release of glutathione from striatal astrocytes after L-DOPA treatment (100 mu M) were inhibited by simultaneous exposure to 3-OMD (100 mu M).
    Conclusions: These data suggest that L-DOPA exerts its neuroprotective effect on dopaminergic neurons via astrocytes and that 3-OMD competes with L-DOPA by acting on target molecule(s) (possibly including glutathione) released from astrocytes. Since some amount of entacapone can cross the blood-brain barrier, this reagent may enhance L-DOPA transportation by inhibiting COMT and increase the astrocyte-mediated neuroprotective effects of L-DOPA on dopaminergic neurons.

    DOI: 10.1186/s12868-016-0289-0

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  • In vitro quantitative determination of the concentration of the polymerization agent methyl 2-benzoylbenzoate in intravenous injection solution and the cytotoxic effects of the chemical on normal human peripheral blood mononuclear cells

    Chiaki Tsuboi, Yoichi Kawasaki, Kei Yoshitome, Kenta Yagi, Taro Miura, Satoru Esumi, Ikuko Miyazaki, Masato Asanuma, Yoshihisa Kitamura, Toshiaki Sendo

    ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH   23 ( 10 )   10262 - 10269   2016年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPRINGER HEIDELBERG  

    In previous studies, we detected the photoinitiators 1-hydroxycyclohexyl phenyl ketone (1-HCHPK) and 2-methyl-4'-(methylthio)-2-morpholinopropiophenone (MTMP) in an intravenous injection solution. Importantly, 1-HCHPK and MTMP have been demonstrated to be cytotoxic to normal human peripheral blood (PB) mononuclear cells (MNC). Cell death (apoptosis) pathways can be classified into two modes, caspase-dependent and -independent pathways. However, it is unclear whether methyl 2-benzoylbenzoate (MBB) induces the caspase-dependent and/or -independent pathway in normal human PBMNC. In the present in vitro study, we examined the levels of MBB in a solution from an intravenous fluid bag and the cytotoxicity of MBB towards normal human PBMNC via the caspase-8-, caspase-9-, or apoptosis-inducing factor (AIF)-mediated apoptosis pathways. We found that extracts from the injection solution had been contaminated with approximately 80 mu M of the photoinitiator MBB. In addition, MBB induced apoptosis in the high concentration range in normal human PBMNC in vitro. Moreover, we found that MBB-induced apoptosis occurs via the caspase-9 pathway, but not the AIF pathway. In conclusion, we suggest that MBB has cytotoxic effects on normal human PBMNC in vitro, which are mediated via the caspase-dependent pathway.

    DOI: 10.1007/s11356-016-6332-y

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  • Anti-high mobility group box 1 antibody exerts neuroprotection in a rat model of Parkinson's disease

    Tatsuya Sasaki, Keyue Liu, Takashi Agari, Takao Yasuhara, Jun Morimoto, Mihoko Okazaki, Hayato Takeuchi, Atsuhiko Toyoshima, Susumu Sasada, Aiko Shinko, Akihiko Kondo, Masahiro Kameda, Ikuko Miyazaki, Masato Asanuma, Cesario V. Borlongan, Masahiro Nishibori, Isao Date

    EXPERIMENTAL NEUROLOGY   275   220 - 231   2016年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ACADEMIC PRESS INC ELSEVIER SCIENCE  

    The high mobility group box-1 (HMGB1) exists as an architectural nuclear protein in the normal state, but displays an inflammatory cytokine-like activity in the extracellular space under pathological condition. Inflammation in the pathogenesis of Parkinson's disease (PD) has been documented. In this study, we investigated the involvement of HMGB1 in the pathology and the neuroprotective effects of neutralizing anti-HMGB1 monoclonal antibody (mAb) on an animal model of PD. Adult female Sprague-Dawley rats were initially injected with 6-hydroxydopmaine (6-OHDA, 20 mu g/4 mu l) into the right striatum, then anti-HMGB1 mAb (1 mg/kg), or control mAb was intravenously administered immediately, at 6 and 24 h after 6-OHDA injection. The treatment with anti-HMGB1 mAb significantly preserved dopaminergic neurons in substantia nigra pars compacta and dopaminergic terminals inherent in the striatum, and attenuated PD behavioral symptoms compared to the control mAb-treated group. HMGB1 was retained in the nucleus of neurons and astrocytes by inhibiting the proinflammation-induced oxidative stress in the anti-HMGB1 mAb-treated group, whereas HMGB1 translocation was observed in neurons at 1 day and astrocytes at 7 days after 6-OHDA injection in the control mAb-treated group. Anti-HMGB1 mAb inhibited the activation of microglia, disruption of blood-brain-barrier (BBB), and the expression of inflammation cytokines such as IL-1 beta. and IL-6. These results suggested that HMGB1 released from neurons and astrocytes was at least partly involved in the mechanism and pathway of degeneration of dopaminergic neurons induced by 6-0HDA exposure. Intravenous administration of anti-HMGB1 mAb stands as a novel therapy for PD possibly acting through the suppression of neuroinflammation and the attenuation of disruption of BOB associated with the disease. (C) 2015 Elsevier Inc. All rights reserved.

    DOI: 10.1016/j.expneurol.2015.11.003

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  • Neuroprotective effects of levetiracetam target xCT in astrocytes in parkinsonian mice

    Ikuko Miyazaki, Shinki Murakami, Nao Torigoe, Yoshihisa Kitamura, Masato Asanuma

    JOURNAL OF NEUROCHEMISTRY   136 ( 1 )   194 - 204   2016年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    Astrocytes but not neurons express cystine/glutamate exchange transporter (xCT), which takes up cystine, and consequently supplies the substrate for GSH synthesis in neurons. It is recognized that GSH synthesis in neurons is dependent on the expression of xCT in astrocytes. Previous studies reported that levetiracetam (LEV), an anti-epileptic drug, increased xCT expression invivo. The purpose of this study was to examine neuroprotective effects of LEV in parkinsonian models and demonstrate xCT in astrocytes as a target of neuroprotection against dopaminergic neurodegeneration. We identified striatal astrocytes cultured with LEV showed significant increase in xCT expression and GSH levels. Preincubation of primary cultured mesencephalic dopamine neurons with conditioned media from LEV-treated astrocytes protected against 6-hydroxydopamine (6-OHDA)-induced neurotoxicity. These protective effects were canceled by xCT inhibitor. Furthermore, reduction of nigrostriatal dopaminergic neurons in 6-OHDA-lesioned parkinsonian mice was significantly abrogated by repeated injections of LEV. Treatment with LEV significantly increased the expression of xCT in striatal astrocytes in the hemi-parkinsonian mice. In conclusion, LEV exerts neuroprotective effects against neurodegeneration via up-regulation of xCT and GSH in astrocytes. Thus, xCT in astrocytes could be a potential target in novel neuroprotective approaches to prevent degeneration of dopaminergic neurons.

    DOI: 10.1111/jnc.13405

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  • Changes in Metallothionein Isoform Expression in the Bones of Ovariectomized Rats

    Chiharu Sogawa, Mika Ikegame, Ikuko Miyazaki, Toshiaki Ara, Yasuhiro Imamura, Yuka Okusha, Kazumi Ohyama, Masato Asanuma, Norio Sogawa, Toshio Yamamoto, Ken-ichi Kozaki

    JOURNAL OF HARD TISSUE BIOLOGY   25 ( 1 )   21 - 26   2016年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:JOURNAL HARD TISSUE BIOLOGY  

    Metal-binding proteins, metallothioneins (MTs), may play important roles in bone metabolism. However, the contribution of MTs to bone metabolism remains obscure. In the present study, we investigated the expression of MT isoforms in bone cells and mRNA for MT isoforms in the tibiae following ovariectomy (OVX). The results obtained showed that MT-I/II and MT-III were expressed in osteoblasts, osteoclasts, and osteocytes 4 weeks after OVX. Peaks in the mRNA expression ratios (OVX/Sham) of MT-I/II and MT-III changed following OVX. The expression ratio of MT-I/II increased after 1 week, whereas that of MT-III increased 4 weeks after OVX. These results suggest that the contribution of MTs to bone metabolism may depend on the isoforms in the cell types and the stage after OVX.

    DOI: 10.2485/jhtb.25.21

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  • Serotonin 1A Receptors on Astrocytes as a Potential Target for the Treatment of Parkinson's Disease

    Ikuko Miyazaki, Masato Asanuma

    CURRENT MEDICINAL CHEMISTRY   23 ( 7 )   686 - 700   2016年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:BENTHAM SCIENCE PUBL LTD  

    Astrocytes are the most abundant neuron-supporting glial cells in the central nervous system. The neuroprotective role of astrocytes has been demonstrated in various neurological disorders such as amyotrophic lateral sclerosis, spinal cord injury, stroke and Parkinson's disease (PD). Astrocyte dysfunction or loss-of-astrocytes increases the susceptibility of neurons to cell death, while astrocyte transplantation in animal studies has therapeutic advantage. We reported recently that stimulation of serotonin 1A (5-HT1A) receptors on astrocytes promoted astrocyte proliferation and upregulated antioxidative molecules to act as a neuroprotectant in parkinsonian mice. PD is a progressive neurodegenerative disease with motor symptoms such as tremor, bradykinesia, rigidity and postural instability, that are based on selective loss of nigrostriatal dopaminergic neurons, and with non-motor symptoms such as orthostatic hypotension and constipation based on peripheral neurodegeneration. Although dopaminergic therapy for managing the motor disability associated with PD is being assessed at present, the main challenge remains the development of neuroprotective or disease-modifying treatments. Therefore, it is desirable to find treatments that can reduce the progression of dopaminergic cell death. In this article, we summarize first the neuroprotective properties of astrocytes targeting certain molecules related to PD. Next, we review neuroprotective effects induced by stimulation of 5-HT1A receptors on astrocytes. The review discusses new promising therapeutic strategies based on neuroprotection against oxidative stress and prevention of dopaminergic neurodegeneration.

    DOI: 10.2174/0929867323666160122115057

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  • Serotonin-1A agonist 8-OH-DPAT alleviates motor dysfunction and motor neuron degeneration in a model of amyotrophic lateral sclerosis.

    Miyazaki I, Murakami S, Nakano T, Torigoe N, Kikuoka R, Kitamura Y, Sendo T, Asanuma M

    Ann. Pharmacol. Pharmaceut.   1 ( 1 )   1003 - 1003   2016年

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  • Doxorubicin and cyclophosphamide treatment produces anxiety-like behavior and spatial cognition impairment in rats: Possible involvement of hippocampal neurogenesis via brain-derived neurotrophic factor and cyclin D1 regulation

    Yoshihisa Kitamura, Sayo Hattori, Saori Yoneda, Saori Watanabe, Erika Kanemoto, Misaki Sugimoto, Toshiki Kawai, Ayumi Machida, Hirotaka Kanzaki, Ikuko Miyazaki, Masato Asanuma, Toshiaki Sendo

    BEHAVIOURAL BRAIN RESEARCH   292   184 - 193   2015年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE BV  

    Many patients who have received chemotherapy to treat cancer experience depressive- and anxiety-like symptoms or cognitive impairment. However, despite the evidence for this, the underlying mechanisms are still not understood. This study investigated behavioral and biochemical changes upon treatment with doxorubicin and cyclophosphamide, focusing on mental and cognitive systems, as well as neurogenesis in male rats. Doxorubicin (2 mg/kg), cyclophosphamide (50 mg/kg), and the combination of doxorubicin and cyclophosphamide were injected intraperitoneally once per week for 4 weeks. In particular, the co-administration of doxorubicin and cyclophosphamide produced anhedonia-like, anxiety-like, and spatial cognitive impairments in rats. It also reduced both the number of proliferating cells in the subgranular zone of the hippocampal dentate gyrus and their survival. Serum brain-derived neurotrophic factor (BDNF) levels were decreased along with chemotherapy-induced decreases in platelet levels. However, hippocampal BDNF levels and Bdnf mRNA levels were not decreased by this treatment. On the other hand, hippocampal cyclin D1 levels were significantly decreased by chemotherapy. These results suggest that the co-administration of doxorubicin and cyclophosphamide induces psychological and cognitive impairment, in addition to negatively affecting hippocampal neurogenesis, which may be related to hippocampal cyclin D1 levels, but not hippocampal BDNF levels. (C) 2015 Elsevier B.V. All rights reserved.

    DOI: 10.1016/j.bbr.2015.06.007

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  • Long-Term Systemic Exposure to Rotenone Induces Central and Peripheral Pathology of Parkinson's Disease in Mice

    Shinki Murakami, Ikuko Miyazaki, Ko Miyoshi, Masato Asanuma

    NEUROCHEMICAL RESEARCH   40 ( 6 )   1165 - 1178   2015年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPRINGER/PLENUM PUBLISHERS  

    Parkinson's disease (PD) is a progressive neurodegenerative disease with motor and non-motor symptoms that precede the onset of motor symptoms. Rotenone is often used to induce PD-like pathology in the central nervous system (CNS) and enteric nervous system (ENS). However, there is little or no information on the temporal changes in other neural tissues and the spread of pathology throughout the entire body organs. Here, we recorded the serial immunohistochemical changes in neurons and glial cells of the striatum, substantia nigra (SN), olfactory bulb (OB), thoracic cord (ThC) and ascending colon (AC) induced by 1-, 3- and 6-week administration of rotenone (50 mg/kg/day) infused subcutaneously in C57BL mice using an osmotic pump. Rotenone exposure for 3 or 6 weeks caused neurodegeneration in the striatum, whereas neuronal damage was seen in the SN and OB only after 6 weeks. Moreover, rotenone induced neurodegeneration in the myenteric plexus of AC but not in ThC. Rotenone also activated glial cells before any apparent neurodegeneration in the CNS but not in the ENS. Our results demonstrated that subcutaneous administration of rotenone can cause progressive neurodegeneration in the OB and AC, in addition to the nigrostriatal pathway, and temporal differential glial activation, and that these changes do not spread retrogradely from OB or ENS to nigrostriatal pathway. The results suggested that the different vulnerability of neurons to the neurotoxic effects of rotenone administrated subcutaneously are due to glial activation in these neural tissues.

    DOI: 10.1007/s11064-015-1577-2

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  • Possible involvement of iron-induced oxidative insults in neurodegeneration

    Takeshi Asano, Masato Koike, Shin-ichi Sakata, Yukiko Takeda, Tomoko Nakagawa, Taku Hatano, Satoshi Ohashi, Manabu Funayama, Kenji Yoshimi, Masato Asanuma, Shinya Toyokuni, Hideki Mochizuki, Yasuo Uchiyama, Nobutaka Hattori, Kazuhiro Iwai

    NEUROSCIENCE LETTERS   588   29 - 35   2015年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER IRELAND LTD  

    Involvement of iron in the development of neurodegenerative disorders has long been suggested, and iron that cannot be stored properly is suggested to induce iron toxicity. To enhance iron uptake and suppress iron storage in neurons, we generated transgenic (Tg) mice expressing iron regulatory protein 2 (IRP2), a major regulator of iron metabolism, in a neuron-specific manner. Although very subtle, IRP2 was expressed in all regions of brain examined. In the Tg mice, mitochondrial oxidative insults were observed including generation of 4-hydroxynonenal modified proteins, which appeared to be removed by a mitochondrial quality control protein Parkin. Inter-crossing of the Tg mice to Parkin knockout mice perturbed the integrity of neurons in the substantia nigra and provoked motor symptoms. These results suggest that a subtle, but chronic increase in IRP2 induces mitochondrial oxidative insults and accelerates neurodegeneration in a mouse model of Parkinson's disease. Thus, the IRP2 Tg may be a useful tool to probe the roles of iron-induced mitochondrial damages in neurodegeraration research. (C) 2014 Elsevier Ireland Ltd. All rights reserved.

    DOI: 10.1016/j.neulet.2014.12.052

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  • ハルミンの薬物依存性ならびに細胞毒性の評価:植物由来幻覚成分の有害作用について.

    舩田正彦, 竹林美佳, 宮崎育子, 浅沼幹人, 青尾直也, 和田 清

    精神保健研究   61 ( 28 )   61 - 72   2015年

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  • Visualization of Astrocytic Primary Cilia in the Mouse Brain by Immunofluorescent Analysis Using the Cilia Marker Arl13b

    Kyosuke Kasaharaa, Ko Miyoshi, Shinki Murakami, Ikuko Miyazaki, Masato Asanuma

    ACTA MEDICA OKAYAMA   68 ( 6 )   317 - 322   2014年12月

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    記述言語:英語   出版者・発行元:OKAYAMA UNIV MED SCHOOL  

    In vertebrates, almost all somatic cells extend a single immotile cilium, referred to as a primary cilium. Increasing evidence suggests that primary cilia serve as cellular antennae in many types of tissues by sensing chemical or mechanical stimuli in the milieu surrounding the cells. In rodents an antibody to adenylyl cyclase 3 (AC3) has been widely used to label the primary cilia of neurons in vivo by immunostaining, whereas the lack of markers for the primary cilia of astrocytes has made it difficult to observe astrocytic primary cilia in vivo. Here, we obtained a visualization of astrocytic primary cilia in the mouse brain. In the somatosensory cortex, a large portion of neurons and astrocytes at postnatal day 10 (P10), and of neurons at P56 had AC3-positive primary cilia, whereas only approx. one-half of the astrocytes in the P56 mice carried primary cilia weakly positive for AC3. In contrast, the majority of astrocytes had ADP-ribosylation factor-like protein 13B (Arl13b)-positive primary cilia in the somatosensory cortex and other brain regions of P56 mice. The lengths of astrocytic primary cilia positive for Arl13b varied among the brain regions. Our data indicate that Arl13b is a noteworthy marker of astrocytic primary cilia in the brain.

    DOI: 10.18926/AMO/53020

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  • Methylphenidate improves learning impairments and hyperthermia-induced seizures caused by an Scn1a mutation

    Iori Ohmori, Nozomi Kawakami, Sumei Liu, Haijiao Wang, Ikuko Miyazaki, Masato Asanuma, Hiroyuki Michiue, Hideki Matsui, Tomoji Mashimo, Mamoru Ouchida

    EPILEPSIA   55 ( 10 )   1558 - 1567   2014年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    ObjectiveDevelopmental disorders including cognitive deficit, hyperkinetic disorder, and autistic behaviors are frequently comorbid in epileptic patients with SCN1A mutations. However, the mechanisms underlying these developmental disorders are poorly understood and treatments are currently unavailable. Using a rodent model with an Scn1a mutation, we aimed to elucidate the pathophysiologic basis and potential therapeutic treatments for developmental disorders stemming from Scn1a mutations.MethodsWe conducted behavioral analyses on rats with the N1417H-Scn1a mutation. With high-performance liquid chromatography, we measured dopamine and its metabolites in the frontal cortex, striatum, nucleus accumbens, and midbrain. Methylphenidate was administered intraperitoneally to examine its effects on developmental disorder-like behaviors and hyperthermia-induced seizures.ResultsBehavioral studies revealed that Scn1a-mutant rats had repetitive behavior, hyperactivity, anxiety-like behavior, spatial learning impairments, and motor imbalance. Dopamine levels in the striatum and nucleus accumbens in Scn1a-mutant rats were significantly lower than those in wild-type rats. In Scn1a-mutant rats, methylphenidate, by increasing dopamine levels in the synaptic cleft, improved hyperactivity, anxiety-like behavior, and spatial learning impairments. Surprisingly, methylphenidate also strongly suppressed hyperthermia-induced seizures.SignificanceDysfunction of the mesolimbic dopamine reward pathway may contribute to the hyperactivity and learning impairments in Scn1a-mutant rats. Methylphenidate was effective for treating hyperactivity, learning impairments, and hyperthermia-induced seizures. We propose that methylphenidate treatment may ameliorate not only developmental disorders but also epileptic seizures in patients with SCN1A mutations.

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  • Neuroprotective Effects of Metallothionein Against Rotenone-Induced Myenteric Neurodegeneration in Parkinsonian Mice

    Shinki Murakami, Ikuko Miyazaki, Norio Sogawa, Ko Miyoshi, Masato Asanuma

    NEUROTOXICITY RESEARCH   26 ( 3 )   285 - 298   2014年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPRINGER  

    Parkinson's disease (PD) is a neurodegenerative disease with motor symptoms as well as non-motor symptoms that precede the onset of motor symptoms. Mitochondrial complex I inhibitor, rotenone, has been widely used to reproduce PD pathology in the central nervous system (CNS) and enteric nervous system (ENS). We reported previously that metallothioneins (MTs) released from astrocytes can protect dopaminergic neurons against oxidative stress. The present study examined the changes in MT expression by chronic systemic rotenone administration in the striatum and colonic myenteric plexus of C57BL mice. In addition, we investigated the effects of MT depletion on rotenone-induced neurodegeneration in CNS and ENS using MT-1 and MT-2 knockout (MT KO) mice, or using primary cultured neurons from MT KO mice. In normal C57BL mice, subcutaneous administration of rotenone for 6 weeks caused neurodegeneration, increased MT expression with astrocytes activation in the striatum and myenteric plexus. MT KO mice showed more severe myenteric neuronal damage by rotenone administration after 4 weeks than wild-type mice, accompanied by reduced astroglial activation. In primary cultured mesencephalic neurons from MT KO mice, rotenone exposure induced neurotoxicity in dopaminergic neurons, which was complemented by addition of recombinant protein. The present results suggest that MT seems to provide protection against neurodegeneration in ENS of rotenone-induced PD model mice.

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  • Striatal Astrocytes Act as a Reservoir for L-DOPA

    Masato Asanuma, Ikuko Miyazaki, Shinki Murakami, Francisco J. Diaz-Corrales, Norio Ogawa

    PLOS ONE   9 ( 9 )   e106362   2014年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PUBLIC LIBRARY SCIENCE  

    L-DOPA is therapeutically efficacious in patients with Parkinson's disease (PD), although dopamine (DA) neurons are severely degenerated. Since cortical astrocytes express neutral amino acid transporter (LAT) and DA transporter (DAT), the uptake and metabolism of L-DOPA and DA in striatal astrocytes may influence their availability in the dopaminergic system of PD. To assess possible L-DOPA-and DA-uptake and metabolic properties of striatal astrocytes, we examined the expression of L-DOPA, DA and DAT in striatal astrocytes of hemi-parkinsonian model rats after repeated L-DOPA administration, and measured the contents of L-DOPA, DA and their metabolite in primary cultured striatal astrocytes after L-DOPA/DA treatment. Repeated injections of L-DOPA induced apparent L-DOPA-and DA-immunoreactivities and marked expression of DAT in reactive astrocytes on the lesioned side of the striatum in hemi-parkinsonian rats. Exposure to DA for 4 h significantly increased the levels of DA and its metabolite DOPAC in cultured striatal astrocytes. L-DOPA was also markedly increased in cultured striatal astrocytes after 4-h L-DOPA exposure, but DA was not detected 4 or 8 h after L-DOPA treatment, despite the expression of aromatic amino acid decarboxylase in astrocytes. Furthermore, the intracellular level of L-DOPA in cultured striatal astrocytes decreased rapidly after removal of extracellular L-DOPA. The results suggest that DA uptaken into striatal astrocytes is rapidly metabolized and that striatal astrocytes act as a reservoir of L-DOPA that govern the uptake or release of L-DOPA depending on extracellular L-DOPA concentration, but are less capable of converting L-DOPA to DA.

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  • Effects of (+)-8-OH-DPAT on the duration of immobility during the forced swim test and hippocampal cell proliferation in ACTH-treated rats

    Ayaka Miyake, Yoshihisa Kitamura, Ikuko Miyazaki, Masato Asanuma, Toshiaki Sendo

    PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR   122   240 - 245   2014年7月

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    記述言語:英語   出版者・発行元:PERGAMON-ELSEVIER SCIENCE LTD  

    In the present study, we examined the effect of ACTH on the immobilization of rats in the forced swim test and hippocampal cell proliferation after administration of the 5-HT1A receptor agonist, R-(+)-8-hydroxy-2-di-n-propylamino tetralin ((+)-8-OH-DPAT). Chronic treatment with (+)-8-OH-DPAT (0.01-0.1 mg/kg, s.c.) significantly decreased the duration of immobility in saline- and ACTH-treated rats. Chronic administration of ACTH caused a significant decrease in hippocampal cell proliferation. However, (+)-8-OH-DPAT significantly normalized cell proliferation in ACTH-treated rats. We then investigated the effects of (+)-8-OH-DPAT on the expression of brain-derived neurotrophic factor (BDNF) and cyclin D1 (elements of cyclic adenosine monophosphate response element-binding protein (CREB)-BDNF and Wnt signaling pathways, respectively) in the hippocampus of saline- and ACTH-treated rats. ACTH treatment significantly decreased the expression of cyclin D1, while treatment with (+)-8-OH-DPAT normalized the expression of cyclin D1 in ACTH-treated rats. However, the expression of BDNF did not change in either saline- or ACTH-treated rats. These findings suggest that the antidepressant effects of (+)-8-OH-DPAT in treatment-resistant animals may be attributed to an enhancement of hippocampal cell proliferation, at least in part due to an enhancement of cyclin D1 expression. (C) 2014 Elsevier Inc All rights reserved.

    DOI: 10.1016/j.pbb.2014.04.003

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  • Lack of Dopaminergic Inputs Elongates the Primary Cilia of Striatal Neurons

    Ko Miyoshi, Kyosuke Kasahara, Shinki Murakami, Mika Takeshima, Natsuko Kumamoto, Asako Sato, Ikuko Miyazaki, Shinsuke Matsuzaki, Toshikuni Sasaoka, Taiichi Katayama, Masato Asanuma

    PLOS ONE   9 ( 5 )   e97918   2014年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PUBLIC LIBRARY SCIENCE  

    In the rodent brain, certain G protein-coupled receptors and adenylyl cyclase type 3 are known to localize to the neuronal primary cilium, a primitive sensory organelle protruding singly from almost all neurons. A recent chemical screening study demonstrated that many compounds targeting dopamine receptors regulate the assembly of Chlamydomonas reinhardtii flagella, structures which are analogous to vertebrate cilia. Here we investigated the effects of dopaminergic inputs loss on the architecture of neuronal primary cilia in the rodent striatum, a brain region that receives major dopaminergic projections from the midbrain. We first analyzed the lengths of neuronal cilia in the dorsolateral striatum of hemi-parkinsonian rats with unilateral lesions of the nigrostriatal dopamine pathway. In these rats, the striatal neuronal cilia were significantly longer on the lesioned side than on the non-lesioned side. In mice, the repeated injection of reserpine, a dopamine-depleting agent, elongated neuronal cilia in the striatum. The combined administration of agonists for dopamine receptor type 2 (D2) with reserpine attenuated the elongation of striatal neuronal cilia. Repeated treatment with an antagonist of D2, but not of dopamine receptor type 1 (D1), elongated the striatal neuronal cilia. In addition, D2-null mice displayed longer neuronal cilia in the striatum compared to wild-type controls. Reserpine treatment elongated the striatal neuronal cilia in D1-null mice but not in D2-null mice. Repeated treatment with a D2 agonist suppressed the elongation of striatal neuronal cilia on the lesioned side of hemi-parkinsonian rats. These results suggest that the elongation of striatal neuronal cilia following the lack of dopaminergic inputs is attributable to the absence of dopaminergic transmission via D2 receptors. Our results provide the first evidence that the length of neuronal cilia can be modified by the lack of a neurotransmitter's input.

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  • Protective Effects of Phytochemical Antioxidants Against Neurotoxin-Induced Degeneration of Dopaminergic Neurons

    Taizo Kita, Masato Asanuma, Ikuko Miyazaki, Mika Takeshima

    JOURNAL OF PHARMACOLOGICAL SCIENCES   124 ( 3 )   313 - 319   2014年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:JAPANESE PHARMACOLOGICAL SOC  

    The specific toxicity to dopaminergic neurons of psychostimulants and neurotoxins has been extensively studied in vivo and in vitro, and findings have been used to establish animal models of amphetamine psychosis or Parkinson's disease. The multiple mechanisms of neurotoxicity operating in these disorders are known to involve oxidative stress or neuroinflammation, producing the characteristic behavioral and neuropathlogical changes arising from injured dopaminergic neurons and glial cells. A number of studies have shown that glia-targeting antioxidants play important roles in protecting against the neurotoxicity caused by psychostimulants or neurotoxins. Phytochemicals, which are non-nutritive plant chemicals, protect dopaminergic neurons and glial cells from damage caused by psychostimulants or neurotoxins. The objective of this review was to evaluate the involvement of glial cells in dopaminergic neuron specific toxicity and to explore the neuroprotective activity of phytochemicals in terms of anti-inflammatory and antioxidant action.

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  • Effects of Bupropion and Pramipexole on Cell Proliferation in the Hippocampus of Adrenocorticotropic Hormone-Treated Rats

    Yuka Onoue, Keiko Kuwatsuka, Ikuko Miyazaki, Masato Asanuma, Yoshihisa Kitamura, Toshiaki Sendo

    BIOLOGICAL & PHARMACEUTICAL BULLETIN   37 ( 2 )   327 - 330   2014年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PHARMACEUTICAL SOC JAPAN  

    The dopamine reuptake inhibitor bupropion and dopamine D2/3 receptor agonist pramipexole have been clinically proven to improve both depression and treatment-resistant depression. We examined its influence on the duration of immobility during the forced swim test in adrenocorticotropic hormone (ACTH)-treated rats and further analyzed the possible role of the dopamine nerve system in this effect. Bupropion and pramipexole significantly decreased the duration of immobility in normal and ACTH-treated rats. We previously demonstrated that the chronic administration of ACTH caused a significant decrease in hippocampal cell proliferation and neurogenesis. In this study, we used the mitotic marker 5-bromo-2'-deoxyridine to investigate the effects of bupropion and pramipexole on cell proliferation in the subgranular zone of the hippocampal dentate gyms following chronic treatment with ACTH. The ACTH treatment for 14 d decreased adult hippocampal cell proliferation. The chronic administration of bupropion for 14 d blocked the loss of cell proliferation resulting from the chronic treatment with ACTH, whereas pramipexole did not. The administration of bupropion may have treatment-resistant antidepressive properties, which may be partly attributed to the normalization of hippocampal cell proliferation.

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  • アストロサイトによる神経機能修飾とパーキンソン病での神経保護

    浅沼幹人

    岡山医学会雑誌   126 ( 3 )   203 - 208   2014年

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  • お茶の旨味成分テアニンのアストログリア細胞における細胞保護効果

    喜多大三, 浅沼幹人, 宮崎育子, 竹島美香

    九州栄養福祉大学研究紀要 第10号   2013年12月

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    記述言語:日本語  

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  • Targeting 5-HT1A receptors in astrocytes to protect dopaminergic neurons in parkinsonian models

    Ikuko Miyazaki, Masato Asanuma, Shinki Murakami, Mika Takeshima, Nao Torigoe, Yoshihisa Kitamura, Ko Miyoshi

    Neurobiology of Disease   59 ( 59 )   244 - 256   2013年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Astrocytes are abundant neuron-supporting glial cells that harbor a powerful arsenal of neuroprotective antioxidative molecules and neurotrophic factors. Here we examined whether enrichment with healthy striatal astrocytes can provide neuroprotection against progressive dopaminergic neurodegeneration. Serotonin 1A (5-HT1A) agonist 8-OH-DPAT induced astrocyte proliferation and increased metallothionein-1/-2 (MT-1/-2), antioxidative molecules, in cultured astrocytes and the striatum of mice. Primary cultured mesencephalic dopamine neurons were protected against oxidative stress by preincubation with conditioned media from 8-OH-DPAT-treated astrocytes. These protective effects were canceled by 5-HT1A antagonist or MT-1/-2-specific antibody. Furthermore, reduction of nigrostriatal dopaminergic neurons in 6-hydroxydopamine-lesioned parkinsonian model mice was significantly abrogated by repeated injections of 8-OH-DPAT. Treatment with 8-OH-DPAT markedly increased the expression of MT in striatal astrocytes in the hemi-parkinsonian mice. Our study provides a promising therapeutic strategy of neuroprotection against oxidative stress and progressive dopaminergic neurodegeneration by demonstrating the efficacy of targeting 5-HT1A receptors in astrocytes. © 2013 Elsevier Inc.

    DOI: 10.1016/j.nbd.2013.08.003

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  • Transplantation of Melanocytes Obtained from the Skin Ameliorates Apomorphine-Induced Abnormal Behavior in Rodent Hemi-Parkinsonian Models

    Masato Asanuma, Ikuko Miyazaki, Francisco J. Diaz-Corrales, Youichirou Higashi, Masayoshi Namba, Norio Ogawa

    PLoS ONE   8 ( 6 )   e65983   2013年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Tyrosinase, which catalyzes both the hydroxylation of tyrosine and consequent oxidation of L-DOPA to form melanin in melanocytes, is also expressed in the brain, and oxidizes L-DOPA and dopamine. Replacement of dopamine synthesis by tyrosinase was reported in tyrosine hydroxylase null mice. To examine the potential benefits of autograft cell transplantation for patients with Parkinson's disease, tyrosinase-producing cells including melanocytes, were transplanted into the striatum of hemi-parkinsonian model rats or mice lesioned with 6-hydroxydopamine. Marked improvement in apomorphine-induced rotation was noted at day 40 after intrastriatal melanoma cell transplantation. Transplantation of tyrosinase cDNA-transfected hepatoma cells, which constitutively produce L-DOPA, resulted in marked amelioration of the asymmetric apomorphine-induced rotation in hemi-parkinsonian mice and the effect was present up to 2 months. Moreover, parkinsonian mice transplanted with melanocytes from the back skin of black newborn mice, but not from albino mice, showed marked improvement in the apomorphine-induced rotation behavior up to 3 months after the transplantation. Dopamine-positive signals were seen around the surviving transplants in these experiments. Taken together with previous studies showing dopamine synthesis and metabolism by tyrosinase, these results highlight therapeutic potential of intrastriatal autograft cell transplantation of melanocytes in patients with Parkinson's disease. © 2013 Asanuma et al.

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  • Protective effect of cepharanthin on cisplatin-induced renal toxicity through metallothionein expression

    Norio Sogawa, Kanji Hirai, Chiharu Sogawa, Kazumi Ohyama, Ikuko Miyazaki, Goichi Tsukamoto, Masato Asanuma, Akira Sasaki, Shigeo Kitayama

    Life Sciences   92 ( 12 )   727 - 732   2013年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Aims Cisplatin (CDDP) is a potent anticancer agent, but severe renal toxicity can limit its use. We investigated the protective effect of cepharanthin (CE), a biscoclaurin alkaloid, on the renal toxicity of CDDP. Main methods Mice were given CDDP along with CE. Effects of CE on CDDP toxicity were investigated by assaying markers of renal toxicity together with MT expression, and by histopathological examination of the kidney. MT-null mice were also examined. Key findings CE induced expression of metallothionein (MT). Pre-administration of CE attenuated an increase in blood urea nitrogen (BUN) concentrations after the CDDP injection. A histochemical analysis demonstrated protection against CDDP-induced necrocytosis of kidney tissues by CE. The protective effect of CE did not occur in the MT-null mice. Significance Pretreatment with CE may reduce the renal toxicity of CDDP through expression of MT. © 2013 Elsevier Inc.

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  • Effect of the 5-HT1A receptor function on antidepressive effect and neurogenesis in ACTH treated rats 査読

    Miyake Ayaka, Kitamura Yoshihisa, Hattori Sayo, Koyama Toshihiro, Miyazaki Ikuko, Asanuma Masato, Sendo Toshiaki

    JOURNAL OF PHARMACOLOGICAL SCIENCES   121   144P   2013年

  • The mechanisms of electroconvulsive stimuli in BrdU-positive cells of the dentate gyrus in ACTH-treated rats

    Keiko Kuwatsuka, Hiromi Hayashi, Yuka Onoue, Ikuko Miyazaki, Toshihiro Koyama, Masato Asanuma, Yoshihisa Kitamura, Toshiaki Sendo

    Journal of Pharmacological Sciences   122 ( 1 )   34 - 41   2013年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    In clinical studies, electroconvulsive stimuli have been associated with improvements in both depression and treatment-resistant depression. In a previous study, treatment with adrenocorticotropic hormone (ACTH) for 14 days decreased adult hippocampal cell proliferation. Furthermore, electroconvulsive stimuli significantly decreased the duration of immobility following repeated administration of ACTH for 14 days in rats. The present study was undertaken to further characterize the mechanism of treatment-resistant antidepressant effects of electroconvulsive stimuli by measuring cell proliferation, brain-derived neurotrophic factor (BDNF) levels, and phosphorylated and total cyclic adenosine monophosphate (cAMP) response element-binding protein (pCREB/CREB) levels in the hippocampus of ACTH-treated rats. Electroconvulsive stimuli increased cell proliferation in both saline-treated and ACTH-treated rats. Mature-BDNF protein levels showed a tendency to decrease in ACTH-treated rats. Electroconvulsive stimuli treatment increased mature-BDNF protein levels in the hippocampus of both saline-treated and ACTH-treated rats. Furthermore, electroconvulsive stimuli increased phospho-Ser133-CREB (pCREB) levels and the ratio of pCREB/CREB in both saline-treated and ACTH-treated rats. These findings suggest that the treatment-resistant antidepressant effects of electroconvulsive stimuli may be attributed, at least in part, to an enhancement of hippocampal cell proliferation. © The Japanese Pharmacological Society.

    DOI: 10.1254/jphs.13015FP

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  • アストロサイトとParkinson病治療

    神経内科   79 ( 2 )   257 - 261   2013年

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  • Neuroprotective effects of serotonin-1a agonist 8-OH-DPAT target astrocytes

    Ikuko Miyazaki, Shinki Murakami, Mika Takeshima, Nao Torigoe, Ko Miyoshi, Yoshihisa Kitamura, Masato Asanuma

    JOURNAL OF PHARMACOLOGICAL SCIENCES   121   138P - 138P   2013年

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    記述言語:英語   出版者・発行元:JAPANESE PHARMACOLOGICAL SOC  

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  • Influence of doxorubicin and cyclophosphamide on psychological behavior in rats 査読

    Kitamura Yoshihisa, Hattori Sayo, Miyake Ayaka, Koyama Toshihiro, Miyazaki Ikuko, Asanuma Masato, Sendo Toshiaki

    JOURNAL OF PHARMACOLOGICAL SCIENCES   121   143P   2013年

  • Centrosomal aggregates and Golgi fragmentation disrupt vesicular trafficking of DAT

    Francisco J. Diaz-Corrales, Ikuko Miyazaki, Masato Asanuma, Diego Ruano, Rosa M. Rios

    NEUROBIOLOGY OF AGING   33 ( 10 )   2462 - 2477   2012年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE INC  

    Lewy bodies containing the centrosomal protein gamma-tubulin and fragmentation of Golgi apparatus (GA) have been described in nigral neurons of Parkinson's disease (PD) patients. However, the relevance of these features in PD pathophysiology remains unknown. We analyzed the impact of proteasome inhibition in the formation of gamma-tubulin-containing aggregates as well as on GA structure. SH-SY5Y cells were treated with the proteasome inhibitor Z-Leu-Leu-Leu-al (MG132) to induce centrosomal-protein aggregates. Then, microtubules (MTs) and Golgi dynamics, as well as the vesicular transport of dopamine transporter (DAT) were evaluated both in vitro and in living cells. MG132 treatment induced gamma-tubulin aggregates which altered microtubule nucleation. MG132-treated cells containing gamma-tubulin aggregates showed fragmentation of GA and perturbation of the trans-Golgi network. Under these conditions, the DAT accumulated at the centrosomal-Golgi region indicating that the vesicular transport of DAT was disrupted. Thus, centrosomal aggregates and fragmentation of GA are 2 closely related processes that could result in the disruption of the vesicular transport of DAT toward the plasma membrane in a model of dopaminergic neuronal degeneration. (C) 2012 Elsevier Inc. All rights reserved.

    DOI: 10.1016/j.neurobiolaging.2011.11.014

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  • Cyclooxygenase-Independent Neuroprotective Effects of Aspirin Against Dopamine Quinone-Induced Neurotoxicity

    Masato Asanuma, Ikuko Miyazaki, Yuri Kikkawa, Naotaka Kimoto, Mika Takeshima, Shinki Murakami, Ko Miyoshi

    NEUROCHEMICAL RESEARCH   37 ( 9 )   1944 - 1951   2012年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPRINGER/PLENUM PUBLISHERS  

    Prostaglandin H synthase exerts not only cyclooxygenase activity but also peroxidase activity. The latter activity of the enzyme is thought to couple with oxidation of dopamine to dopamine quinone. Therefore, it has been proposed that cyclooxygenase inhibitors could suppress dopamine quinone formation. In the present study, we examined effects of various cyclooxygenase inhibitors against excess methyl L-3,4-dihydroxyphenylalanine (L-DOPA)-induced quinoprotein (protein-bound quinone) formation and neurotoxicity using dopaminergic CATH.a cells. The treatment with aspirin inhibited excess methyl L-DOPA-induced quinoprotein formation and cell death. However, acetaminophen did not show protective effects, and indomethacin and meloxicam rather aggravated these methyl L-DOPA-induced changes. Aspirin and indomethacin did not affect the level of glutathione that exerts quenching dopamine quinone in dopaminergic cells. In contrast with inhibiting effects of higher dose in the previous reports, relatively lower dose of aspirin that affected methyl L-DOPA-induced quinoprotein formation and cell death failed to prevent cyclooxygenase-induced dopamine chrome generation in cell-free system. Furthermore, aspirin but not acetaminophen or meloxicam showed direct dopamine quinone-scavenging effects in dopamine-semiquinone generating systems. The present results suggest that cyclooxygenase shows little contribution to dopamine oxidation in dopaminergic cells and that protective effects of aspirin against methyl L-DOPA-induced dopamine quinone neurotoxicity are based on its cyclooxygenase-independent property.

    DOI: 10.1007/s11064-012-0813-2

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  • EFFLUENT FREE RADICALS ARE ASSOCIATED WITH RESIDUAL RENAL FUNCTION AND PREDICT TECHNIQUE FAILURE IN PERITONEAL DIALYSIS PATIENTS

    Hiroshi Morinaga, Hitoshi Sugiyama, Tatsuyuki Inoue, Keiichi Takiue, Yoko Kikumoto, Masashi Kitagawa, Shigeru Akagi, Kazushi Nakao, Yohei Maeshima, Ikuko Miyazaki, Masato Asanuma, Makoto Hiramatsu, Hirofumi Makino

    PERITONEAL DIALYSIS INTERNATIONAL   32 ( 4 )   453 - 461   2012年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:MULTIMED INC  

    Objective: Residual renal function (RRF) is associated with low oxidative stress in peritoneal dialysis (PD). In the present study, we investigated the relationship between the impact of oxidative stress on RRF and patient outcomes during PD.
    Methods: Levels of free radicals (FRs) in effluent from the overnight dwell in 45 outpatients were determined by electron spin resonance spectrometry. The FR levels, clinical parameters, and the level of 8-hydroxy-2'-deoxyguanosine were evaluated at study start. The effects of effluent FR level on technique and patient survival were analyzed in a prospective cohort followed for 24 months.
    Results: Levels of effluent FRs showed significant negative correlations with daily urine volume and residual renal Kt/V, and positive correlations with plasma beta(2)-microglobulin and effluent 8-hydroxy-2'-deoxyguanosine. A highly significant difference in technique survival (p &lt; 0.05), but not patient survival, was observed for patients grouped by effluent FR quartile. The effluent FR level was independently associated with technique failure after adjusting for patient age, history of cardiovascular disease, and presence of diabetes mellitus (p &lt; 0.001). The level of effluent FRs was associated with death-censored technique failure in both univariate (p &lt; 0.001) and multivariate (p &lt; 0.01) hazard models. Compared with patients remaining on PD, those withdrawn from the modality had significantly higher levels of effluent FRs (p &lt; 0.005).
    Conclusions: Elevated effluent FRs are associated with RRF and technique failure in stable PD patients. These findings highlight the importance of oxidative stress as an unfavorable prognostic factor in PD and emphasize that steps should be taken to minimize oxidative stress in these patients. Perit Dial Int 2012; 32(4): 453-461

    DOI: 10.3747/pdi.2011.00032

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  • Dipeptidyl compounds ameliorate the serum-deprivation-induced reduction in cell viability via the neurotrophin-activating effect in SH-SY5Y cells

    Ken-ichi Tanaka, Hiroya Ogo, Hiroaki Kaji, Kaori Miyatake, Erika Tokudome, Kanako Sonoda, Norio Ogawa, Masato Asanuma

    NEUROLOGICAL RESEARCH   34 ( 6 )   619 - 622   2012年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:MANEY PUBLISHING  

    Objectives and methods: We have searched for low-molecular-weight compounds as potent new non-immunosuppressive immunophilin ligands (NI-IPLs) that are stronger than existent NI-IPLs such as GPI1046 and/or V10367 from the perspective of neuroprotective efficacy. We selected six dipeptidyl compounds as new NI-IPL candidates, and first examined the effects of each of these compounds on the serum-deprivation-induced reduction in the viability of SH-SY5Y cells. In addition, we clarified the effects of these compounds on neurotrophin release into medium in SH-SY5Y cells.
    Results: Pre-treatment with Leu-Ile and Ile-Ile prevented the serum deprivation-induced reduction in cell viability in SH-SY5Y cells. In naive SH-SY5Y cells, treatment with Leu-Ile and Ile-Ile for 24 hours significantly increased both brain-derived neurotrophic factor and glial cell-line-derived neurotrophic factor releases in comparison with relative vehicle treatments. Moreover, none of the dipeptidyl compounds could prevent the concanavalin A-induced enhancement in interleukin-2 and interleukin-4 release in mouse spleen cells.
    Discussion: The immunosuppressive effect is not essential to the neuroprotective properties of dipeptidyl compounds, and Leu-Ile and Ile-Ile have neurotrophin-activating effects, like FK506 and its existing non-immunosuppressive derivatives.

    DOI: 10.1179/1743132812Y.0000000001

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  • テアニンの中枢作用に関する文献的考察.

    喜多大三, 浅沼幹人, 宮崎育子, 竹島美香

    九州栄養福祉大学研究紀要   9   45 - 58   2012年

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  • Protective effects of baicalein against excess L-DOPA-induced dopamine quinone neurotoxicity

    Mika Takeshima, Maiko Murata, Natsuho Urasoe, Shinki Murakami, Ikuko Miyazaki, Masato Asanuma, Taizo Kita

    NEUROLOGICAL RESEARCH   33 ( 10 )   1050 - 1056   2011年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:MANEY PUBLISHING  

    Objectives: Baicalein, a flavonoid derived from the root of Scutelaria baicalensis Georgi, possesses antioxidative properties including reactive oxygen species scavenging and lipid peroxidation inhibiting activities. The present study was undertaken to investigate the neuroprotective effect of baicalein against dopamine (DA) neurotoxicity induced by exposure to a synthetic DA precursor, L-3,4-dihydroxyphenylalanine (L-DOPA), in cultured dopaminergic CATH. a cells.
    Methods and results: Exposure to L-DOPA for 24 hours reduced the number of viable cells and enhanced protein-bound quinone (quinoprotein) formation in the cell. Both effects were prevented by simultaneous treatment with baicalein. In addition, baicalein prevented the formation of DA semiquinone radicals from DA in an in vitro cell-free system. Long-term baicalein treatment for 96 hours also protected against excess L-DOPA-induced cell death, and also increased glutathione (GSH) levels in CATH. a cells.
    Discussion: Our results indicate that baicalein has neuroprotective properties against excess L-DOPA-induced DA neurotoxicity through the suppression of DA quinone formation. Furthermore, the long-term treatment of baicalein upregulates intracellular GSH contents, which may also exert neuroprotective effects against oxidative stress-induced neuronal damage.

    DOI: 10.1179/1743132811Y.0000000032

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  • Factors That Influence Primary Cilium Length

    Ko Miyoshi, Kyosuke Kasahara, Ikuko Miyazaki, Masato Asanuma

    ACTA MEDICA OKAYAMA   65 ( 5 )   279 - 285   2011年10月

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    記述言語:英語   出版者・発行元:OKAYAMA UNIV MED SCHOOL  

    Almost all mammalian cells carry one primary cilium that functions as a biosensor for chemical and mechanical stimuli. Genetic damages that compromise cilia formation or function cause a spectrum of disorders referred to as ciliapathies. Recent studies have demonstrated that some pharmacological agents and extracellular environmental changes can alter primary cilium length. Renal injury is a well-known example of an environmental insult that triggers cilia length modification. Lithium treatment causes primary cilia to extend in several cell types including neuronal cells; this phenomenon is likely independent of glycogen synthase kinase-3 beta inhibition. In renal epithelial cell lines, deflection of the primary cilia by fluid shear shortens them by reducing the intracellular cyclic AMP level, leading to a subsequent decrease in mechanosensitivity to fluid shear. Primary cilium length is also influenced by the dynamics of actin filaments and microtubules through the levels of soluble tubulin in the cytosol available for primary cilia extension. Thus, mammalian cells can adapt to the extracellular environment by modulating the primary cilium length, and this feedback system utilizing primary cilia might exist throughout the mammalian body. Further investigation is required concerning the precise molecular mechanisms underlying the control of primary cilium length in response to environmental factors.

    DOI: 10.18926/AMO/47009

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  • α7 Nicotinic acetylcholine receptors in the central amygdaloid nucleus alter naloxone-induced withdrawal following a single exposure to morphine.

    Ishida S, Kawasaki Y, Araki H, Asanuma M, Matsunaga H, Sendo T, Kawasaki H, Gomita Y, Kitamura Y

    Psychopharmacology   214 ( 4 )   923 - 931   2011年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1007/s00213-010-2101-7

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  • Astrocyte-Derived Metallothionein Protects Dopaminergic Neurons from Dopamine Quinone Toxicity

    Ikuko Miyazaki, Masato Asanuma, Yuri Kikkawa, Mika Takeshima, Shinki Murakami, Ko Miyoshi, Norio Sogawa, Taizo Kita

    GLIA   59 ( 3 )   435 - 451   2011年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-LISS  

    Our previous studies demonstrated the involvement of quinone formation in dopaminergic neuron dysfunction in the L-DOPA-treated parkinsonian model and in methamphetamine (METH) neurotoxicity. We further reported that the cysteine-rich metal-binding metallothionein (MT) family of proteins protects dopaminergic neurons against dopamine (DA) quinone neurotoxicity by its quinone-quenching property. The aim of this study was to examine MT induction in astrocytes in response to excess DA and the potential neuroprotective effects of astrocyte-derived MTs against DA quinone toxicity. DA exposure significantly upregulated MT-1/-2 in cultured striatal astrocytes, but not in mesencephalic neurons. This DA-induced MT upregulation in astrocytes was blocked by treatment with a DA-transporter (DAT) inhibitor, but not by DA-receptor antagonists. Expression of nuclear factor erythroid 2-related factor (Nrf2) and its binding activity to antioxidant response element of MT-1 gene were significantly increased in the astrocytes after DA exposure. Nuclear translocation of Nrf2 was suppressed by the DAT inhibitor. Quinone formation and reduction of mesencephalic DA neurons after DA exposure were ameliorated by preincubation with conditioned media from DA-treated astrocytes. These protective effects were abrogated by MT-1/-2-specific antibody. Adding exogenous MT-1 to glial conditioned media also showed similar neuroprotective effects. Furthermore, MT-1/-2 expression was markedly elevated specifically in reactive astrocytes in the striatum of L-DOPA-treated hemi-parkinsonian mice or METH-injected mice. These results suggested that excess DA taken up by astrocytes via DAT upregulates MT-1/-2 expression specifically in astrocytes, and that MTs or related molecules secreted specifically by astrocytes protect dopaminergic neurons from damage through quinone quenching and/or scavenging of free radicals. (C)2010 Wiley-Liss, Inc.

    DOI: 10.1002/glia.21112

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  • Chronic Treatment with Imipramine and Lithium Increases Cell Proliferation in the Hippocampus in Adrenocorticotropic Hormone-Treated Rats

    Yoshihisa Kitamura, Maho Doi, Keiko Kuwatsuka, Yuka Onoue, Ikuko Miyazaki, Kazuaki Shinomiya, Toshihiro Koyama, Toshiaki Sendo, Hiromu Kawasaki, Masato Asanuma, Yutaka Gomita

    BIOLOGICAL & PHARMACEUTICAL BULLETIN   34 ( 1 )   77 - 81   2011年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PHARMACEUTICAL SOC JAPAN  

    Adult hippocampal neurogenesis is reported to change in animal models of depression and antidepressants. We have used the mitotic marker 5-bromo-2'-deoxyyridine to address the effects of imipramine and lithium on cell proliferation and survival following chronic treatment with adrenocorticotropic hormone (ACTH) in the subgranular zone of the hippocampal dentate gyrus. ACTH treatment for 14d decreased adult hippocampal cell proliferation and survival. Coadministration of imipramine and lithium for 14d blocked the loss of cell proliferation but not cell survival resulting from the chronic treatment with ACTH. The coadministration of imipramine and lithium may have treatment-resistant antidepressive properties, which may be attributed, in part, to a normalization of hippocampal cell proliferation.

    DOI: 10.1248/bpb.34.77

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  • Intra-amygdaloid injection of alpha 7 nicotinic acetylcholine receptor agonist attenuates naloxone-induced place aversion in rats following a single exposure to morphine 査読

    Ishida Shigeru, Kawasaki Yoichi, Asanuma Masato, Matsunaga Hisashi, Sendo Toshiaki, Araki Hiroaki, Kawasaki Hiromu, Kitamura Yoshihisa

    JOURNAL OF PHARMACOLOGICAL SCIENCES   115   147P   2011年

  • パーキンソン病とアストロサイト─新たな神経保護療法の標的.

    浅沼幹人, 宮崎育子

    Clinical Neuroscience   29 ( 11 )   1295 - 1297   2011年

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  • Reply to Ahmad Ghanizadeh, A Novel Hypothesized Clinical Implication of Zonisamide for Autism.

    Asanuma M, Miyazaki I

    Ann Neurol   69   426 - 427   2011年

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  • L-テアニンのグリア細胞に対する保護作用に関する研究─アストロサイトにおけるL-テアニンによる抗酸化保護作用の賦活─.

    喜多大三, 浅沼幹人, 宮崎育子, 竹島美香

    九州栄養福祉大学研究紀要   8   43 - 53   2011年

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  • High glucose increases metallothionein expression in renal proximal tubular epithelial cells.

    Ogawa D, Asanuma M, Miyazaki, I, Tachibana H, Wada J, Sogawa N, Sugaya T, Kitamura S, Maeshima Y, Shikata K, Makino F

    Exp Diabetes Res   2011   1 - 8   2011年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1155/2011/534872

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  • Effects of Imipramine and Lithium on the Suppression of Cell Proliferation in the Dentate Gyrus of the Hippocampus in Adrenocorticotropic Hormone-treated Rats

    Maho Doi, Ikuko Miyazaki, Tomoko Nagamachi, Kazuaki Shinomiya, Hisashi Matsunaga, Toshiaki Sendo, Hiromu Kawasaki, Masato Asanuma, Yutaka Gomita, Yoshihisa Kitamura

    ACTA MEDICA OKAYAMA   64 ( 4 )   219 - 223   2010年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:OKAYAMA UNIV MED SCHOOL  

    We examined the influence of chronic adrenocorticotropic hormone (ACTH) treatment on the number of Ki-67-positive cells in the dentate gyrus of the hippocampus in rats. ACTH treatment for 14 days decreased the number of such cells. The administration of imipramine or lithium alone for 14 days had no effect in saline-treated rats. The effect of ACTH was blocked by the administration of imipramine. Furthermore, the coadministration of imipramine and lithium for 14 days significantly increased the number of Ki-67-positive cells in both the saline and ACTH-treated rats. The coadministration of imipramine and lithium normalized the cell proliferation in the dentate gyrus of the hippocampus in rats treated with ACTH.

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  • Effects of bupropion on the forced swim test and release of dopamine in the nucleus accumbens in ACTH-treated rats

    Yoshihisa Kitamura, Takahiko Yagi, Kouhei Kitagawa, Kazuaki Shinomiya, Hiromu Kawasaki, Masato Asanuma, Yutaka Gomita

    NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY   382 ( 2 )   151 - 158   2010年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPRINGER  

    The dopamine reuptake inhibitor bupropion has clinically been proven to improve depression and treatment-resistant depression. We examined its influence on the duration of immobility during the forced swim test in adrenocorticotropic hormone (ACTH)-treated rats and further analyzed the possible role of dopamine receptors in this effect. Additionally, the mechanism by which bupropion acts in this model was explored specifically in relation to the site of action through the use of microinjections into the medial prefrontal cortex and nucleus accumbens. Bupropion significantly decreased the duration of immobility in normal and ACTH-treated rats. This effect was blocked by D2 and D3 receptor antagonists in normal rats. Furthermore, infusions of bupropion into the nucleus accumbens, but not medial prefrontal cortex, decreased the immobility of normal and ACTH-treated rats during the forced swim test. Bupropion treatment plus repeated ACTH treatment significantly increased the extracellular dopamine concentration. These findings suggest the antidepressant-like effect of bupropion to be related to levels of dopamine in the rat nucleus accumbens.

    DOI: 10.1007/s00210-010-0521-x

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  • Induction of Parkinsonism-Related Proteins in the Spinal Motor Neurons of Transgenic Mouse Carrying a Mutant SOD1 Gene

    Nobutoshi Morimoto, Makiko Nagai, Kazunori Miyazaki, Yasuyuki Ohta, Tomoko Kurata, Yasushi Takehisa, Yoshio Ikeda, Tohru Matsuura, Masato Asanuma, Koji Abe

    JOURNAL OF NEUROSCIENCE RESEARCH   88 ( 8 )   1804 - 1811   2010年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-LISS  

    Amyotrophic lateral sclerosis is a progressive and fatal disease caused by selective death of motor neurons, and a number of these patients carry mutations in the superoxide dismutase 1 (SOD1) gene involved in ameliorating oxidative stress. Recent studies indicate that oxidative stress and disruption of mitochondrial homeostasis is a common mechanism for motor neuron degeneration in amyotrophic lateral sclerosis and the loss of midbrain dopamine neurons in Parkinson&apos;s disease. Therefore, the present study investigated the presence and alterations of familial Parkinson&apos;s disease-related proteins, PINK1 and DJ-1, in spinal motor neurons of G93ASOD1 transgenic mouse model of amyotrophic lateral sclerosis. Following onset of disease, PINK1 and DJ-1 protein expression increased in the spinal motor neurons. The activated form of p53 also increased and translocated to the nuclei of spinal motor neurons, followed by increased expression of p53-activated gene 608 (PAG608). This is the first report demonstrating that increased expression of PAG608 correlates with activation of phosphorylated p53 in spinal motor neurons of an amyotrophic lateral sclerosis model. These results provide further evidence of the profound correlations between spinal motor neurons of amyotrophic lateral sclerosis and parkinsonism-related proteins. (C) 2010 Wiley-Liss, Inc.

    DOI: 10.1002/jnr.22341

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  • Neuroprotective Effects of Zonisamide Target Astrocyte

    Masato Asanuma, Ikuko Miyazaki, Francisco J. Diaz-Corrales, Naotaka Kimoto, Yuri Kikkawa, Mika Takeshima, Ko Miyoshi, Miho Murata

    ANNALS OF NEUROLOGY   67 ( 2 )   239 - 249   2010年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-LISS  

    Objective: Recent double-blind, controlled trials in Japan showed that the antiepileptic agent zonisamide (ZNS)improves the cardinal symptoms of Parkinson&apos;s disease. Glutathione (GSH) exerts antioxidative activity through quenching reactive oxygen species and dopamine quinone. GSH depletion within dopaminergic neurons impairs mitochondrial complex I activity, followed by age-dependent nigrostriatal neurodegeneration. This study examined changes in GSH and GSH synthesis-related molecules, and the neuroprotective effects of ZNS on dopaminergic neurodegeneration using 6-hydroxydopamine-injected hemiparkinsonian mice brain and cultured neurons or astrocytes.
    Methods and Results: ZNS increased both the cell number and GSH levels in astroglial C6 cells, but not in dopaminergic neuronal CATH.a cells. Repeated injections of ZNS (30mg/kg intraperitoneally) for 14 days also significantly increased GSH levels and S100 beta-positive astrocytes in mouse basal ganglia. Repeated ZNS injections (30mg/kg) for 7 days in the hemiparkinsonian mice increased the expression of cystine/glutamate exchange transporter xCT in activated astrocytes, which supply cysteine to neurons for GSH synthesis. Treatment of these mice with ZNS also increased GSH levels and completely suppressed striatal levodopa-induced quinone formation. Reduction of nigrostriatal dopamine neurons in the lesioned side of hemiparkinsonian mice was significantly abrogated by repeated injections of ZNS with or without adjunctive levodopa starting 3 weeks after 6-hydroxydopamine lesioning.
    Interpretation: These results provide new pharmacological evidence for the effects of ZNS. ZNS markedly increased GSH levels by enhancing the astroglial cystine transport system and/or astroglial proliferation via S100 beta production or secretion. ZNS acts as a neuroprotectant against oxidative stress and progressive dopaminergic neurodegeneration. ANN NEUROL 2010;67:239-249

    DOI: 10.1002/ana.21885

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  • Effect of bupropion on dopaminergic mechanism in regulating antidepressant-like effect in the ACTH-treated rats 査読

    Yagi Takahiko, Miyazaki Toshiaki, Kitagawa Kouhei, Shinomiya Kazuaki, Asanuma Masato, Sendo Toshiaki, Kitamura Yoshihisa

    JOURNAL OF PHARMACOLOGICAL SCIENCES   112   178P   2010年

  • Involvement of nicotinic acetylcholine receptor on the conditioned place aversion behavior and c-Fos expression induced by naloxone in single-dose morphine-treated rats 査読

    Ikuta Yuichi, Ishida Shigeru, Miyazaki Ikuko, Asanuma Masato, Araki Hiroaki, Matsunaga Hisashi, Kitamura Yoshihisa, Sendo Toshiaki

    JOURNAL OF PHARMACOLOGICAL SCIENCES   112   187P   2010年

  • Intra-amygdaloid injection of nicotine attenuates naloxone-induced place aversion in single-dose morphine-treated rats 査読

    Ishida Shigeru, Ikuta Yuichi, Asanuma Masato, Matsunaga Hisashi, Sendo Toshiaki, Araki Hiroaki, Kawasaki Hiromu, Kitamura Yoshihisa

    JOURNAL OF PHARMACOLOGICAL SCIENCES   112   187P   2010年

  • Effects of cell proliferation and astroglial activity by the chronic treatment of ACTH in the hippocampal dentate gyrus of adult rats 査読

    Doi Maho, Nagamachi Tomoko, Egawa Maki, Miyazaki Ikuko, Kawasaki Hiromu, Sendo Toshiaki, Asanuma Masato, Kitamura Yoshihisa

    JOURNAL OF PHARMACOLOGICAL SCIENCES   112   178P   2010年

  • Lithium treatment elongates primary cilia in the mouse brain and in cultured cells

    Ko Miyoshi, Kyosuke Kasahara, Ikuko Miyazaki, Masato Asanuma

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   388 ( 4 )   757 - 762   2009年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ACADEMIC PRESS INC ELSEVIER SCIENCE  

    The molecular mechanisms underlying the therapeutic effects of lithium, a first-line antimanic mood stabilizer, have not yet been fully elucidated. Treatment of the algae Chlamydomonas reinhardtii with lithium has been shown to induce elongation of their flagella, which are analogous structures to vertebrate cilia. In the mouse brain, adenylyl cyclase 3 (AC3) and certain neuropeptide receptors colocalize to the primary cilium of neuronal cells, suggesting a chemosensory function for the primary cilium in the nervous system. Here we show that lithium treatment elongates primary cilia in the mouse brain and in cultured cells. Brain sections from mice chronically fed with Li(2)CO(3) were subjected to immunofluorescence study. Primary cilia carrying both AC3 and the receptor for melanin-concentrating hormone (MCH) were elongated in the dorsal striatum and nucleus accumbens of lithium-fed mice, as compared to those of control animals. Moreover, lithium-treated NIH3T3 cells and cultured striatal neurons exhibited elongation of the primary cilia. The present results provide initial evidence that a psychotropic agent can affect ciliary length in the central nervous system, and furthermore suggest that lithium exerts its therapeutic effects via the upregulation of cilia-mediated MCH sensing. These findings thus contribute novel insights into the pathophysiology of bipolar mood disorder and other psychiatric diseases. (C) 2009 Elsevier Inc. All rights reserved.

    DOI: 10.1016/j.bbrc.2009.08.099

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  • Pericentrin, a centrosomal protein related to microcephalic primordial dwarfism, is required for olfactory cilia assembly in mice

    Ko Miyoshi, Kyosuke Kasahara, Ikuko Miyazaki, Shoko Shimizu, Manabu Taniguchi, Shinsuke Matsuzaki, Masaya Tohyama, Masato Asanuma

    FASEB JOURNAL   23 ( 10 )   3289 - 3297   2009年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:FEDERATION AMER SOC EXP BIOL  

    The Drosophila pericentrin-like protein has been shown to be essential for the formation of the sensory cilia of chemosensory and mechanosensory neurons by mutant analysis in flies, while the in vivo function of pericentrin, a well-studied mammalian centrosomal protein related to microcephalic primordial dwarfism, has been unclear. To determine whether pericentrin is required for ciliogenesis in mammals, we generated and analyzed mice with a hypomorphic mutation of Pcnt encoding the mouse pericentrin. Immunofluorescence analysis demonstrated that olfactory cilia of chemosensory neurons in the nasal olfactory epithelium were malformed in the homozygous mutant mice. On the other hand, the assembly of motile and primary cilia of non-neuronal epithelial cells and the formation of sperm flagella were not affected in the Pcnt-mutant mice. The defective assembly of olfactory cilia in the mutant was apparent from birth. The mutant animals displayed reduced olfactory performance in agreement with the compromised assembly of olfactory cilia. Our findings suggest that pericentrin is essential for the assembly of chemosensory cilia of olfactory receptor neurons, but it is not globally required for cilia formation in mammals.-Miyoshi, K., Kasahara, K., Miyazaki, I., Shimizu, S., Taniguchi, M., Matsuzaki, S., Tohyama, M., Asanuma, M. Pericentrin, a centrosomal protein related to microcephalic primordial dwarfism, is required for olfactory cilia assembly in mice. FASEB J. 23, 3289-3297 ( 2009). www.fasebj.org

    DOI: 10.1096/fj.08-124420

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  • NEUROPROTECTIVE PROPERTIES OF ASTROCYTES THROUGH INDUCTION OF QUINONE-QUENCHING MOLECULES IN PARKINSONIAN MODEL

    Miyazaki, I, Y. Kikkawa, M. Takeshima, K. Miyoshi, M. Asanuma

    JOURNAL OF NEUROCHEMISTRY   110   107 - 107   2009年9月

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    記述言語:英語   出版者・発行元:WILEY-BLACKWELL PUBLISHING, INC  

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  • REDUCTION OF PPAR-gamma IN METHAMPHETAMINE-INDUCED NEUROTOXICITY AND PROTECTIVE EFFECTS OF INTERFERON-gamma

    M. Asanuma, Miyazaki, I, Y. Kikkawa, M. Takeshima, K. Miyoshi, T. Kita

    JOURNAL OF NEUROCHEMISTRY   110   49 - 49   2009年9月

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    記述言語:英語   出版者・発行元:WILEY-BLACKWELL PUBLISHING, INC  

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  • Effects of galantamine on L-NAME-induced behavioral impairment in Y-maze task in mice

    Ken-ichi Tanaka, Takao Yagi, Ryosuke Shimakoshi, Koji Azuma, Takeshi Nanba, Hiroya Ogo, Akiko Tamura, Masato Asanuma

    NEUROSCIENCE LETTERS   462 ( 3 )   235 - 238   2009年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER IRELAND LTD  

    Nitric oxide (NO) may play a role in the established processes of learning and memory. We examined the effects of N-omega-nitro-L-arginine methylester (L-NAME), a nonselective inhibitor of NO synthase (NOS), on the performance of mice in a Y-maze task. L-NAME (100 mg/kg) markedly impaired spontaneous alternation behavior. However, galantamine (0.5 mg/kg) significantly attenuated this L-NAME-induced impairment. To clarify the molecular basis underlying galantamine's protective effects against L-NAME-induced impairment of spontaneous alternation behavior, we tested the ability of mecamylamine, an antagonist of nicotinic ACh receptor (nAChR), and scopolamine, an antagonist of muscarinic ACh receptor, to reduce galantamine's protective effects, and found that only the former had such an ability. Galantamine significantly also reduced L-NAME-induced decreases in NOx levels. However, mecamylamine cancelled galantamine's efficacy in countering the L-NAME-induced decrease in NOx levels. In the present study, we have determined that galantamine's protection against L-NAME-induced impairment of spontaneous alternation behavior in the Y-maze task might be mediated mainly by NOergic activation via the nAChR-related pathway. (c) 2009 Elsevier Ireland Ltd. All rights reserved.

    DOI: 10.1016/j.neulet.2009.07.024

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  • Effects of pramipexole on the duration of immobility during the forced swim test in normal and ACTH-treated rats

    Kouhei Kitagawa, Yoshihisa Kitamura, Toshiaki Miyazaki, Junya Miyaoka, Hiromu Kawasaki, Masato Asanuma, Toshiaki Sendo, Yutaka Gomita

    NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY   380 ( 1 )   59 - 66   2009年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPRINGER  

    The dopamine D2/D3 receptor agonist pramipexole has clinically been proven to improve depression or treatment-resistant depression. However, the involvement of the dopamine receptor system on the effect of pramipexole on depression remains unclear. We examined the influence of pramipexole on the duration of immobility during the forced swim test in normal and adrenocorticotropic hormone (ACTH)-treated rats and further analyzed the possible role of dopamine receptors in this effect. Additionally, the mechanism by which pramipexole acts in this model was explored specifically in relation to the site of action through the use of microinjections into the intramedial prefrontal cortex and nucleus accumbens. Pramipexole (0.3-1 mg/kg) significantly decreased the duration of immobility in normal and ACTH-treated rats. This effect was blocked by L-741,626, a D2 receptor antagonist, and nafadotride, a D3 receptor antagonist, in normal rats. Furthermore, infusions of pramipexole into the intranucleus accumbens, but not the medial prefrontal cortex, decreased the immobility of normal and ACTH-treated rats during the forced swim test. Taken together, the results of these experiments suggested that pramipexole, administered into the intranucleus accumbens rather than the medial prefrontal cortex, exerted an antidepressant-like effect on ACTH-treated rats via the dopaminergic system. The immobility-decreasing effect of pramipexole may be mediated by dopamine D2 and D3 receptors.

    DOI: 10.1007/s00210-009-0405-0

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  • Approaches to Prevent Dopamine Quinone-Induced Neurotoxicity

    Ikuko Miyazaki, Masato Asanuma

    NEUROCHEMICAL RESEARCH   34 ( 4 )   698 - 706   2009年4月

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    記述言語:英語   出版者・発行元:SPRINGER/PLENUM PUBLISHERS  

    Dopamine (DA) and its metabolites containing two hydroxyl residues exert cytotoxicity in dopaminergic neuronal cells, primarily due to the generation of highly reactive DA and DOPA quinones. Quinone formation is closely linked to other representative hypotheses such as mitochondrial dysfunction, inflammation, oxidative stress, and dysfunction of the ubiquitin-proteasome system, in the pathogenesis of neurodegenerative diseases such as Parkinson&apos;s disease and methamphetamine-induced neurotoxicity. Therefore, pathogenic effects of the DA quinone have focused on dopaminergic neuron-specific oxidative stress. Recently, various studies have demonstrated that some intrinsic molecules and several drugs exert protective effects against DA quinone-induced damage of dopaminergic neurons. In this article, we review recent studies on some neuroprotective approaches against DA quinone-induced dysfunction and/or degeneration of dopaminergic neurons.

    DOI: 10.1007/s11064-008-9843-1

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  • Reduction of Nuclear Peroxisome Proliferator-Activated Receptor gamma Expression in Methamphetamine-Induced Neurotoxicity and Neuroprotective Effects of Ibuprofen

    Takeshi Tsuji, Masato Asanuma, Ikuko Miyazaki, Ko Miyoshi, Norio Ogawa

    NEUROCHEMICAL RESEARCH   34 ( 4 )   764 - 774   2009年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPRINGER/PLENUM PUBLISHERS  

    We examined changes in nuclear peroxisome proliferator-activated receptor gamma (PPAR gamma) in the striatum in methamphetamine (METH)-induced dopaminergic neurotoxicity, and also examined effects of treatment with drugs possessing PPAR gamma agonistic properties. The marked reduction of nuclear PPAR gamma-expressed cells was seen in the striatum 3 days after METH injections (4 mg/kg x 4, i.p. with 2-h interval). The reduction of dopamine transporter (DAT)-positive signals and PPAR gamma expression, and accumulation of activated microglial cells were significantly and dose-dependently attenuated by four injections of a nonsteroidal anti-inflammatory drug and a PPAR gamma ligand, ibuprofen (10 or 20 mg/kg x 4, s.c.) given 30 min prior to each METH injection, but not by either a low or high dose of aspirin. Either treatment of ibuprofen or aspirin, that showed no effects on METH-induced hyperthermia, significantly blocked the METH-induced striatal cyclooxygenase (COX) expression. Furthermore, the treatment of an intrinsic PPAR gamma ligand 15d-PG J2 also attenuated METH injections-induced reduction of striatal DAT. Therefore, the present study suggests the involvement of reduction of PPAR gamma expression in METH-induced neurotoxicity. Taken together with the previous report showing protective effects of other PPAR gamma ligand, these results imply that the protective effects of ibuprofen against METH-induced neurotoxicity may be based, in part, on its anti-inflammatory PPAR gamma agonistic properties, but not on its COX-inhibiting property or hypothermic effect.

    DOI: 10.1007/s11064-008-9863-x

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  • Involvement of PPAR-gamma in methamphetamine-induced neurotoxicity and protective effect of interferon-gamma 査読

    Fukuoka Saki, Hozumi Hiroaki, Kimoto Naotaka, Kikkawa Yuri, Tsuji Takeshi, Miyazaki Ikuko, Kitamura Yoshihisa, Sendo Toshiaki, Kita Taizo, Asanuma Masato

    JOURNAL OF PHARMACOLOGICAL SCIENCES   109   220P   2009年

  • Effects of dopamine transporter expression on treatment of ACTH in rats 査読

    Emoto Sayaka, Kitamura Yoshihisa, Miyazaki Ikuko, Kitagawa Kouhei, Nagamachi Tomoko, Doi Maho, Ishimaru Yui, Asanuma Masato, Sendo Toshiaki

    JOURNAL OF PHARMACOLOGICAL SCIENCES   109   162P   2009年

  • Involvement of dopaminergic system on place aversion induced by naloxone in single-dose morphine-treated rats 査読

    Ishida Shigeru, Morohashi Kazunori, Ikuta Yuichi, Fuchi Ken-ichiro, Kawasaki Yoichi, Asanuma Masato, Araki Hiroaki, Sendo Toshiaki, Kitamura Yoshihisa, Kawasaki Hiromu

    JOURNAL OF PHARMACOLOGICAL SCIENCES   109   221P   2009年

  • DOPAMINE-INDUCED BEHAVIORAL CHANGES AND OXIDATIVE STRESS IN METHAMPHETAMINE-INDUCED NEUROTOXICITY

    Taizo Kita, Ikuko Miyazaki, Masato Asanuma, Mika Takeshima, George C. Wagner

    NEW CONCEPTS OF PSYCHOSTIMULANTS INDUCED NEUROTOXICITY   88   43 - 64   2009年

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    記述言語:英語   掲載種別:論文集(書籍)内論文   出版者・発行元:ELSEVIER ACADEMIC PRESS INC  

    DOI: 10.1016/S0074-7742(09)88003-3

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  • 食材および食品に含まれる化学物質の生理活性とその機能 -ドパミン神経培養系におけるフィチン酸の作用-.

    村田麻衣子, 村田麻衣子, 青柳東彦, 安東勢津子, 浅沼幹人, 喜多大三

    九州栄養福祉大学研究紀要   6   75 - 86   2009年

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  • A study on bioactivity and function of chemical compounds in food and foodstuff: Search for angiotensin I-converting enzyme inhibitory substances in some edible mushrooms using fluorescent substrate.

    Aoyagi H, Tsukamoto Y, Furuno C, Ando S, Matsubara K, Kita T, Asanuma M

    九州栄養福祉大学研究紀要   6   9 - 20   2009年

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  • Dopamine Induces Supernumerary Centrosomes and Subsequent Cell Death through Cdk2 up-Regulation in Dopaminergic Neuronal Cells

    Francisco J. Diaz-Corrales, Masato Asanuma, Ikuko Miyazaki, Ko Miyoshi, Nobutaka Hattori, Norio Ogawa

    NEUROTOXICITY RESEARCH   14 ( 4 )   295 - 305   2008年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPRINGER  

    Aggregation of proteins in the centrosome is implicated in the pathophysiology of Parkinson&apos;s disease. However, the relevance of the centrosome in neurodegeneration is still obscure. Centrosome duplication is initiated by the cyclin E/cyclin-dependent kinase 2 (Cdk2) complex. The present study determined changes in cyclin E or Cdk2 expression and in the centrosomal structure in dopaminergic neuronal CATH.a cells exposed to 50, 100 and 150 mu M dopamine (DA) for 24 h. DA induced significant increase in Cdk2 protein and cyclin E protein, but not cyclin a mRNA. In DA-treated cells, the intense cyclin E- and Cdk2-immunofluorescence signals were co-localized around large and supernumerary centrosomes, and these two parameters of centrosome amplification were significantly increased compared with the control. Simultaneous co-treatment with DA and a Cdk2 inhibitor blocked centrosome amplification and enhanced cell viability. Our results demonstrated that DA could lead to cyclin E accumulation and Cdk2 up-regulation triggering supernumerary centrosomes and apoptotic cell death.

    DOI: 10.1007/BF03033854

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  • Protective effects of interferon-gamma against methamphetamine-induced neurotoxicity (vol 177, pg 123, 2008) 査読

    Hozumi Hiroaki, Asanuma Masato, Miyazaki Ikuko, Fukuoka Saki, Kikkawa Yuri, Kimoto Naotaka, Kitamura Yoshihisa, Sendo Toshiaki, Kita Taizo, Gomita Yutaka

    TOXICOLOGY LETTERS   180 ( 3 )   231   2008年8月

  • Effects of HMGB1 on ischemia-reperfusion injury in the rat heart

    Susumu Oozawa, Shuji Mori, Toru Kanke, Hideo Takahashi, Keyue Liu, Yasuko Tomono, Masato Asanuma, Ikuko Miyazaki, Masahiro Nishibori, Shunji Sano

    CIRCULATION JOURNAL   72 ( 7 )   1178 - 1184   2008年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:JAPANESE CIRCULATION SOC  

    Background Coronary ischemia-reperfusion (I/R) injury causes cardiomyocyte necrosis in a multi-step process that includes an inflammatory reaction. A recent study has suggested that high-mobility group box 1 (HMGB 1) is a late mediator of lethal sepsis and an early mediator of inflammation and necrosis following I/R injury. In the present study a neutralizing monoclonal antibody (mAb) for HMGB1 was used to clarify the role of HMGB 1 in cardiac I/R injury.
    Methods and Results Rats underwent 30 min of left coronary artery occlusion followed by 60 min reperfusion. An intravenous injection of anti-HMGB1 mAb or control IgG was administered just before reperfusion. The infarct size was enlarged in the anti-HMGB1 mAb group in comparison with the control group (p&lt;0.05). The treatment of anti-HMGB1 mAb significantly increased the plasma troponin-T and norepinephrine (NE) content in the heart in comparison with the control (p&lt;0.05). Moreover, the production of dihydroxyphenylglycol was reduced in the anti-HMGB1-treated group (p&lt;0.05).
    Conclusion This study shows for the first time the effects of treatment with neutralizing anti-HMGB1 mAb on I/R injury in the rat heart. The findings support the novel view that I/R-induced HMGB1 may be an important factor in the modulation of interstitial NE.

    DOI: 10.1253/circj.72.1178

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  • Dopaminergic neuron-specific oxidative stress caused by dopamine itself

    Ikuko Miyazaki, Masato Asanuma

    ACTA MEDICA OKAYAMA   62 ( 3 )   141 - 150   2008年6月

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    記述言語:英語   出版者・発行元:OKAYAMA UNIV MED SCHOOL  

    Oxidative stress, including the reactive oxygen or nitrogen species generated in the enzymatical oxidation or auto-oxidation of an excess amount of dopamine, is thought to play an important role in dopaminergic neurotoxicity. Dopamine and its metabolites containing 2 hydroxyl residues exert cytotoxicity in dopaminergic neuronal cells, primarily due to the generation of highly reactive dopamine and DOPA quinones. Dopamine and DOPA quinones may irreversibly alter protein function through the formation of 5-cysteinyl-catechols on the proteins. Furthermore, the quinone formation is closely linked to other representative hypotheses such as mitochondrial dysfunction, inflammation, oxidative stress, and dysfunction of the ubiquitin-proteasome system, in the pathogenesis of neurodegenerative diseases. Therefore, pathogenic effects of the dopamine quinone have recently focused on dopaminergic neuron-specific oxidative stress. In this article, we primarily review recent studies on the pathogenicity of quinone formation, in addition to several neuroprotective approaches against dopamine quinone-induced dysfunction of dopaminergic neurons.

    DOI: 10.18926/AMO/30980

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  • Nonsteroidal anti-inflammatory drugs in experimental parkinsonian models and Parkinson's disease

    Masato Asanuma, Ikuko Miyazaki

    CURRENT PHARMACEUTICAL DESIGN   14 ( 14 )   1428 - 1434   2008年5月

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    記述言語:英語   出版者・発行元:BENTHAM SCIENCE PUBL LTD  

    A number of experimental studies using parkinsonian models have revealed that nonsteroidal anti-inflammatory drugs (NSAIDs) have neuroprotective properties against dopaminergic neurotoxicity not only by their cyclooxygenase-inhibiting effect but also by other specific properties or some unknown pharmacological effects. This article reviews heterogeneous pharmacological properties of NSAIDs including inhibitory effect against nitric oxide synthesis, agonistic action for peroxisome proliferator-activated receptor or possible suppressive effects against dopamine quinone generation, and also reviews their neuroprotective effects in the experimental parkinsonian models and pathogenesis of Parkinson's disease. Several epidemiological studies recently clarified that the use of nonaspirin NSAIDs but not aspirin was associated with a lower prevalence of Parkinson's disease, in contrast with neuroprotective effects of aspirin in the experimental studies. It also discusses the discrepancy between results in the experimental parkinsonian models and epidemiological data in prevalence of Parkinson's disease on the effects of NSAIDs.

    DOI: 10.2174/138161208784480153

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  • [New perspectives on the mechanism of methamphetamine-induced neurotoxicity]. 査読

    Kita T, Takeshima M, Wagner GC, Hozumi H, Miyazaki I, Asanuma M

    Nihon shinkei seishin yakurigaku zasshi = Japanese journal of psychopharmacology   28 ( 2 )   49 - 61   2008年4月

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    記述言語:日本語  

    PubMed

    J-GLOBAL

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  • Specific induction of PAG608 in cranial and spinal motor neurons of L-DOPA-treated parkinsonian rats

    Masako Shimizu, Ikuko Miyazaki, Youichirou Higashi, Maria J. Eslava-Alva, Francisco J. Diaz-Coffales, Masato Asanuma, Norio Ogawa

    NEUROSCIENCE RESEARCH   60 ( 4 )   355 - 363   2008年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER IRELAND LTD  

    We identified p53-activated gene 608 (PAG608) as a specifically induced gene in striatal tissue of L-DOPA (100 mg/kg)-injected hemi-parkinsonian rats using differential display assay. In the present study, we further examined morphological distribution of PAG608 in the central nervous system of L-DOPA-treated hemi-parkinsonian rats. PAG608 expression was markedly induced in fibers and neuronal cells of the lateral globus pallidus and reticular thalamic nucleus adjacent to internal capsule, specifically in the parkinsonian side of L-DOPA-treated models. The protein was also constitutively expressed in motor neurons specifically in either side of the pontine nucleus and motor nuclei of trigeminal and facial nerves. Furthermore, L-DOPA-induced PAG608 expression on motor neurons in the contralateral side of the ventral horn of the spinal cord and the lateral corticospinal tract without cell loss. The specific induction of PAG608 6-48 h after L-DOPA injection in the extrapyramidal tracts, pyramidal tracts and corresponding lower motor neurons of the spinal cords suggests its involvement in molecular events in stimulated motor neurons. Taken together with the constitutive expression of PAG608 in the motor nuclei of cranial nerves, PAG608 may be a useful marker of stressed or activated lower motor neurons. (C) 2007 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.

    DOI: 10.1016/j.neures.2007.12.006

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  • Protective effects of interferon-gamma against methamphetamine-induced neurotoxicity

    Hiroaki Hozumi, Masato Asanuma, Ikuko Miyazaki, Saki Fukuoka, Yuri Kikkawa, Naotaka Kimoto, Yoshihisa Kitamura, Toshiaki Sendo, Taizo Kita, Yutaka Gomita

    TOXICOLOGY LETTERS   177 ( 2 )   123 - 129   2008年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER IRELAND LTD  

    Repeated injections of methamphetamine (METH) cause degeneration of striatal dopaminergic nerve terminals. In the present study, we examined the effects of interferon-gamma (IFN-gamma) on METH-induced striatal neurotoxicity in mice. Intraperitoneal injection of IFN-gamma before METH injection significantly prevented METH-induced reduction of striatal dopamine transporter (DAT)-positive signals and hyperthermia. Furthermore, intracerebroventricular injection of IFN-gamma before METH treatment markedly prevented METH-induced reduction of DAT. Interestingly, central IFN-gamma injection had no effect on METH-induced hyperthermia. In addition, IFN-gamma injected centrally after METH treatment, but not systemically, 1 h after the final METH injection significantly protected against METH-induced neurotoxicity. Our results suggest that IFN-gamma injected systemically or its related molecule protects against METH-induced neurotoxicity through intracerebral molecular pathways, while it can prevent METH-induced hyperthermia through different molecular events. (C) 2008 Elsevier Ireland Ltd. All rights reserved.

    DOI: 10.1016/j.toxlet.2008.01.005

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  • The roles of amino acid residues at positions 216 and 219 in the structural stability and metabolic functions of rat cytochrome P450 2D1 and 2D2

    Shizuo Narimatsu, Kimio Kiryu, Rei Yonemoto, Manabu Yoshino, Mitsuko Kobatake, Daichi Kazamori, Saori Hagino, Kazufumi Masuda, Takashi Katsu, Masato Asanuma, Takuya Kumamoto, Tsutomu Ishikawa, Yoshihiko Funae, Shigeru Yamano, Nobumitsu Hanioka, Shinsaku Naito

    CHEMICO-BIOLOGICAL INTERACTIONS   172 ( 1 )   11 - 21   2008年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER IRELAND LTD  

    We examined the effects of the mutual substitution of amino acid residues at positions 216 and 219 between rat CYP2D1 and CYP2D2 on their microsomal contents and enzymatic functions using a yeast cell expression system and 1-metloxy-N,N- diisopropyltryptamine (5-MeO-DIPT) as a substrate. CYP2D1 has amino acid residues, leucine and valine, at positions of 216 and 219, respectively, whereas CYP2D2 has phenylalanine and aspartic acid at the same positions. In reduced carbon monoxide-difference spectroscopic analysis, the substitution of Asp-219 of CYP2D2 by valine markedly increased a peak at 450 nm and concomitantly decreased a peak at 420 nm, while the replacement of Phe-216 of CYP2D2 with leucine gave no observable change. The double substitution of Phe-216 and Asp-219 by leucine and valine, respectively, yielded a typical CYP spectrum. The substitution of Val-219 of CYP2D1 by aspartic acid decreased the CYP content to one-half, whereas the replacement of Leu-216 with phenylalanine did not have any effect. The double substitution of Leu-216 and Val-219 of CYP2D1 by phenylalanine and aspartic acid, respectively, diminished the CYP content by 90%. CYP2D1 catalyzed both 5-MeO-DIPT N-deisopropylation and O-demethylation at relatively low levels, while CYP2D2 catalyzed 5-MeO-DIPT O-demethylation efficiently. The substitution of the amino acid at position 216 substantially increased 5-MeO-DIPT oxidation activities of the two CYP2D enzymes. The replacement of the amino acid at position 219 increased the 5-MeO-DIPT O- and N-dealkylation activities of CYP2D1, whereas it decreased the 5-MeO-DIPT O-demethylation activity of CYP2D2. These results indicate that amino acid residues at positions 216 and 219 have important roles in the enzymatic functions of rat CYPD1 and CYP2D2. (C) 2007 Elsevier Ireland Ltd. All rights reserved.

    DOI: 10.1016/j.cbi.2007.11.010

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  • Oxidation of 5-methoxy-N,N-diisopropyltryptamine in rat liver microsomes and recombinant cytochrome P450 enzymes

    Shizuo Narimatsu, Rei Yonemoto, Kazufumi Masuda, Takashi Katsu, Masato Asanuma, Tooru Kamata, Munehiro Katagi, Hitoshi Tsuchihashi, Takuya Kumamoto, Tsutomu Ishikawa, Shinsaku Naito, Shigeru Yamano, Nobumitsu Hanioka

    BIOCHEMICAL PHARMACOLOGY   75 ( 3 )   752 - 760   2008年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PERGAMON-ELSEVIER SCIENCE LTD  

    The oxidative metabolism of 5-methoxy-N,N-diisopropyltryptamine (5-MeO-DIPT), a tryptamine-type designer drug, was studied using rat liver microsomal fractions and recombinant cytochrome P450 (CYP) enzymes. 5-MeO-DIPT was biotransformed mainly into a side-chain N-deisopropylated metabolite and partially into an aromatic ring O-demethylated metabolite in liver microsomal fractions from untreated rats of both sexes. This metabolic profile is different from our previous findings in human liver microsomal fractions, in which the aromatic ring O-demethylation was the major pathway whereas the side-chain N-deisopropylation was minor [Narimatsu S, Yonemoto R, Saito K, Takaya K, Kumamoto T, Ishikawa T, et al. oxidative metabolism of 5-methoxy-N,N-diisopropyltryptamine (Foxy) by human liver microsomes and recombinant cytochrome P450 enzymes. Biochem Pharmacol 2006;71:1377-85]. Kinetic and inhibition studies indicated that the side-chain N-dealkylation is mediated by CYP2C11 and CYP3A2, whereas the aromatic ring O-demethylation is mediated by CYP2D2 and CYP2C6 in untreated male rats. Pretreatment of male rats with p-naphthoflavone (BNF) produced an aromatic ring 6-hydroxylated metabolite. Recombinant rat and human CYP1A1 efficiently catalyzed 5-MeO-DIPT 6-hydroxylation under the conditions used. These results provide valuable information on the metabolic fate of 5-MeO-DIPT in rats that can be used in the toxicological study of this designer drug. (c) 2007 Elsevier Inc. All rights reserved.

    DOI: 10.1016/j.bcp.2007.09.019

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  • Preventing effects of a novel anti-parkinsonian agent zonisamide on dopamine quinone formation

    Masato Asanuma, Ikuko Miyazaki, Francisco J. Diaz-Corrales, Ko Miyoshi, Norio Ogawa, Miho Murata

    NEUROSCIENCE RESEARCH   60 ( 1 )   106 - 113   2008年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER IRELAND LTD  

    The neurotoxicity of dopamine (DA) quinones as dopaminergic neuron-specific oxidative stress is considered to play a role in the pathogenesis and/or progression of Parkinson's disease (PD), since DA quinones conjugate with several key PD pathogenic molecules (e.g., tyrosine hydroxylase, alpha-synuclein and parkin) to form protein-bound quinone (quinoprotein) and consequently inhibit their functions. Zonisamide (ZNS) is used as an anti-epileptic agent but also improved the cardinal symptoms of PD in recent clinical trials in Japan. To evaluate the effects of ZNS on excess cytosolic free DA-induced quinone toxicity, we examined changes in DA quinone-related indices after ZNS treatment both in in vitro cell-free system and in cultured cells. Co-incubation of DA and ZNS in a cell-free system caused conversion of DA to stable melanin via formation of DA-semiquinone radicals and DA chrome. Long-term (5 days) treatment with ZNS decreased quinoprotein and increased DA/DOPA chromes in dopaminergic CATH.a cells. ZNS significantly inhibited quinoprotein formation induced by treatment with tetrahydrobiopterin and ketanserin that elevate cytosolic free DA in the cells. Our results suggest that the novel anti-parkinsonian agent ZNS possesses preventing effects against DA quinone formation induced by excess amount of cytosolic DA outside the synaptic vesicles. (c) 2007 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.

    DOI: 10.1016/j.neures.2007.10.002

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  • Effects of chronic ACTH treatment on astrocytes and neurogenesis in adult rat hippocampus 査読

    Nagamachi Tomoko, Miyazaki Ikuko, Emoto Sayaka, Do Maho, Kawasaki' Hiromu, Asanuma Masato, Kitamura Yoshihisa, Sendo Toshiaki, Gomita Yutaka

    JOURNAL OF PHARMACOLOGICAL SCIENCES   106   188P   2008年

  • Involvement of nucleus accumbens dopaminergic system on place aversion induced by naloxone in single-dose morphine-treated rats 査読

    Ishida Shigeru, Morohashi Kazunori, Ikuta Yuichi, Fuchi Ken-ichiro, Kawasaki Yoichi, Asanuma Masato, Araki Hiroaki, Sendo Toshiaki, Kitamura Yoshihisa, Kawasaki Hiromu

    YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN   128   67   2008年

  • メタンフェタミン神経毒性発現に関する研究の新展開

    喜多大三, 竹島美香, Wagner GC, 穂積宏彰, 宮崎育子, 浅沼幹人

    日本神経精神薬理学会雑誌   28   49 - 61   2008年

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  • 小胞外過剰ドパミンによるドパミン神経障害における共通因子としてのキノン体生成

    宮崎育子, 浅沼幹人, Diaz-Corrales FJ, 三好 耕, 小川紀雄

    岡山医学会雑誌   119   235 - 239   2008年

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  • テアニンの培養ドパミン神経およびグリア細胞系への作用

    染矢 恵, 竹島美香, 村田麻衣子, 宮崎育子, 浅沼幹人, 喜多大三

    九州栄養福祉大学研究紀要   5   69 - 81   2008年

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  • Increased susceptibility to oxidant-mediated tissue injury and peritoneal fibrosis in acatalasemic mice

    Naomi Fukuoka, Hitoshi Sugiyama, Tatsuyuki Inoue, Yoko Kikumoto, Kei-ichi Takiue, Hiroshi Morinaga, Kazushi Nakao, Yohei Maeshima, Masato Asanuma, Da-Hong Wang, Keiki Ogino, Noriyoshi Masuoka, Hirofumi Makino

    AMERICAN JOURNAL OF NEPHROLOGY   28 ( 4 )   661 - 668   2008年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:KARGER  

    Background: Peritoneal fibrosis is a major complication leading to the loss of peritoneal function in patients undergoing peritoneal dialysis. However, the effect of catalase depletion on peritoneal fibrosis has not yet been investigated. Methods: The impact of catalase deficiency on progressive peritoneal fibrosis has been studied in homozygous acatalasemic mutant mice or control wild-type mice by intraperitoneal injection of chlorhexidine gluconate (CG) every other day for 14 days. Results: The CG injections resulted in a thicker peritoneal membrane, reflecting peritoneal fibrosis with accumulation of interstitial type I collagen, peritoneal deposition of lipid peroxidation products (4-hydroxy-2-nonenal and 4-hydroxy-2-hexenal), and an elevated level of 8-hydroxy-2&apos;-deoxyguanosine in peritoneal fluid in both mouse groups on day 14. The extent of these changes, however, was significantly higher in acatalasemic mice than in wild-type mice. The level of catalase activity remained low in the acatalasemic peritoneum without the compensatory upregulation of glutathione peroxidase, but with an insufficient upregulation of superoxide dismutase activity in CG-injected mice. Conclusions: Acatalasemia, therefore, exacerbates oxidant tissue injury and induces the peritoneum to develop irreversible fibrosis which is the most important complication of peritoneal dialysis. This study suggests that catalase plays a crucial role in the defense against oxidant-mediated peritoneal injury in a mouse peritoneal fibrosis model. Copyright (C) 2008 S. Karger AG, Basel.

    DOI: 10.1159/000121357

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  • 食品および食材に含まれる化学物質のモノアミン神経培養系に及ぼす作用に関する研究

    村田麻衣子, 竹島美香, 染矢 恵, 宮崎育子, 浅沼幹人, 喜多大三

    九州栄養福祉大学研究紀要   5   55 - 67   2008年

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  • Protective effects of metallothionein against dopamine quinone-induced dopaminergic neurotoxicity

    Ikuko Miyazaki, Masato Asanuma, Hiroaki Hozumi, Ko Miyoshi, Norio Sogawa

    FEBS LETTERS   581 ( 25 )   5003 - 5008   2007年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE BV  

    Dopamine (DA) quinone as DA neuron-specific oxidative stress conjugates with cysteine residues in functional proteins to form quinoproteins. Here, we examined the effects of cysteine-rich metal-binding proteins, metallothionein (NIT)-1 and -2, on DA quinone-induced neurotoxicity. NIT quenched DA semiquinones in vitro. In dopaminergic cells, DA exposure increased quinoproteins and decreased cell viability; these were ameliorated by pretreatment with MT-inducer zinc. Repeated L-DOPA administration markedly elevated striatal quinoprotein levels and reduced the DA nerve terminals specifically on the lesioned side in NIT-knockout parkinsonian mice, but not in wild-type mice. Our results suggested that intrinsic NIT protects against L-DOPA-induced DA quinone neurotoxicity in parkinsonian mice by its quinone-quenching property. (c) 2007 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

    DOI: 10.1016/j.febslet.2007.09.046

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  • Common anti-inflammatory drugs are potentially therapeutic for Parkinson's disease?

    Masato Asanuma, Ikuko Miyazaki

    EXPERIMENTAL NEUROLOGY   206 ( 2 )   172 - 178   2007年8月

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    記述言語:英語   出版者・発行元:ACADEMIC PRESS INC ELSEVIER SCIENCE  

    DOI: 10.1016/j.expneurol.2007.05.006

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  • 5-Methoxy-N,N-diisopropyltryptamine (Foxy), a selective and high affinity inhibitor of serotonin transporter

    C. Sogawa, N. Sogawa, J. Tagawa, A. Fujino, K. Ohyama, M. Asanuma, M. Funada, S. Kitayama

    TOXICOLOGY LETTERS   170 ( 1 )   75 - 82   2007年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER IRELAND LTD  

    5-Methoxy-N,N-diisopropyltryptamine (5-MeO-DIPT) is a synthetic orally active hallucinogenic tryptamine derivative, known also as Foxy or Foxy methoxy. However, few studies have examined its effects in vitro. In the present study, we investigated the actions of 5-MeO-DIPT against monoamine neurotransmitter transporters, including the transporters for dopamine (DAT), norepinephrine (NET), and serotonin (SERT), using COS-7 cells heterologously expressing these transporters and rat brain synaptosomes. 5-MeO-DIPT specifically inhibited the uptake of [H-3]serotonin (5-HT) by the SERT-expressing COS-7 cells and rat striatal synaptosomes in a high affinity manner at concentrations similar to those for cocaine. The effect was reversible and competitive. 5-MeO-DIPT failed to stimulate reverse transport of [H-3]5-HT through SERT, while it prevented the releasing action of methamphetamine. 5-MeO-DIPT induced cell toxicity at high concentrations in COS-7 cells, and it was not influenced by the expression of SERT. These results demonstrated that 5-MeO-DIPT acts as a competitive SERT inhibitor and has an inability to cause reverse transport, underlying its serotonergic actions. (C) 2007 Elsevier Ireland Ltd. All rights reserved.

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  • Suppression of p53-activated gene, PAG608, attenuates methamphetamine-induced neurotoxicity

    Masato Asanuma, Ikuko Miyazaki, Youichirou Higashi, Francisco J. Diaz-Corrales, Masako Shimizu, Ko Miyoshi, Norio Ogawa

    NEUROSCIENCE LETTERS   414 ( 3 )   263 - 267   2007年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER IRELAND LTD  

    The p53-activated gene 608 (PAG608) is a proapoptotic gene activated and regulated by p53 expression in oxidative stress-induced apoptosis of neuronal cells. In this study, we determined the role of PAG608 in methamphetamine-induced neurotoxicity. Treatment of mouse dopaminergic CATH.a cells with 2 mM methamphetamine increased PAG608 expression at 3 h followed by increase in phosphorylated p53 expression. Transient transfection of PAG608 antisense cDNA or RNA interference using PAG608 small interfering RNA significantly attenuated the dose-dependent decrease in cell viability of CATH.a cells by methamphetamine (1-4 mM) exposure. In monoaminergic neuronal B65 cells, which contain serotonin rather than dopamine, methamphetamine-induced cell death was also significantly but partially protected by transient transfection of PAG608 antisense cDNA. Furthermore, cell death of PC 12 cells produced by methamphetamine (1-5 mM) was almost completely prevented by stable expression of PAG608 antisense cDNA, compared with significant reduction of cell viability in control PC12 cells. Our results showed that suppression of PAG608 using transient and stable transfection with PAG608 anti sense cDNA or small interfering RNA attenuates methamphetamine-induced death of various monoaminergic neuronal cells, suggesting that methamphetamine neurotoxicity in monoaminergic cells is related, at least in part, to induction of PAG608 expression. (c) 2006 Elsevier Ireland Ltd. All rights reserved.

    DOI: 10.1016/j.neulet.2006.12.036

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  • OXIDATIVE METABOLISM OF 5-MeO-DIPT BY RAT CYP2DENZYMES

    Kazamori, Daichi, Yonemoto, Rei, Hagino, Saori, Hanioka, Nobumitsu, Masuda, Kazufumi, Katsu, Takashi, Asanuma, Masato, Kiryu, Kimio, Naito, Shinsaku, Kumamoto, Takuya, Ishikawa, Tsutomu, Yamano, Shigeru, Funae, Yoshihiko, Narimatsu, Shizuo

    DRUG METABOLISM REVIEWS   39   115 - 116   2007年

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    掲載種別:研究論文(学術雑誌)  

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  • Electron spin resonance measurement of oxidative stress in peritoneal dialysate effluents in patients with peritoneal dialysis in association with peritoneal fibrosis

    Yoko Kikumoto, Hitoshi Sugiyama, Naomi Fukuoka, Tatsuyuki Inoue, Mizuho Kobayashi, Kazushi Nakao, Yohei Maeshima, Ikuko Miyazaki, Masato Asanuma, Makoto Hiramatsu, Hirofumi Makino

    NEPHROLOGY DIALYSIS TRANSPLANTATION   22   299 - 299   2007年

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    記述言語:英語   出版者・発行元:OXFORD UNIV PRESS  

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  • 食品容器および食器より溶出する化学物質のドパミン神経障害性に関する研究─ビスフェノールAの培養ドパミン神経系への作用─

    喜多大三, 竹島美香, 田中弓子, 宮崎育子, 浅沼幹人

    九州栄養福祉大学研究紀要   4   89 - 97   2007年

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  • Characterization of pericentrin isoforms in vivo

    Ko Miyoshi, Masato Asanuma, Ikuko Miyazaki, Shinsuke Matsuzaki, Masaya Tohyama, Norio Ogawa

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   351 ( 3 )   745 - 749   2006年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ACADEMIC PRESS INC ELSEVIER SCIENCE  

    Pericentrin was first identified as a mouse centrosomal protein and is now referred to as pericentrin A. A larger homologous protein in humans with a C-terminal calmodulin-binding domain was later identified as pericentrin B. Pericentrin has been shown to be one of the key components in ciliogenesis.. but in vivo pericentrin products have remained ambiguous. Here we characterized pericentrin isoforms in mice. Two pericentrin transcripts of 9.5 and 6.9 kb were recognized on the mouse tissue Northern blots, while a cRNA probe for a 5'-terminal sequence shared by pericentrin A and B failed to hybridize to the 6.9-kb message. Two pericentrin cDNAs were identified, which encoded pericentrin B and a novel isoform, pericentrin S, sharing with pericentrin B a C-terminal calmodulin-binding motif. Three pericentrin proteins of 360, 255, and 250 kDa revealed by immunoprecipitation analysis were thought to correspond to pericentrin B, pericentrin S, and an unknown N-terminal product. (c) 2006 Elsevier Inc. All rights reserved.

    DOI: 10.1016/j.bbrc.2006.10.101

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  • Involvement of STAT3 in bladder smooth muscle hypertrophy following bladder outlet obstruction

    Osamu Fujita, Masato Asanuma, Teruhiko Yokoyama, Ikuko Miyazaki, Norio Ogawa, Hiromi Kumon

    ACTA MEDICA OKAYAMA   60 ( 6 )   299 - 309   2006年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:OKAYAMA UNIV MED SCHOOL  

    We examined the involvement of the signal transducer and activator of transcription 3 (STAT3) in bladder outlet obstruction (BOO)-induced bladder smooth muscle hypertrophy using a rat in vivo and in vitro study. BOO induced increases in bladder weight and bladder smooth muscle thickness I week after the operation. By using antibody microarrays, 64 of 389 proteins blotted on the array met our selection criteria of an INR value between &gt;= 2.0 and &lt;= 0.5. This result revealed up-regulation of transcription factors, cell cycle regulatory proteins, apoptosis-associated proteins and so on. On the other hand, down-regulation (INR value &lt;= 0.5) of proteins was not found. In a profiling study, we found an increase in the expression of STAT3. A significant increase in nuclear phosphorylated STAT3 expression was confirmed in bladder smooth muscle tissue by immunohistochemistry and Western blot analysis. Cyclical stretch-relaxation (I Hz) at 120% elongation significantly increased the expression of STAT3 and of alpha-smooth muscle actin in primary cultured bladder smooth muscle cells. Furthermore, the blockade of STAT3 expression by the transfection of STAT3 small interfering RNA (siRNA) significantly prevented the stretch-induced increase in alpha-smooth muscle actin expression. These results suggest that STAT3 has an important role in the induction of bladder smooth muscle hypertrophy.

    DOI: 10.18926/AMO/30724

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  • Molecular basis of 6-hydroxydopamine-induced caspase activations due to increases in oxidative stress in the mouse striatum

    Ken-ichi Tanaka, Norio Ogawa, Masato Asanuma

    NEUROSCIENCE LETTERS   410 ( 2 )   85 - 89   2006年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER IRELAND LTD  

    To clarify the possible role of in the in vivo toxic effects of 6-hydroxydopamine (6-OHDA), especially caspase activations, we examined its effects on striatal lipid peroxidation (LPO) and caspase activations in 6-OHDA-lesioned mice. Both dopamine (DA) levels and DA turnover were significantly changed by the 6-OHDA i.c.v. injection compared with the pre-injection level in the striatum. In addition, the striatal glutathione (GSH) content fluctuated and was significantly decreased both at 3 and 14 days after 6-OHDA i.e.v. injection. Moreover, superoxide dismutase (SOD) activity at 7 days after 6-OHDA i.c.v. injection was transiently and significantly increased compared with the pre-injection level. The levels of thiobarbituric acid-reactive substances (TBA-RS) were significantly increased at 1, 3 and 14 days. 6-OHDA significantly increased the activities of all three caspases, except for the caspase-3 activity at 7 days throughout the experimental period compared with the pre-injection level. In conclusion, 6-OHDA-induced dopaminergic dysfunction is mainly due to caspase activations by increases in oxidative stress in the mouse striatum. (c) 2006 Elsevier Ireland Ltd. All rights reserved.

    DOI: 10.1016/j.neulet.2006.08.021

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  • Nonsteroidal anti-inflammatory drugs in Parkinson's disease: possible involvement of quinone formation

    Masato Asanuma, Ikuko Miyazaki

    EXPERT REVIEW OF NEUROTHERAPEUTICS   6 ( 9 )   1313 - 1325   2006年9月

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    記述言語:英語   出版者・発行元:EXPERT REVIEWS  

    It has been revealed that nonsteroidal anti-inflammatory drugs (NSAIDs) have neuroprotective properties based not only on their cyclooxygenase-inhibitory action, but also on other properties including their inhibitory effects on the synthesis of nitric oxide radicals and agonistic action for peroxisome proliferator-activated receptor gamma, in addition to some as yet unknown properties. Recently, a number of experimental and clinical studies have examined the neuroprotective effects of NSAIDs on the pathogenesis of several neurodegenerative diseases, including Parkinson's disease. In this article, various pharmacological effects of NSAIDs (except for their cyclooxygenase-inhibitory action) are reviewed, and possible neuroprotective effects of NSAIDs on Parkinson's disease are discussed. The neurotoxicity of dopamine quinones, or DOPA quinones, has recently received attention as a dopaminergic neuron-specific oxidative stress that is known to play a role in the pathogenesis of Parkinson's disease and neurotoxin-induced parkinsonism. NSAIDs inhibit prostaglandin H synthase, thus suppressing dopamine oxidation and subsequent dopamine quinone formation. Therefore, this article also reviews possible suppressive effects of some NSAIDs against dopamine quinone generation. Expert Rev. Neurotherapeutics 6(9), 1313-1325 (2006)

    DOI: 10.1586/14737175.6.9.1313

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  • Embryonic expression of pericentrin suggests universal roles in ciliogenesis

    Ko Miyoshi, Kazunari Onishi, Masato Asanuma, Ikuko Miyazaki, Francisco J. Diaz-Corrales, Norio Ogawa

    DEVELOPMENT GENES AND EVOLUTION   216 ( 9 )   537 - 542   2006年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPRINGER  

    Pericentrin (Pcnt) is a giant coiled-coil protein known to mediate microtubule organization. It has been recently reported that mitosis-specific centrosomal anchoring of gamma tubulin complexes by Pcnt acts to control mitotic spindle organization, though little is known about the in vivo expression of Pcnt. In this study, we investigated Pcnt expression in mouse embryos. In situ hybridization analysis revealed preferential expression of Pcnt in quiescent G(0) phase cells throughout the embryo with an unexpectedly low expression level in proliferating cells, suggesting that Pcnt might not play an important role in mitotic proliferation. Immunofluorescence analysis confirmed preferential expression of the Pcnt protein in G(0) phase cells. Moreover, Pcnt was shown to be localized to the base of primary cilia in multiple embryonic tissues, in agreement with a recent study demonstrating the involvement of Pcnt in primary cilia formation using cultured mammalian cells.

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  • Oxidative metabolism of 5-methoxy-N,N-diisopropyltryptamine (Foxy) by human liver microsomes and recombinant cytochrome P450 enzymes

    S Narimatsu, R Yonemoto, K Saito, K Takaya, T Kumamoto, T Ishikawa, M Asanuma, M Funada, K Kiryu, S Naito, Y Yoshida, S Yamamoto, N Hanioka

    BIOCHEMICAL PHARMACOLOGY   71 ( 9 )   1377 - 1385   2006年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PERGAMON-ELSEVIER SCIENCE LTD  

    In vitro quantitative studies of the oxidative metabolism of (S-methoxy-N,N-diisopropyl-tryptamine, 5-MeO-DIPT, Foxy) were performed using human liver microsomal fractions and recombinant CYP enzymes and synthetic 5-MeO-DIPT metabolites. 5-MeO-DIPT was mainly oxidized to O-demethylated (5-OH-DIPT) and N-deisopropylated (S-MeO-IPT) metabolites in pooled human liver microsomes. In kinetic studies, 5-MeO-DIPT O-demethylation showed monophasic kinetics, whereas its N-deisopropylation showed triphasic kinetics. Among six recombinant CYP enzymes (CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4) expressed in yeast or insect cells, only CYP2D6 exhibited 5-MeO-DIPT O-demethylase activity, while CYP1A2, CYP2C8, CYP2C9, CYP2C19 and CYP3A4 showed 5-MeO-DIPT N-deisopropylase activities. The apparent K, value of CYP2D6 was close to that for 5-MeO-D1PT O-demethylation, and the K-m values of other CYP enzymes were similar to those of the low-Km (CYP2C19), intermediate-K-m (CYP1A2, CYP2C8 and CYP3A4) and high-K-m phases (CYP2C9), respectively, for N-deisopropylation in human liver microsomes. in inhibition studies, quinidine (1 mu M), an inhibitor of CYP2D6, almost completely inhibited human liver microsomal 5-MeO-DIPT O-demethylation at a substrate concentration of 10 mu M.

    DOI: 10.1016/j.bcp.2006.01.015

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  • Methamphetamine-induced dopaminergic neurotoxicity is regulated by quinone formation-related molecules

    Miyazaki, I, M Asanuma, FJ Diaz-Corrales, M Fukuda, K Kitaichi, K Miyoshi, N Ogawa

    FASEB JOURNAL   20 ( 1 )   571 - +   2006年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:FEDERATION AMER SOC EXP BIOL  

    Recently, the neurotoxicity of dopamine (DA) quinone formation by auto-oxidation of DA has focused on dopaminergic neuron-specific oxidative stress. In the present study, we examined DA quinone formation in methamphetamine (METH)-induced dopaminergic neuronal cell death using METH-treated dopaminergic cultured CATH. a cells and METH-injected mouse brain. In CATH. a cells, METH treatment dose-dependently increased the levels of quinoprotein (protein-bound quinone) and the expression of quinone reductase in parallel with neurotoxicity. A similar increase in quinoprotein levels was seen in the striatum of METH (4 mg/kg X4, i.p., 2 h interval)-injected BALB/c mice, coinciding with reduction of DA transporters. Furthermore, pretreatment of CATH. a cells with quinone reductase inducer, butylated hydroxyanisole, significantly and dose-dependently blocked METH-induced elevation of quinoprotein, and ameliorated METH-induced cell death. We also showed the protective effect of tyrosinase, which rapidly oxidizes DA and DA quinone to form stable melanin, against METH-induced dopaminergic neurotoxicity in vitro and in vivo using tyrosinase null mice. Our results indicate that DA quinone formation plays an important role, as a dopaminergic neuron-specific neurotoxic factor, in METH-induced neurotoxicity, which is regulated by quinone formation-related molecules.

    DOI: 10.1096/fj.05-4996fje

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  • L-DOPA treatment from the viewpoint of neuroprotection - Possible mechanism of specific and progressive dopaminergic neuronal death in Parkinson's disease

    N Ogawa, M Asanuma, Miyazaki, I, FJ Diaz-Corrales, K Miyoshi

    JOURNAL OF NEUROLOGY   252   23 - 31   2005年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:DR DIETRICH STEINKOPFF VERLAG  

    With regard to the mechanism of selective dopaminergic neuronal death, experimental results of studies on the neurotoxicity of MPTP and rotenone indicate that degeneration of dopamine neurons is closely related to mitochondrial dysfunction, inflammatory process and oxidative stress, particularly with regard to the generation of quinones as dopamine neuron-specific oxidative stress. Thus, it is now clear that the presence of high levels of discompartmentalized free dopamine in sdopaminergic neurons may explain the specific vulnerability of dopaminergic neurons through the generation of highly toxic quinones.

    DOI: 10.1007/s00415-005-4006-7

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  • Common anti-apoptotic roles of parkin and alpha-synuclein in human dopaminergic cells (vol 332, pg 233, 2005)

    Y Machida, T Chiba, A Takayanagi, Y Tanaka, M Asanuma, N Ogawa, A Koyama, T Iwatsubo, S Ito, PH Jansen, N Shimizu, K Tanaka, Y Mizuno, N Hattori

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   334 ( 3 )   970 - 970   2005年9月

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    記述言語:英語   出版者・発行元:ACADEMIC PRESS INC ELSEVIER SCIENCE  

    DOI: 10.1016/j.bbrc.2005.06.156

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  • Prednisolone inhibits proliferation of cultured pulmonary artery smooth muscle cells of patients with idiopathic pulmonary arterial hypertension

    A Ogawa, K Nakamura, H Matsubara, H Fujio, T Ikeda, K Kobayashi, Miyazaki, I, M Asanuma, K Miyaji, D Miura, KF Kusano, H Date, T Ohe

    CIRCULATION   112 ( 12 )   1806 - 1812   2005年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

    Background - Idiopathic pulmonary arterial hypertension (IPAH) is associated with proliferation of smooth muscle cells (SMCs) in small pulmonary arteries. There is no therapy that specifically inhibits SMC proliferation. Recent studies reported that prednisolone (PSL) inhibits the postangioplasty proliferation of SMCs in atherosclerotic arteries. In this study, we tested the hypothesis that PSL has antiproliferative effects on pulmonary artery SMCs of patients with IPAH.
    Methods and Results - Pulmonary artery SMCs were harvested from the pulmonary arteries of 6 patients with IPAH who underwent lung transplantation. Control SMCs were obtained from 5 patients with bronchogenic carcinoma who underwent lung lobectomy. After incubation in the presence of platelet-derived growth factor ( PDGF), PSL was added at different concentrations and cell proliferation was assessed by H-3-thymidine incorporation. PSL ( 2 x 10(-4) and 2 x 10(-3) mol/L) significantly inhibited PDGF-stimulated proliferation ( P &lt; 0.05) of SMCs from patients with IPAH but did not affect cell viability of SMCs, as confirmed by trypan blue staining. In cell cycle analysis using a microscope-based multiparameter laser scanning cytometer, PSL inhibited the progression of SMCs from G(0)/G(1) to the S phase. This inhibition was associated with increased p27 expression level. PSL ( 2 x 10(-4) mol/L) also inhibited PDGF-induced SMC migration.
    Conclusions - Our results indicate that PSL has an antiproliferative effect on cultured SMCs of pulmonary arteries from patients with IPAH and suggest that PSL may be potentially useful therapeutically in patients with IPAH.

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  • Dopamine agonist pergolide prevents levodopa-induced quinoprotein formation in Parkinsonian striatum and shows quenching effects on dopamine-semiquinone generated in vitro 査読

    Ikuko Miyazaki, Masato Asanuma, Francisco J. Diaz-Corrales, Ko Miyoshi, Norio Ogawa

    Clinical Neuropharmacology   28 ( 4 )   155 - 160   2005年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The neurotoxicity of dopamine (DA) quinones that appears in dopaminergic neuron-specific oxidative stress has recently been shown to play a role in the pathogenesis and/or progression of Parkinson disease. To clarify the effects of a DA agonist, pergolide, on the levodopa-induced elevation of quinones, the authors examined, striatal changes in quinoprotein using a hemi-parkinsonian mouse model. The level of striatal quinoprotein was significantly elevated specifically on the parkinsonian side, but not on the control side, after repeated levodopa administration. This levodopa-induced increase in striatal quinoprotein was almost completely suppressed by adjunctive administration with pergolide on the lesioned side. Furthermore, it was clarified that pergolide scavenged DA-semiquinones generated in vitro in a dose-dependent manner. These suppressive and quenching effects of pergolide against cytotoxic DA quinones may play a key role in its neuroprotective mechanism in the parkinsonian brain. Copyright © 2005 by Lippincott Williams &amp
    Wilkins.

    DOI: 10.1097/01.wnf.0000175523.33334.24

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  • Pramipexole has ameliorating effects on levodopa-induced abnormal dopamine turnover in parkinsonian striatum and quenching effects on dopamine-semiquinone generated in vitro

    M Asanuma, Miyazaki, I, FJ Diaz-Corrales, M Shimizu, K Tanaka, N Ogawa

    NEUROLOGICAL RESEARCH   27 ( 5 )   533 - 539   2005年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:MANEY PUBLISHING  

    Objectives and methods: To clarify the effects of a non-ergot do amine agonist pramipexole on levodopa-induced abnormal dopamine metabolism in the parkinsonian model, we examined striatal changes in dopamine and its metabolites after repeated administration of pramipexole and/or levodopa using 6-hydroxydopamine-lesioned hemi-parkinsonian mice. Moreover, the effects of pramipexole on dopamine-semiquinones were also accessed using an in vitro dopamine-semiquinone generating system to elucidate its neuroprotective property against dopamine quinone-induced neurotoxicity that appears as dopamine neuron-specific oxidative stress.
    Results: Combined administration of pramipexole (0.5 or 1 mg/kg/day, 7 days) selectively suppressed the levodopa-induced (50 mg/kg/day) increase of striatal dopamine turnover in the parkinsonian side, but not in the non-lesioned side. In addition to the antioxidant properties previously reported, it was clarified that pramipexole scavenged dopamine-semiquinones generated in a dose-dependent manner either in simultaneous incubation or post-incubation.
    Discussion: The neurotoxicity of dopamine quinones that appear as dopaminergic neuronspecific oxidative stress has recently been known to play a role in the pathogenesis of Parkinson's disease and neurotoxin-induced parkinsonism. Therefore, the present results revealed that pramipexole possesses neuroprotective effects against abnormal dopamine metabolism in excessively levodopa-administered parkinsonian brains and against cytotoxic dopamine quinones generated from excess dopamine, preventing consequentry dopaminergic neuronal damage induced by excess dopamine or levodopa.

    DOI: 10.1179/016164105X22093

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  • ドパミン受容体アゴニストによるドパミンニューロン死の制御.

    浅沼幹人

    Clinical Neuroscience   23, 1342-1343   2005年

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  • 酸化ストレスによる神経障害と神経保護療法─ドパミン神経特異的酸化ストレスとしてのキノン体毒性.

    浅沼幹人, 小川紀雄

    医学のあゆみ   215, 785-792   2005年

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  • 薬物依存・毒性発現にかかわる分子の分子生物学的検索法─網羅的プロファイリングを中心に.

    浅沼幹人, 宮崎育子

    日本薬理学雑誌   126, 30-34   2005年

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  • Rotenone induces aggregation of gamma-tubulin protein and subsequent disorganization of the centrosome: Relevance to formation of inclusion bodies and neurodegeneration

    FJ Diaz-Corrales, M Asanuma, Miyazaki, I, K Miyoshi, N Ogawa

    NEUROSCIENCE   133 ( 1 )   117 - 135   2005年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PERGAMON-ELSEVIER SCIENCE LTD  

    Neurodegenerative disorders are characterized by progressive loss of specific neurons in the central nervous system. Although they have different etiologies and clinical manifestations, most of them share similar histopathologic characteristics such as the presence of inclusion bodies in both neurons and glial cells, which represent intracellular aggregation of misfolded or aberrant proteins. In Parkinson's disease, formation of inclusion bodies has been associated with the aggresome-related process and consequently with the centrosome. However, the significance of the centrosome in the neurodegenerative process remains obscure. In the present study, the morphological and functional changes in the centrosome induced by rotenone, a common insecticide used to produce experimental Parkinsonism, were examined both in vitro and in vivo. Aggregation of gamma-tubulin protein, which is a component of the centrosome matrix and recently identified in Lewy bodies of Parkinson's disease, was observed in primary cultures of mesencephalic cells treated with rotenone. Rotenone-treated neurons and astrocytes showed enlarged and multiple centro-somes. These centrosomes also displayed multiple aggregates of alpha-synuclein protein. Neurons with disorganized centrosomes exhibited neurite retraction and microtubule destabilization, and astrocytes showed disturbances of mitotic spindles. The Golgi apparatus, which is closely related to the centrosome, was dispersed in both rotenone-treated neuronal cells and the substantia nigra of rotenone-treated rats. Our findings suggested that recruitment of abnormal proteins in the centrosome contributed to the formation of inclusion bodies, and that rotenone markedly affected the structure and function of the centrosome with consequent induction of cytoskeleton disturbances, disassembly of the Golgi apparatus and collapse of neuronal cells. (c) 2005 IBRO. Published by Elsevier Ltd. All rights reserved.

    DOI: 10.1016/j.neuroscience.2005.01.044

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  • Direct evidence for expression of dopamine receptors in astrocytes from basal ganglia

    Miyazaki, I, M Asanuma, FJ Diaz-Corrales, K Miyoshi, N Ogawa

    BRAIN RESEARCH   1029 ( 1 )   120 - 123   2004年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE BV  

    Expression of dopamine receptors (DA-Rs) in astrocytes was examined in vitro and in vivo using primary cultured astrocytes and brain slices from rat basal ganglia. Astrocytes from basal ganglia expressed DA D1-, D3-, D4- and D5-receptors and D4-mediated signal transduction in response to DA, suggesting possible involvement of astrocytes in the pharmacological action of atypical antipsychotic drugs and in DA response in some neurological diseases. (C) 2004 Elsevier B.V. All rights reserved.

    DOI: 10.1016/j.brainres.2004.09.014

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  • Quinone formation as dopaminergic neuron-specific oxidative stress in the pathogenesis of sporadic Parkinson's disease and neurotoxin-induced parkinsonism

    M Asanuma, Miyazaki, I, FJ Diaz-Corrales, N Ogawa

    ACTA MEDICA OKAYAMA   58 ( 5 )   221 - 233   2004年10月

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    記述言語:英語   出版者・発行元:OKAYAMA UNIV MED SCHOOL  

    Parkinson's disease (PD) is a progressive neurodegenerative disease characterized by dopaminergic neuron-specific degeneration in the substantia, nigra. A number of gene mutations and deletions have been reported to play a role in the pathogenesis of familial PD. Moreover, a number of pathological and pharmacological studies on sporadic PD and dopaminergic neurotoxin-induced parkinsonism have hypothesized that mitochondrial dysfunction, inflammation, oxidative stress, and dysfunction of the ubiquitin-proteasome system all play important roles in the pathogenesis and progress of PD. However, these hypotheses do not yet fully explain the mechanisms of dopaminergic neuron-specific cell loss in PD. Recently, the neurotoxicity of dopamine quinone formation by auto-oxidation of dopamine has been shown to cause specific cell death of dopaminergic neurons in the pathogenesis of sporadic PD and dopaminergic neurotoxin-induced parkinsonism. Furthermore, this quinone formation is closely linked to other representative hypotheses in the pathogenesis of PD. In this article, we mainly review recent studies on the neurotoxicity of quinone formation as a dopaminergic neuron-specific oxidative stress and its role in the etiology of PD, in addition to several neuroprotective approaches against dopamine quinone-induced toxicity.

    DOI: 10.18926/AMO/32105

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  • Expression of metallothionein-III and cell death in differentiated catecholaminergic neuronal cells

    Y Higashi, M Asanuma, Miyazaki, I, N Ogawa

    NEUROLOGICAL RESEARCH   26 ( 6 )   671 - 676   2004年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:MANEY PUBLISHING  

    Metallothionein (MT)-III, an isomer of metallothionein, is also known to be a growth inhibitory factor. MT-III has been reported to decrease the number of surviving neuronal cells in culture medium containing brain extract. Using differentiated catecholaminergic neuronal CATH.a cells treated with dibutyryl cyclic AMP, we examined MT-III expression and the effect of mouse forebrain extract on cell viability. Increase in MT-III expression was revealed in the differentiated cells. Moreover, treatment with mouse forebrain extract induced apoptotic cell death in differentiated CATH.a cells, accompanied by decreases in both MT-III and a neuronal differentiation marker, growth-associated protein-43, expression in surviving cells. These results imply that MT-III expression during the developmental period may be associated with the regulation of normal neural differentiation.

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  • Metallothioneins and neurodegenerative diseases

    Hozumi, I, M Asanuma, M Yamada, Y Uchida

    JOURNAL OF HEALTH SCIENCE   50 ( 4 )   323 - 331   2004年8月

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    記述言語:英語   出版者・発行元:PHARMACEUTICAL SOC JAPAN  

    A symposium on the clinical aspects of metallothioneins (MTs) in neurodegenerative diseases was held at the 2003 Society of Metallothionein Meeting in Gifu, Japan. The objectives of the symposium were to review and speculate on the potential roles of MTs, especially MT-3 in neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and spinocerebellar degeneration (SCD). Dr. Uchida discussed the controversial problem regarding the expression of MT-3 in AD brains. Dr. Asanuma addressed the function of MTs in the progression of PD and Dr. Hozumi described the therapeutic potential of MTs for ALS, while Dr. Yamada provided immunohistochemical findings of MT-3 in SCD for the first time. Although there are still controversial problems on MTs, this review provides proof that MTs are promising potential therapeutic targets for therapy for some neurodegenerative diseases.

    DOI: 10.1248/jhs.50.323

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  • Molecular basis of anti-apoptotic effect of immunophilin ligands on hydrogen peroxide-induced apoptosis in human glioma cells

    K Tanaka, M Asanuma, N Ogawa

    NEUROCHEMICAL RESEARCH   29 ( 8 )   1529 - 1536   2004年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:KLUWER ACADEMIC/PLENUM PUBL  

    To clarify the molecular basis of the cytoprotective properties of immunophilin ligands (IPLs), the anti-apoptotic effects of IPLs were determined in human glioma U251 cells. GPI1046 and V10367, non-immunosuppressive IPLs (NI-IPLs), as well as FK506, an immunosuppressive IPL (I-IPL), had cytoprotective effects against hydrogen peroxide (H2O2)-induced apoptotic cell death in U251 cells. H2O2 increased both the ratio of bax/bcl-2 and the p53 mRNA expression. However, pretreatment with FK506 and V10367 significantly prevented any increase in this ratio or p53 mRNA expression. GPI1046 also reduced the ratio of bax/bcl-2 to the normal level. In addition, H2O2 significantly increased activities of all three caspases, caspase-3, caspase-8, and caspase-9, in comparison with non-H2O2 controls. However, FK506 prevented the increase of these caspase activities. On the other hand, it is well-known that glutathione (GSH) and neurotrophic factor (NTF) is related to the induction of apoptosis in neuronal cells. In U251 cells, FK506, GPI1046 and V10367 had GSH-activating and NTF-activating effects. Thus, the immunosuppressive effect is not essential for the cytoprotective properties of IPLs, and IPLs have multiple beneficial properties such as the antiapoptotic effect, GSH-activating effect, and NTF-activating effect, although the anti-apoptotic effect of NI-IPLs is independent of the regulation of apoptotic activators such as caspase-3.

    DOI: 10.1023/B:NERE.0000029565.92587.25

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  • Parkin attenuates manganese-induced dopaminergic cell death

    Y Higashi, M Asanuma, Miyazaki, I, N Hattori, Y Mizuno, N Ogawa

    JOURNAL OF NEUROCHEMISTRY   89 ( 6 )   1490 - 1497   2004年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:BLACKWELL PUBLISHING LTD  

    Manganese as environmental factor is considered to cause parkinsonism and induce endoplasmic reticulum stress-mediated dopaminergic cell death. We examined the effects of manganese on parkin, identified as the gene responsible for familial Parkinson's disease, and the role of parkin in manganese-induced neuronal cell death. Manganese dose-dependently induced cell death of dopaminergic SH-SY5Y and CATH.a cells and cholinergic Neuro-2a cells, and that the former two cell types were more sensitive to manganese toxicity than Neuro-2a cells. Moreover, manganese increased the expression of endoplasmic reticulum stress-associated genes, including parkin, in SH-SY5Y cells and CATH.a cells, but not in Neuro-2a cells. Treatment with manganese resulted in accumulation of parkin protein in SH-SY5Y cells and its redistribution to the perinuclear region, especially aggregated Golgi complex, while in Neuro-2a cells neither expression nor redistribution of parkin was noted. Manganese showed no changes in proteasome activities in either cell. Transient transfection of parkin gene inhibited manganese- or manganese plus dopamine-induced cell death of SH-SY5Y cells, but not of Neuro-2a cells. Our results suggest that the attenuating effects of parkin against manganese- or manganese plus dopamine-induced cell death are dopaminergic cell-specific compensatory reactions associated with its accumulation and redistribution to perinuclear regions but not with proteasome system.

    DOI: 10.1111/j.1471-4159.2004.02445.x

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  • DISC1 localizes to the centrosome by binding to kendrin

    K Miyoshi, M Asanuma, Miyazaki, I, FJ Diaz-Corrales, T Katayama, M Tohyama, N Ogawa

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   317 ( 4 )   1195 - 1199   2004年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ACADEMIC PRESS INC ELSEVIER SCIENCE  

    Disrupted-In-Schizophrenia 1 (DISC1) was identified as a novel gene disrupted by a (1; 11)(q42.1;q 14.3) translocation that segregated with major mental disorders in a Scottish family. Using the yeast two-hybrid system, we screened a human brain cDNA library for interactors of the DISC1 protein. One of the positive clones encoded kendrin/pericentrin-B, a giant protein known to localize specifically to the centrosome. The interaction between DISCI and kendrin in mammalian cells was demonstrated by an immunoprecipitation assay. Residues 446-533 of DISC1 were essential for the interaction with kendrin. Immunocytochemical analysis revealed the colocalization of DISC1 and kendrin to the centrosome. These data indicate that DISC1 localizes to the centrosome by binding to kendrin. Kendrin has been reported to anchor the gamma-tubulin complex to the centrosome, providing microtubule nucleation sites. The present study suggests the possible involvement of DISC1 in the pathophysiology of mental disorders due to its putative effect on centrosomal function. (C) 2004 Elsevier Inc. All rights reserved.

    DOI: 10.1016/j.bbrc.2004.03.163

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  • Rotenone induces disassembly of the Golgi apparatus in the rat dopaminergic neuroblastoma B65 cell line

    FJ Diaz-Corrales, M Asanuma, Miyazaki, I, N Ogawa

    NEUROSCIENCE LETTERS   354 ( 1 )   59 - 63   2004年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCI IRELAND LTD  

    It has been reported that the Golgi apparatus (GA) is fragmented in some neurodegenerative diseases. However, the significance of the GA fragmentation or disassembly in neurodegeneration is still obscure. To clarify the involvement of this organelle in apoptosis of neuronal cells, we examined the morphological changes in the GA induced by rotenone, a pesticide that produces selective dopaminergic neurodegeneration. In dopaminergic neuroblastoma B65 cells, a 5-day rotenone treatment (50 nM) promoted cell damage. Rotenone-treated cells showed round nuclei, diffuse signals of the GA and cytosolic redistribution of cytochrome c. Nevertheless, these type of cells without nuclear fragmentation did not show any caspase-3 expression. These results indicate that rotenone induces disassembly of the GA in the early stages of the apoptotic process. (C) 2003 Elsevier Ireland Ltd. All rights reserved.

    DOI: 10.1016/j.neulet.2003.09.059

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  • 心不全における酸化ストレスの関与-基礎的ならびに臨床的検討

    中村一文, 草野研吾, 垣下幹夫, 三浦 綾, 久松研一, 西井伸洋, 伴場主一, 渡辺敦之, 藤尾栄起, 宮地克維, 永瀬 聡, 森田 宏, 斎藤博則, 江森哲郎, 浅沼幹人, 宮崎正博, 中村陽一, 松原広己, 大江 透

    岡山医学会雑誌   116,9-16   2004年

  • Mechanisms of cell death in Parkinson's disease

    Norio Ogawa, Masato Asanuma, Ko Miyoshi

    Japanese Journal of Clinical Medicine   62   1629 - 1634   2004年

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  • パーキンソン病における細胞死の機序.

    小川紀雄, 浅沼幹人, 三好 耕

    日本臨床   62,1629-1634   2004年

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  • Neuroprotective effects of nonsteroidal anti-inflammatory drugs on neurodegenerative diseases

    M Asanuma, Miyazaki, I, N Ogawa

    CURRENT PHARMACEUTICAL DESIGN   10 ( 6 )   695 - 700   2004年

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    記述言語:英語   出版者・発行元:BENTHAM SCIENCE PUBL LTD  

    It is well known that nonsteroidal anti-inflammatory drugs (NSAIDs) possess anti-inflammatory, analgesic and antipyretic properties by inhibiting cyclooxygenase (COX), a prostaglandin-synthesizing enzyme. It has also been revealed that NSAIDs exert inhibitory effects on the generating system of nitric oxide radicals and modulating effects on transcription factors which are related to inflammatory reactions including cytokine expression. Recently, a number of studies have been conducted focusing on the neuroprotective effects of NSAIDs, since it has been reported that inflammatory processes are associated with the pathogenesis of several neurodegenerative diseases including Alzheimer's disease and Parkinson's disease. In the experimental model of Parkinson's disease, NSAIDs have also exerted neuroprotective effects which are based not only on their COX-inhibiting effects but also on other properties: inhibitory effects on nitric oxide synthesis, action as agonists for peroxisome proliferator-activated receptor gamma, and some unknown pharmacological effects. In this article, various pharmacological effects of NSAIDs except their inhibitory action on COX are reviewed, and possible neuroprotective effects of NSAIDs have been discussed on neurodegenerative diseases, especially Parkinson's disease.

    DOI: 10.2174/1381612043453072

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  • Parkinson病薬物治療の将来 ―進行抑制薬実現の可能性.

    小川紀雄, 浅沼幹人, 田中健一

    医学のあゆみ   208,583-588   2004年

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  • 実験的パーキンソニズムに使われる薬剤.〜MPTP,6-ヒドロキシドパミンならびにロテノン〜.

    浅沼幹人, 宮崎育子, 小川紀雄

    医薬ジャーナル   40,111-116   2004年

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  • 遺伝子改変によるパーキンソン病モデル.

    浅沼幹人, 宮崎育子

    脳の科学   292,165-170   2004年

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  • 酸化ストレスとミトコンドリア機能障害,炎症反応.―孤発性パーキンソン病とドパミン神経毒研究から得たもの.

    浅沼幹人

    内科   93,611-615   2004年

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  • β遮断薬による心不全・不整脈治療の基礎と臨床ーカルベジロールを中心としてーβ遮断薬と酸化ストレス.

    中村一文, 垣下幹夫, 草野研吾, 三浦 綾, 久松研一, 永瀬 聡, 森田 宏, 斉藤博則, 江森哲郎, 浅沼幹人, 小川紀雄, 宮崎正博, 中村陽一, 松原広己, 伏見和郎, 豊國伸哉, 大江 透

    Jpn J Electrocardiology   2004年

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  • Direct evidence for increased angiotensin II-induced cardiac angiotensin II type hydroxyl radicals in hypertrophy through 1a receptor

    M Kakishita, K Nakamura, M Asanuma, H Morita, H Saito, K Kusano, Y Nakamura, T Emori, H Matsubara, T Sugaya, N Ogawa, T Ohe

    JOURNAL OF CARDIOVASCULAR PHARMACOLOGY   42   S67 - S70   2003年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

    Oxidative stress is known to contribute to numerous cardiac disease processes. However, the contribution of reactive oxygen species to cardiac hypertrophy has not yet been fully investigated. The aim of the present study was therefore to determine whether levels of reactive oxygen species were increased in angiotensin II-induced cardiac hypertrophy. We continuously administered angiotensin II (1.1 mg/kg per day) into wild-type and angiotensin 11 type-1a receptor knockout mice for 2 weeks. The angiotensin H treatment increased blood pressure and heart weight/body weight ratio in wild-type mice but not in knockout mice. The generation of hydroxyl radicals in heart tissue homogenate was directly assessed with electron spin resonance spectroscopy using a spin trapping agent, alphaphenyl-N-tert butylnitrone. Angiotensin II significantly increased hydroxyl radical production 2.2-fold (p &lt; 0.01) in the hearts of wildtype mice but not in knockout mice. The present study provided direct evidence for increased production of hydroxyl radicals in angiotensin II-induced cardiac hypertrophy through angiotensin 11 type-1a receptor. These findings in this study may provide important insights into the development of hypertrophy and the transition of hypertrophy to heart failure.

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  • Methamphetamine-induced neurotoxicity in mouse brain is attenuated by ketoprofen, a non-steroidal anti-inflammatory drug

    M Asanuma, T Tsuji, Miyazaki, I, K Miyoshi, N Ogawa

    NEUROSCIENCE LETTERS   352 ( 1 )   13 - 16   2003年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCI IRELAND LTD  

    We examined effects of non-steroidal anti-inflammatory drugs (NSAIDs) on methamphetamine (METH)-induced neurotoxicity. Marked reduction of dopamine transporter-positive signals and accumulation of microglial cells in the striatum after METH injections (4 mg/kg x 4, i.p. with 2 h-interval) were significantly and dose-dependently attenuated by four injections of ketoprofen (2 or 5 mg/kg X 4, s.c.) given 30 min prior to each METH injection, but not by either a low or high dose of aspirin. The present results suggest that the protective effects of ketoprofen against METH-induced neurotoxicity and microgliosis might be based on its inhibitory activity on inflammatory response or on microglia activation, but not on its cyclooxygenase-inhibiting property. This provides a possible new strategy against METH-induced neurotoxicity using commonly used NSAIDs. (C) 2003 Elsevier Ireland Ltd. All rights reserved.

    DOI: 10.1016/S0304-3940(03)01001-2

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  • Overexpression of Cu-Zn superoxide dismutase protects neuroblastoma cells against dopamine cytotoxicity accompanied by increase in their glutathione level

    ME Haque, M Asanuma, Y Higashi, Miyazaki, I, K Tanaka, N Ogawa

    NEUROSCIENCE RESEARCH   47 ( 1 )   31 - 37   2003年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCI IRELAND LTD  

    Dopamine (DA) was shown to exert toxic effects on cultured neurons through autoxidation or oxidative deamination, followed by formation of highly reactive quinone compounds and superoxide radicals. In the present study, therefore, any involvement of Cu-Zn superoxide dismutase (SOD) in DA toxicity was evaluated by transfection of Cu-Zn SOD cDNA. The transient transfection of Cu-Zn SOD cDNA inhibited the DA-induced decrease of dopaminergic neuroblastoma cells. Moreover, Cu-Zn SOD cDNA-transfection significantly increased the glutathione (GSH) level when the cells were exposed to DA. However, such Cu-Zn SOD-overexpression failed to show any protective effects against hydrogen peroxide. The Cu-Zn SOD-overexpressing cells also showed significantly higher levels of GSH upon DA exposure than did the empty vector-transfected cells. The increase in the GSH level in response to hydrogen peroxide remained almost identical in empty vector-transfected or Cu-Zn SOD-overexpressed cells. The level of GSH in DA-treated Cu-Zn SOD-overexpressing cells was 2.5-fold higher than that increased by hydrogen peroxide exposure. The catechol structure of DA molecule is probably involved in the mechanism of increasing GSH level. Furthermore, the Cu-Zn SOD-overexpressing cells inhibited the activation of caspase-3 upon DA exposure. Therefore, Cu-Zn SOD overexpression may temporarily inhibit or delay DA autoxidation and consequently increase the GSH level, which then prevents the activation of apoptotic pathway and subsequent cell death. (C) 2003 Elsevier Science Ireland Ltd and the Japan Neuroscience Society. All rights reserved.

    DOI: 10.1016/S0168-0102(03)00166-4

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  • Apoptosis-inducing neurotoxicity of dopamine and its metabolites via reactive quinone generation in neuroblastoma cells

    ME Haque, M Asanuma, Y Higashi, Miyazaki, I, K Tanaka, N Ogawa

    BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS   1619 ( 1 )   39 - 52   2003年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE BV  

    Neurotoxic properties Of L-dopa and dopamine (DA)-related compounds were assessed in human neuroblastoma SH-SY5Y cells with reference to their structural relationship. L-Dopa and its metabolites containing two free hydroxyl residues on their benzene ring showed toxicity in the cell, which was prevented by superoxide dismutase (SOD) and reduced glutathione (GSH), but not by catalase. Furthermore, a synthetic derivative of DA, 3-hydroxy-4-methoxyphenethylamine (HMPE) containing methoxy residue at position 4 in the benzene ring, exerted partial cytotoxicity, which was not prevented by SOD, GSH or catalase. However, the metabolites containing methoxy residue at position 3 failed to show a toxic effect in the SH-SY5Y cells. Moreover, DA induced apoptotic cell death, which was observed by nuclear and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) staining and measurement of caspase-3 activity; this compound up-regulated apoptotic factor p53 while down-regulating anti-apoptotic factor Bcl-2. In the cell-free in vitro electron spin resonance (ESR) spectrometry, DA possessing two hydroxyl groups showed generation of DA-semiquinone radicals, which were markedly prevented by addition of SOD or GSH but not by catalase. On the other hand, methylation of one of the hydroxyl residues on the benzene ring of DA converted DA to an unoxidizable compound (3-MT or HMPE), and caused it to lose the property to produce serniquinione radicals. It has been previously reported that SOD acting as a superoxide: semiquitione oxidoreductase prevents quinone formation, and that reduced GSH through forming a complex with DA-quinone prevents quinone binding to the thiol group of the intact protein. Therefore, the present results suggest that DA and its metabolites containing two hydroxyl residues exert cytotoxicity mainly due to generation of highly reactive quinones. (C) 2002 Elsevier Science B.V. All rights reserved.

    DOI: 10.1016/S0304-4165(02)00440-3

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  • Dopamine- or L-DOPA-induced neurotoxicity: The role of dopamine quinone formation and tyrosinase in a model of Parkinson's disease

    M Asanuma, Miyazaki, I, N Ogawa

    NEUROTOXICITY RESEARCH   5 ( 3 )   165 - 176   2003年

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    記述言語:英語   出版者・発行元:F P GRAHAM PUBLISHING CO  

    Dopamine (DA)- or L-dihydroxyphenylalanine- (L-DOPA-) induced neurotoxicity is thought to be involved not only in adverse reactions induced by long-term L-DOPA therapy but also in the pathogenesis of Parkinson!s disease. Numerous in vitro and in vivo studies concerning DA- or L-DOPA-induced neurotoxicity have been reported in recent decades. The reactive oxygen or nitrogen species generated in the enzymatical oxidation or auto-oxidation of an excess amount of DA induce neuronal damage and/or apoptotic or non-apoptotic cell death; the DA-induced damage is prevented by various intrinsic and extrinsic antioxidants. DA and its metabolites containing two hydroxyl residues exert cytotoxicity in dopaminergic neuronal cells mainly due to the generation of highly reactive DA and DOPA quinones which are dopaminergic neuron-specific cytotoxic molecules. DA and DOPA quinones may irreversibly alter protein function through the formation of 5-cysteinyl-catechols on the proteins. For example, the formation of DA quinone-alpha-synuclein consequently increases cytotoxic protofibrils and the covalent modification of tyrosine hydroxylase by DA quinones. The melanin-synthetic enzyme tyrosinase in the brain may rapidly oxidize excess amounts of cytosolic DA and L-DOPA, thereby preventing slowly progressive cell damage by auto-oxidation of DA, thus maintaning DA levels. Since tyrosinase also possesses catecholamine-synthesizing activity in the absence of tyrosine hydroxylase (TH), the double-edged synthesizing and oxidizing functions of tyrosinase in the dopaminergic system suggest its potential for application in the synthesis of DA, instead of TH in the degeneration of dopaminergic neurons, and in the normalization of abnormal DA turnover in long-term L-DOPA-treated Parkinson's disease patients.

    DOI: 10.1007/BF03033137

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  • アルツハイマー病脳で減少しているgrowth inhibitory factor (GIF) の加齢にともなう変化.

    浅沼幹人, 宮崎育子, 東 洋一郎, 田中健一, 小川紀雄

    分子精神医学   2003年

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  • 非ステロイド性消炎鎮痛薬の神経保護作用の新展開.

    浅沼幹人, 宮崎育子, 辻 武史, 小川紀雄

    日本神経精神薬理学会雑誌   23, 111-119   2003年

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  • ドパミンおよびその誘導体のキノン体生成を介したアポトーシス誘導性.

    浅沼幹人, 宮崎育子, Haque ME, 東 洋一郎, 小川紀雄

    Prog Med   2003年

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  • The p53-activated gene, PAG608, requires a zinc finger domain for nuclear localization and oxidative stress-induced

    Y Higashi, M Asanuma, Miyazaki, I, ME Haque, N Fujita, K Tanaka, N Ogawa

    JOURNAL OF BIOLOGICAL CHEMISTRY   277 ( 44 )   42224 - 42232   2002年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC  

    The p53-activated gene PAG608, which encodes a nuclear zinc finger protein, is a p53-inducible gene that contributes to p53-mediated apoptosis. However, the mechanisms by which PAG608 is involved in the apoptosis of neuronal cells are still obscure. In this study, we demonstrated that expression of p53 was induced by 100 muM 6-hydroxydopamine (6-OHDA), accompanied by increased PAG608 expression in PC12 cells. On the other hand, transient or permanent transfection of antisense PAG608 cDNA into PC12 cells significantly prevented apoptotic cell death induced by 100 muM 6-OHDA or 200 muM hydrogen peroxide but not by 250 muM 1-methyl-4phenylpyridinium ion. The 6-OHDA-induced activation of caspase-3, DNA fragmentation, loss of mitochondria membrane potential, and induction of p53 and Bax were also prevented in PC12 cells that stably expressed antisense PAG608 cDNA. These results suggest that PAG608 is associated with the apoptotic pathway induced by these oxidative stress-generating reagents, upstream of the collapse in the mitochondrial membrane potential in PC12 cells. Interestingly, transient transfection with PAG608 cDNA increased p53 expression in both PC12 cells and B65 cells, indicating that PAG608 induced by p53 is able to induce p53 expression in these cells inversely. Furthermore, transient transfection of a truncated mutant PAG608 cDNA, lacking the first zinc finger domain, inhibited 6-OHDA-induced cell death and altered the nuclear and nucleolar localization of wild-type PAG608 in PC12 cells. These results suggest that PAG608 may induce or regulate p53 expression and translocate to the nucleus and nucleolus using its first zinc finger domain during oxidative stress-induced apoptosis of catecholamine-containing cells.

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  • Age-related changes in expression of metallothionein-III in rat brain

    Miyazaki, I, M Asanuma, Y Higashi, CA Sogawa, K Tanaka, N Ogawa

    NEUROSCIENCE RESEARCH   43 ( 4 )   323 - 333   2002年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCI IRELAND LTD  

    Metallothionein (MT)-III is a metal binding protein, called growth inhibitory factor, and is mainly expressed in the central nervous system. Since MT-III decreases in the brain of Alzheimer's disease (AD), a growing interest has been focused on its relationship to neurodegenerative diseases. To clarify age-related changes in the MT-III expression and its inducibility against oxidative stress, we analyzed the expression of MT-III and its mRNA in the brain of lipopolysaccharide (LPS)-treated aged rats. In the frontal cortex, basal expression of MT-III mRNA was significantly increased with aging, while it was observed no induction of MT-III mRNA against LPS administration in the aged rat brain. MT-III immunopositive cells were increased in the frontal, parietal and piriform cortices, hypothalamus and amygdaloid nucleus with aging. The LPS treatment induced MT-III expression in the brain of young-adult rats, but not in the aged rat brain. Furthermore, the MT-III induction with LPS treatment was mainly observed in oligodendrocyte and microglia. In the present study, we showed that inducibility of brain MT-III against oxidative stress may be reduced with aging. Since it has been reported that MT-III has neuroprotective roles as an antioxidant, present results suggest that MT-III is closely related to the neurodegeneration in the aged animals. (C) 2002 Elsevier Science Ireland Ltd and the Japan Neuroscience Society. All rights reserved.

    DOI: 10.1016/S0168-0102(02)00057-3

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  • The dopamine agonist cabergoline provides neuroprotection by activation of the glutathione system and scavenging free radicals

    M Yoshioka, K Tanaka, Miyazaki, I, N Fujita, Y Higashi, M Asanuma, N Ogawa

    NEUROSCIENCE RESEARCH   43 ( 3 )   259 - 267   2002年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCI IRELAND LTD  

    Free radicals are involved in the pathogenesis and/or progression of Parkinson's disease (PD). Several ergot derivative dopamine (DA) agonists have been reported to scavenge free radicals in vitro and to show a neuroprotective effect in vivo. We investigated the in vitro free radical scavenging and antioxidant activities of cabergoline, a long-acting ergot DA agonist, as well as its ability to activate glutathione (GSH), catalase (Cat) and superoxide dismutase (SOD) activating effects and its in vivo neuroprotective properties against 6-hydroxydopamine (6-OHDA) intracerebroventricularly (i.c.v.) in mice. The striatal DA turnover induced by i.c.v. injection of 6-OHDA was completely normalized by pretreatment with cabergoline. Moreover, cabergoline scavenged free radicals in vitro and significantly reduced lipid peroxidation in vitro and in vivo. Furthermore, daily administration of cabergoline to mice significantly increased striatal GSH levels by activation of RNA expressions of GSH-related enzymes, although striatal Cat and SOD activities did not change. In addition, our present results suggest that repeated administration of cabergoline attenuates both 6-OHDA-induced nigrostriatal DAergic dysfunction and DA neuronal cell death, since cabergoline also had a neuroprotective effect in the immunohistochemical experiment. In conclusion, our findings indicate that the multiple antioxidant mechanisms of cabergoline, such as activation of the GSH system and the direct free radical scavenging activity, may explain the neuroprotective effect of this ergot DA agonist. (C) 2002 Elsevier Science Ireland Ltd and the Japan Neuroscience Society. All rights reserved.

    DOI: 10.1016/S0168-0102(02)00040-8

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  • Aggravation of 6-hydroxydopamine-induced dopaminergic lesions in metal lothionein-I and -II knock-out mouse brain

    M Asanuma, Miyazaki, I, Y Higashi, K Tanaka, ME Haque, N Fujita, N Ogawa

    NEUROSCIENCE LETTERS   327 ( 1 )   61 - 65   2002年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCI IRELAND LTD  

    The effects of two major isoforms of metallothioneins (MTs), MT-I and -II, on dopaminergic neurotoxicity of 6-hydroxydopamine (6-OHDA) were examined using intracerebroventricularly 6-OHDA-injected MT-I, II knock-out (KO) mice. The loss of dopamine neurons in the substantia nigra pars compacta induced by the 6-OHDA injection was significantly aggravated in the MT-I, II KO mice, compared with that in the 6-OHDA-injected wild-type mice. The present results, taken together with the antioxidant properties of MT-I and -II suggest that MT-I and -II exert neuroprotective effects against the dopaminergic neurotoxicity of 6-OHDA at the nigral cell body by scavenging free radicals. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved.

    DOI: 10.1016/S0304-3940(02)00346-4

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  • Methamphetamine-induced increase in striatal p53 DNA-binding activity is attenuated in Cu,Zn-superoxide dismutase transgenic mice

    M Asanuma, Miyazaki, I, Y Higashi, JL Cadet, N Ogawa

    NEUROSCIENCE LETTERS   325 ( 3 )   191 - 194   2002年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCI IRELAND LTD  

    The striatal DNA-binding activities of p53 as a transcription factor were gradually increased at several days after a single methamphetamine (METH) injection, while they were more rapidly increased within several hours after repeated METH injections (x 4 with a 2 h interval). The elevation of striatal p53 DNA-binding after repeated METH injections was markedly attenuated in Cu,Zn-superoxide dismutase transgenic mice, but not affected by treatments with N-methyl-Daspartate or D1 receptor antagonists. The present results suggest that METH-induced production of reactive oxygen species activates striatal p53 DNA-binding activity; this, in turn, may activate other downstream pathways that are responsible for chronic neurotoxicity of METH. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved.

    DOI: 10.1016/S0304-3940(02)00291-4

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  • テトラサイクリン誘導体ミノサイクリンの種々の神経障害に対する保護作用.

    浅沼幹人

    ファルマシア   38,1105-1106   2002年

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  • ニューロメラニン合成酵素チロシナーゼのドパミン神経障害への関与.

    浅沼幹人, 東 洋一郎, 宮崎育子, 小川紀雄

    Prog Med   2002年

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  • Progressive cortical atrophy after forebrain ischemia in diabetic rats

    F Kondo, M Asanuma, Miyazaki, I, Y Kondo, K Tanaka, H Makino, N Ogawa

    NEUROSCIENCE RESEARCH   39 ( 3 )   339 - 346   2001年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCI IRELAND LTD  

    The morphological changes in the brain of diabetic rats were examined up to 8 weeks after transient forebrain ischemia produced by transient occlusion of both carotid arteries. Using histochemistry, we also examined the extent and rate of development of atrophic changes in the brain, appearance of astrocytes, activated microglia, and glucose transporter 1 (GLUT1) in streptozotocin-treated rat brains after forebrain ischemia. Atrophic changes appeared in the hippocampus in both non-diabetic- and diabetic-ischemic groups 4 weeks after ischemia. In diabetic-ischemic rats, the atrophic changes were more severe and progressed more rapidly in the hippocampus, and were also observed in the frontal, temporal and parietal cortices, but not in any cortical areas of the non-diabetic-ischemic rats and non-ischemic-diabetic rats. We observed reduced density of GLUT1 in all corticaI regions and hippocampus in ischemic-diabetic rats at 4-8 weeks, when the number of activated microglias and astroglias increased in all cortical regions. Although severe atrophic changes were observed in the gray matter, no serious injury was noted in the white matter in the diabetic-ischemic group. Our results indicate that brain ischemia in the presence of diabetes causes more severe late-onset damage culminating in brain atrophy, compared with non-diabetics. (C) 2001 Elsevier Science Ireland Ltd and the Japan Neuroscience Society. All rights reserved.

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  • Neuroprotective effects of non-steroidal anti-inflammatory drugs by direct scavenging of nitric oxide radicals

    M Asanuma, S Nishibayashi-Asanuma, Miyazaki, I, M Kohno, N Ogawa

    JOURNAL OF NEUROCHEMISTRY   76 ( 6 )   1895 - 1904   2001年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:BLACKWELL SCIENCE LTD  

    Recently, it has been reported that inflammatory processes are associated with the pathophysiology of Alzheimer's disease and that treatment of non-steroidal anti-inflammatory drugs reduce the risk for Alzheimer's disease. in the present study, we examined nitric oxide radical quenching activity of non-steroidal anti-inflammatory drugs;and steroidal drugs using our established direct in vitro nitric oxide radical detecting system by electron spin resonance spectrometry. The non-steroidal anti-inflammatory drugs, aspirin, mefenamic acid, indomethacin and ketoprofen directly and dose-dependently scavenged generated nitric oxide radicals, in experiments of nitric oxide radical donor, NOC18-induced neuronal damage, these four non-steroidal drugs significantly prevented the NOC18-induced reduction of cell viability and apoptotic nuclear changes in neuronal cells without affecting the induction of inducible nitric oxide synthase-like immunoreactivity. However, ibuprofen, naproxen or steroidal drugs, which had less or no scavenging effects in vitro showed almost no protective effects against NOC18-induced cell toxicity. These results suggest that the protective effects of the former four non-steroidal anti-inflammatory drugs against apoptosis might be mainly due to their direct nitric oxide radical scavenging activities in neuronal cells. These direct NO quenching activities represent novel effects of nonsteroidal anti-inflammatory drugs. Our findings identified novel pharmacological mechanisms of these drugs to exert not only their anti-inflammatory, analgesic, antipyretic activities but also neuroprotective activities against neurodegeneration.

    DOI: 10.1046/j.1471-4159.2001.00205.x

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  • Delta opioid peptide [D-Ala(2), D-Leu(5)]enkephalin causes a near complete blockade of the neuronal damage induced by a single high dose of methamphetamine: Examining the role of p53

    T Hayashi, H Hirata, M Asanuma, B Ladenheim, L Tsao, JL Cadet, TP Su

    SYNAPSE   39 ( 4 )   305 - 312   2001年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-LISS  

    The delta opioid peptide [D-Ala(2), D-Leu(5)]enkephalin (DADLE) has been reported to block the neurotoxicity induced by multiple administrations of a moderate dose of methamphetamine (METH). We examined in this study if DADLE might block the neurotoxicity caused by a single high dose of METH in CD-1 mice, The levels of dopamine transporter (DAT), tyrosine hydroxylase (TH), major biogenic amines including DA, 5-hydroxytryptamine (5-HT), and their metabolites were examined. In addition, since the tumor suppressor p53 has been implicated in the neurotoxicity of METH, this study also examined the levels of p53 mRNA and protein affected by METH and DADLE. METH (25 mg/kg, i.p.) caused significant losses of DAT, TH, DA, 3,4-dihydroxyphenylacetic acid (DOPAC), and 5-HT in the striatum within 72 h. The administration of a single dose of DADLE (20 mg/kg, i.p., 30 min before METH) caused a complete blockade of all losses induced by METH except for that of the DA content (a similar to 50% blockade). DADLE did not affect the changes of rectal temperature induced by the administration of the high dose of METH, METH increased p53 mRNA in the striatum and the hippocampus of CD-1 mouse. DADLE abolished the p53 mRNA increase caused by METH. METH tended to increase the p53 protein level at earlier time points. However, METH significantly decreased the p53 protein level by about 30% at the 72-h time point. DADLE blocked both the increase of p53 mRNA and the decrease of p53 protein caused by METH. These results demonstrate a neuroprotective effect of DADLE against the neuronal damage and the alteration of p53 gene expression caused by a single high dose of METH. The results also indicate an apparent discordance between the protein level of p53 and the neurotoxicity caused by a high dose of METH. Synapse 39:305-312, 2001, Published 2001 Wiley-Liss, Inc.dagger.

    DOI: 10.1002/1098-2396(20010315)39:4<305::AID-SYN1013>3.0.CO;2-E

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  • Localization, regulation, and function of metallothionein-III/growth inhibitory factor in the brain

    CA Sogawa, M Asanuma, N Sogawa, Miyazaki, I, T Nakanishi, H Furuta, N Ogawa

    ACTA MEDICA OKAYAMA   55 ( 1 )   1 - 9   2001年2月

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    記述言語:英語   出版者・発行元:OKAYAMA UNIV MED SCHOOL  

    The metallothionein (MT) family is a class of low molecular, intracellular, and cysteine-rich proteins with a high affinity for metals. Although the first of these proteins was discovered nearly 40 years ago, their functional significance remains obscure, Four major isoforms (MT-I, MT-II, MT-III, and MT-IV) have been identified in mammals. MT-I and MT-II are ubiquitously expressed in various organs including the brain, while expression of MT-III and MT-IV is restricted in specific organs. MT-III was detected predominantly in the brain, and characterized as a central nervous system-specific isomer, The role of MTs in the central nervous system has become an intense focus of scientific research. An isomer of MTs, MT-III, of particular interest, was originally discovered as a growth inhibitory factor, and has been found to be markedly reduced in the brain of patients with Alzheimer's disease and several other neurodegenerative diseases, MT-III fulfills unique biological roles in homeostasis of the central nervous system and in the etiology of neuropathological disorders.

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  • Molecular mechanism in activation of glutathione system by ropinirole, a selective dopamine D2 agonist

    K Tanaka, Miyazaki, I, N Fujita, ME Haque, M Asanuma, N Ogawa

    NEUROCHEMICAL RESEARCH   26 ( 1 )   31 - 36   2001年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:KLUWER ACADEMIC/PLENUM PUBL  

    We have previously reported that ropinirole, a non-ergot dopamine agonist, has neuroprotective effects against h-hydroxydopamine in mice based on in vivo antioxidant properties such as the glutathione (GSH)-activating effect. In the present study, we determined that the effects of ropinirole on the level of expression of GSH-related enzyme mRNA, these enzymes were shown to regulate GSH contents in the brain. This study focused on the mechanism of GSH enhancement by ropinirole. Striatal GSH contents were significantly increased by 7-day daily administration of ropinirole. Furthermore, the expression levels of gamma -glutamylcysteine synthetase (gamma -GCS), glutathione peroxidase (GPx), glutathione reductase (GR) and glutathione S-transferase (GST) mRNA increased following daily injections of ropinirole for 7 days. In addition, ropinirole treatment for 7 days suppressed auto-oxidation in mouse striatal homogenates, in contrast to the vehicle treatment. In conclusion, ropinirole was able to suppress auto-oxidation, most probably by increasing GSH levels due to an increase of GSH synthesis. In addition, it is likely that auto-oxidation was also suppressed by the activation of GSH-regulating enzymes such as GPx, GR, and GST in the mouse striatum. Thus, our results indicate that the GSH-activating effect of ropinirole may render this dopamine agonist beneficial as a neuroprotective drug.

    DOI: 10.1023/A:1007672414239

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  • フリーラジカルと脳障害.

    浅沼幹人, 小川紀雄

    Clin. Neurosci.   19,5,555-559   2001年

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  • 酸化ストレスと神経細胞死.

    小川紀雄, 浅沼幹人

    Clin. Neurosci.   19,6,665-667   2001年

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  • Immunophilin ligands prevent H2O2-induced apoptotic cell death by increasing glutathione levels in neuro 2A neuroblastoma cells

    K Tanaka, N Fujita, M Asanuma, N Ogawa

    ACTA MEDICA OKAYAMA   54 ( 6 )   275 - 280   2000年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:OKAYAMA UNIV MED SCHOOL  

    We examined the effects of FK506 and its non-immunosuppressive derivative, GPI1046, on H2O2-induced reduction of cell viability and apoptotic cell death in Neuro 2A cells. Our results suggest that the protective properties of GPI1046 against H2O2-induced reduction of cell viability are equipotent with those of FK506 and may be mediated by increased intracellular concentrations of glutathione (GSH). In addition, both FK506 and GPI1046 prevented apoptotic cell death in Neuro 2A cells, although the antiapoptotic effect of FK506 was somewhat stronger than that of GPI1046. These findings suggest that non-immunosuppressive immunophilin ligands such as GPI1046 might be potentially useful in treatment of neurodegenerative diseases without serious side effects such as immune deficiency.

    DOI: 10.18926/AMO/32278

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  • Expression of metallothionein-III mRNA and its regulation by levodopa in the basal ganglia of hemi-parkinsonian rats

    Miyazaki, I, CA Sogawa, M Asanuma, Y Higashi, K Tanaka, T Nakanishi, N Ogawa

    NEUROSCIENCE LETTERS   293 ( 1 )   65 - 68   2000年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCI IRELAND LTD  

    In the brain, metallothionein (MT)-III exhibits a free radical scavenging activity. Here we examined the expression of MT-III mRNA in the basal ganglia of 6-hydroxydopamine (6-OHDA)-lesioned hemi-parkinsonian rats and its regulation by levodopa. The level of MT-III mRNA was significantly decreased in the striatum of 6-OHDA-lesioned side. Levodopa treatment significantly increased the expression of striatal MT-III mRNA in the non-lesioned side, but showed no significant effect in the 6-OHDA-lesioned side. These results suggest that the regulation of MT-III mRNA may be related to the progressive degeneration in parkinsonism. (C) 2000 Published by Elsevier Science Ireland Ltd.

    DOI: 10.1016/S0304-3940(00)01488-9

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  • Inhibition of tyrosinase reduces cell viability in catecholaminergic neuronal cells

    Y Higashi, M Asanuma, Miyazaki, I, N Ogawa

    JOURNAL OF NEUROCHEMISTRY   75 ( 4 )   1771 - 1774   2000年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

    The biosynthesis of dopamine (DA) in catecholaminergic neurons is regulated by tyrosine hydroxylase, which converts tyrosine into 3,4-dihydroxyphenylalanine (L-DOPA). In melanocytes, tyrosinase catalyzes both the hydroxylation of tyrosine and the consequent oxidation of L-DOPA to form melanin. Although ii has been demonstrated that tyrosinase is also expressed in the brain. the physiological role of tyrosinase in the brain is stilt obscure. In this study. to investigate the role of tyrosinase in catecholaminergic neuronal cells, we examined the effects of tyrosinase inhibition on the viability of CATH,a and SH-SY5Y cells using tyrosinase inhibitors-specifically, phenylthiourea (PTU) and 5-hydroxyindole (5-HI)-and the transfection of antisense tyrosinase cDNA. Both inhibitors significantly reduced the cell viability of CATH.a cells in a dose-dependent manner. PTU also specifically enhanced DA-induced cell death, but 5-HI did not. This discrepancy in cell death is probably due to the inhibitors' different mechanism of action: 5-HI inhibits the hydroxylation or tyrosine as a competitor for the substrate to induce cell death that may be due to depletion of DA, whereas PTU mainly inhibits the enzymatic oxidation of L-DOPA and DA rather than tyrosine hydroxylation to increase consequently autooxidation of DA. Indeed. the intracellular DA content in CATH.a cells was enhanced by PTU exposure. In contrast, PTU showed no enhancing effects on DA-induced cell death of SH-SY5Y cells, which express little tyrosinase. Furthermore. transfection with antisense tyrosinase cDNA into CATH.a cells dramatically reduced cell viability and significantly enhanced DA-induced cell death. These results suggest that tyrosinase controls the intracellular DA content by biosynthesis or enzymatic oxidation of DA, and the dysfunction of this activity induces cell death by elevation of intracellular DA level and consequent gradual autooxidation of DA to generate reactive oxygen species.

    DOI: 10.1046/j.1471-4159.2000.0751771.x

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  • Direct interactions of methamphetamine with the nucleus

    M Asanuma, T Hayashi, SV Ordonez, N Ogawa, JL Cadet

    MOLECULAR BRAIN RESEARCH   80 ( 2 )   237 - 243   2000年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE BV  

    Possible direct effects of methamphetamine (METH) on transcription factors AP-1 and cAMP response element-binding. protein (CREB) in the nucleus were assessed by electrophoretic mobility-shift assay. In vitro addition of METH to nuclear extract from brain tissue increased DNA-binding activities of both transcription factors. In addition, injections of METH to mice induced increases in the binding of AP-I and CREB, which were depleted by preincubating the nuclear extract with anti-METH antibody. We also examined the cellular distribution of METH in mesencephalic neuronal cells using an immunofluorescence experiment with anti-METH antibody. METH-like immunoreactivity was seen to accumulate in the cytosol 4-6 h after the METH treatment. Furthermore, METH-positive signals were also observed in the nuclei of the: METH-treated cells. The present study is the first demonstration that METH can have direct effects on DNA-binding protein complex by redistributing not only in the cytosol but also into the nucleus. (C) 2000 Elsevier Science B.V. All rights reserved.

    DOI: 10.1016/S0169-328X(00)00128-5

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  • Bromocriptine markedly suppresses levodopa-induced abnormal increase of dopamine turnover in the parkinsonian striatum

    N Ogawa, K Tanaka, M Asanuma

    NEUROCHEMICAL RESEARCH   25 ( 6 )   755 - 758   2000年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:KLUWER ACADEMIC/PLENUM PUBL  

    Bromocriptine, a dopamine agonist, is commonly used in combination with levodopa for the treatment of Parkinson's disease (PD). To investigate the theoretical basis of such combination therapy, we examined the effects of bromocriptine administered alone or in combination with levodopa on dopamine turnover in the striatum of hemi-parkinsonism rats. The parkinsonian striatum showed a 3.4-fold increase of dopamine turnover relative to the control striatum, as often observed in the brain of PD patients. A 7-day course of levodopa therapy markedly increased dopamine turnover in the parkinsonian striatum (53-fold of control level) than in the control striatum (5-fold of the control level). However, bromocriptine specifically and markedly suppressed the levodopa-induced abnormal activation of dopamine turnover in the parkinsonian striatum. Our findings explain the pharmacological basis for the introduction of bromocriptine during long-term levodopa therapy.

    DOI: 10.1023/A:1007530720544

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  • Protective effect of oren-gedoku-to against induction of neuronal death by transient cerebral ischemia in the C57BL/6 mouse

    Y Kondo, F Kondo, M Asanuma, K Tanaka, N Ogawa

    NEUROCHEMICAL RESEARCH   25 ( 2 )   205 - 209   2000年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:KLUWER ACADEMIC/PLENUM PUBL  

    We examined the neuroprotective effects of oren-gedoku-to (TJ15), a herbal medicine, after transient forebrain ischemia. Transient forebrain ischemia was induced by occlusion of both common carotid arteries for 15 min in C57BL/6 mice treated with TJ15. In the control ischemic group without TJ15 treatment, histologic examination of brain tissue collected seven days after reperfusion showed death of pyramidal cells in CA2-3 area of the hippocampus, unilaterally or bilaterally. In mice treated with oral TJ15 (845 mg/kg/day) for five weeks, the frequency of ischemic neuronal death was significantly lower. Immunohistochemistry for Cu/Zn-superoxide dismutase (Cu/Zn-SOD) showed strongly reactive astrocytes in the hippocampus of ischemic mice treated with TJ15. Damage to nerve cells by free radicals plays an important role in the induction of neuronal death by ischemia-reperfusion injury. Our results suggest that TJ15 protects against ischemic neuronal death by increasing the expression of Cu/Zn-SOD and suggest that oren-gedoku-to reduces the exposure of hippocampal neurons to oxidative stress.

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  • Antioxidants protect against dopamine-induced metallothionein-III (GIF) mRNA expression in mouse glial cell line (VR-2g)

    CA Sogawa, Miyazaki, I, N Sogawa, M Asanuma, N Ogawa, H Furuta

    BRAIN RESEARCH   853 ( 2 )   310 - 316   2000年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE BV  

    Metallothionein (MT)-III, originally discovered as a growth inhibitory factor (GIF), is a brain specific isomer of MTs and is markedly reduced in the brain of patients with Alzheimer's disease (AD) or other neurodegenerative diseases. We analyzed the level and regulation of mRNA expression of MT-III in immortalized fetal mouse brain glial cells (VR-2g) by reverse transcriptase-polymerase chain reaction (RT-PCR). We have recently reported that dopamine (DA) increases the expression of MT-III mRNA in vitro. In this study, we investigated the mechanism of such increase by examining the effects of DA agonists (SKF38393 or bromocriptine) and DA antagonists (SCH23390 or sulpiride) on the expression of MT-III mRNA. MT-III mRNA did not change by either agonist and DA-increased MT-III mRNA was not inhibited by either antagonist. These results suggested that the induction of MT-III mRNA by DA was not mediated by stimulation of DA receptors. On the other hand, DA-induced MT-III mRNA expression was strongly inhibited by the addition of antioxidants (glutathione, vitamin E or ascorbic acid), indicating thar DA-enhanced MT-III mRNA was mediated by reactive oxygen species. Our results suggest that oxidative stress may be one of the principle factors that modulate MT-III mRNA expression. (C) 2000 Elsevier Science B.V. All rights reserved.

    DOI: 10.1016/S0006-8993(99)02284-2

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  • フリーラジカルと神経細胞死.

    浅沼幹人, 小川紀雄

    Clinical Neuroscience   18: 415-417   2000年

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  • Bifemelane hydrochloride protects against cytotoxicity of hydrogen peroxide on cultured rat neuroblastoma cell line

    Miyazaki, I, E Iwata-Ichikawa, M Asanuma, M Iida, N Ogawa

    NEUROCHEMICAL RESEARCH   24 ( 7 )   857 - 860   1999年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:KLUWER ACADEMIC/PLENUM PUBL  

    Free radicals are involved in neuronal damage. Bifemelane hydrochloride has been reported to protect neural tissues against ischemic damage and age-related neurodegeneration. We examined the protective effects of bifemelane HCl and the relation between its effectiveness and free radical formation in hydrogen peroxide (H2O2)-induced cytotoxicity using cultured rat neuroblastoma cell line (B50). Cytotoxicity was examined by using the lactate dehydrogenase (LDH) assay and cell viability by the WST-1 assay. H2O2 reduced the survival of B50 cells in a dose-dependent manner, and treatment of these cells with 75 mu M or 100 mu M H2O2 reduced their viability by 50% relative to the control group. B50 cells were treated with 5 or 10 mu M bifemelane for 2 days followed by treatment with 75 mu M or 100 mu M H2O2 H2O2 cytotoxicity was reduced by pretreatment with bifemelane. We also examined the effect of bifemelane on lipid peroxide formation in B50 cells using thiobarbituric acid reactive substances assay. Pretreatment of B50 cells with 10 mu M bifemelane for 2 days reduced lipid peroxide formation to approximately 54% of the control group. Our results suggest that bifemelane hydrochloride provides a protective effect against H2O2 cytotoxicity partly due to its anti-oxidative properties.

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  • Glial cells protect neurons against oxidative stress via transcriptional up-regulation of the glutathione synthesis

    E Iwata-Ichikawa, Y Kondo, Miyazaki, I, M Asanuma, N Ogawa

    JOURNAL OF NEUROCHEMISTRY   72 ( 6 )   2334 - 2344   1999年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

    We examined the effects of oxidative stress on rat cultured mesencephalic neurons and glial cells. Glial cells were more resistant to g-hydroxydopamine (6-OHDA) and H2O2 toxicity than neurons. In glial cells, incubation with 6-OHDA and H2O2 induced a significant increase in the expression of gamma-glutamylcysteine synthetase (the rate-limiting enzyme in glutathione synthesis) mRNA, which correlated well with increased TPA-response element (TRE)-binding activity. Furthermore, a subsequent elevation in cellular total glutathione content was also observed. In neurons, both agents decreased TRE-binding activity, and these cells failed to up-regulate the glutathione synthesis. We also examined the mechanisms of the neuroprotective effects of glial cells using a glia conditioned medium. Neurons maintained in glia conditioned medium up-regulated the level of TRE-binding activity, gamma-glutamylcysteine synthetase mRNA expression, and total glutathione content in response to 6-OHDA or H2O2, and became more resistant to both agents than cells maintained in a normal medium. Neurons maintained in normal medium failed to up-regulate the glutathione synthesis. Our results suggest that transcriptional up-regulation of glutathione synthesis in glial cell appears to mediate brain glial cell resistance against oxidative stress, and that glial cells protect neurons via transcriptional up-regulation of the antioxidant system.

    DOI: 10.1046/j.1471-4159.1999.0722334.x

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  • Nitric oxide modulates muscarinic acetylcholine receptor binding in the cerebral cortex of gerbils

    M Gomez-Vargas, M Asanuma, S Nishibayashi-Asanuma, E Iwata, N Ogawa

    NEUROCHEMICAL RESEARCH   24 ( 5 )   629 - 635   1999年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:KLUWER ACADEMIC/PLENUM PUBL  

    To determine whether nitric oxide (NO) acts as a modulator of muscarinic acetylcholine receptor (mACh-R) function, we performed a radioligand receptor assay using [H-3]quinuclidinyl benzylate ([H-3]QNB), the NO radical (NO .) donor 3-(2-Hydroxy-1-methyl-2-nitrosohydrazino)N-methyl-1-propanamine (NOC7) and a gerbil brain cortical membrane preparation. NOC7 (at 10 mu M, 100 mu M or 1 mM concentrations) significantly reduced the [H-3]QNB binding K-d values (from 0.196 +/- 0.009 nM in the control, to 0.151 +/- 0.013, 0.144 +/- 0.012 and 0.153 +/- 0.007 nM respectively). NOC7 did not alter the displacement curves of atropine or carbachol. Reduction of SH groups with dithiothreitol, in the presence of the NO donor, significantly increased [H-3]QNB binding affinity whereas alkylation by N-ethylmaleimide markedly decreased it. The observed enhancing effect on mACh-R binding affinity for [H-3]QNB, may reflect conformational changes in the receptors mediated by the NO generated, and these changes might be explained by NO reactions with such groups through conditions supporting redox reactions intrinsic to the NO molecule, similar to those occurring in redox regulatory sites reported for other neurotransmitter pathways in the CNS.

    DOI: 10.1023/A:1021044107323

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  • Early treatment with cyclosporin A ameliorates the reduction of muscarinic acetylcholine receptors in gerbil hippocampus after transient forebrain ischemia

    Y Kondo, M Asanuma, E Iwata, F Kondo, Miyazaki, I, N Ogawa

    NEUROCHEMICAL RESEARCH   24 ( 1 )   9 - 13   1999年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:KLUWER ACADEMIC/PLENUM PUBL  

    Recent evidence has suggested that cyclosporin A (CsA), an immunosuppressive agent, has neuroprotective properties. However, its mechanisms associated with this activity remain unclear. We have previously shown that post-ischemic administration of CsA daily for 14 days prevented the decrease of muscarinic acetylcholine receptor binding in the hippocampus in the gerbil model of 5-min transient forebrain ischemia. In the present study, CsA (5 mg/kg, subcutaneously) was administered to each animal just after, 2 and 6 h after ischemia so as not to exert its immunosuppressive effect. Initial CsA treatment significantly restored the declined muscarinic acetylcholine receptor binding of the hippocampus 14 days after ischemia similar to the previous report. However, CsA. did not alter reactive changes of astrocytes and microglia in the CA1 area of the hippocampus, which had been suppressed by daily administration. These results indicate that CsA could positively modulate the hippocampal acetylcholine neurotransmission system broken down through the ischemia-induced pyramidal cell death and its action mechanism may have no relation to the immunosuppressive properties.

    DOI: 10.1023/A:1020915727119

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  • パーキンソン病と活性酸素・窒素種.

    浅沼幹人, 小川紀雄

    神経研究の進歩   43: 264-274   1999年

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  • Neural transplantation normalizes dopaminegic dysfunction in an animal model of Parkinson's disease.

    Ogawa, N, Mizukawa, K, Nishino, H, Asanuma, M, Yamamoto, M

    J. Brain Sci.   25   133 - 138   1999年

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  • Chronic cerebral hypoperfusion disrupts discriminative behavior in acquired-learning rats

    K Tanaka, N Wada, K Hori, M Asanuma, M Nomura, N Ogawa

    JOURNAL OF NEUROSCIENCE METHODS   84 ( 1-2 )   63 - 68   1998年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE BV  

    We describe an 'acquired-learning' rat model that was used to investigate the effects of chronic cerebral hypoperfusion on the maintenance of previously acquired discriminative behavior using the discriminating learning task. Male Wistar rats, aged 11 weeks, were trained to discriminate between lamp-on and lamp-off states under an operant-type learning procedure. After 30 sessions, we selected 'acquired-learning' rats with an average discrimination ratio higher than 75% recorded during the last three sessions. Chronic hypoperfusion was then induced by permanent ligation of both common carotid arteries under pentobarbital anesthesia. The rats were tested after surgery over a period of 12 weeks and brain tissue was analyzed for muscarinic acetylcholine receptor (mACh-R) binding. Cerebral hypoperfusion resulted in a significant reduction in the discrimination ratio throughout the observation period, compared with sham-operated rats. However, chronic hypoperfusion would not affect on motor function. The maximum number of mACh-R examined 12 weeks after the operation was significantly reduced in the frontal cortex and hippocampus in the hypoperfusion group. Impaired discrimination learning was associated with a reduction in mACh-R. Our findings suggest that chronic cerebral hypoperfusion in acquired-learning rats is a useful model for investigating the pathophysiology of dementia and that cortical and/or hippocampal cholinergic systems contributes to learning impairment, at least, in our learning task. (C) 1998 Elsevier Science B.V. All rights reserved.

    DOI: 10.1016/S0165-0270(98)00092-2

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  • Melatonin attenuates methamphetamine-induced toxic effects on dopamine and serotonin terminals in mouse brain

    H Hirata, M Asanuma, JL Cadet

    SYNAPSE   30 ( 2 )   150 - 155   1998年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-LISS  

    Methamphetamine (METH) is a drug of abuse that causes deleterious effects to brain monoaminergic systems. These toxic effects are thought to be due to oxidative stress. The pineal hormone, melatonin, has been shown to have neuroprotective effects against toxic quinones and oxidative stress produced by catecholamines. The present study was thus undertaken to assess possible protective effects of melatonin against METH-induced neurotoxic effects on the striatum and the nucleus accumbens by using autoradiographic techniques. Four dosages (5, 20, 40, 80 mg/kg) of melatonin were administered to mice intraperitoneally 30 minutes prior to the injections of METH (4 x 5 mg/kg) given at 2-hour intervals. The lowest doses of melatonin (5 mg/kg) had no significant effects against METH-induced toxicity. However, the higher doses (40 or 80 mg/kg) of melatonin significantly attenuated METH-induced toxic effects on both dopamine and serotonin systems. These data provide further evidence for a possible role of oxidative stress in METH-induced toxicity. Synapse 30:150-155, 1998. (C) Wiley-Liss, Inc.(dagger)

    DOI: 10.1002/(SICI)1098-2396(199810)30:2<150::AID-SYN4>3.0.CO;2-B

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  • Methamphetamine-induced increase in striatal NF-κB DNA-binding activity is attenuated in superoxide dismutase transgenic mice.

    Asanuma, M, Cadet, J.L

    Mol. Brain Res.   60 ( 2 )   305 - 309   1998年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/S0169-328X(98)00188-0

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  • Attenuation of 6-hydroxydopamine-induced dopaminergic nigrostriatal lesions in superoxide dismutase transgenic mice

    M Asanuma, H Hirata, JL Cadet

    NEUROSCIENCE   85 ( 3 )   907 - 917   1998年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PERGAMON-ELSEVIER SCIENCE LTD  

    6-Hydroxydopamine is a neurotoxin that produces degeneration of the nigrostriatal dopaminergic pathway in rodents. Its toxicity is thought to involve the generation of superoxide anion secondary to its autoxidation. To examine the effects of the overexpression of Cu,Zn-superoxide dismutase activity on 6-hydroxydopamine-induced dopaminergic neuronal damage, we have measured the effects of 6-hydroxydopamine on striatal and nigral dopamine transporters and nigral tyrosine hydroxylase-immunoreactive neurons in Cu,Zn-superoxide dismutase transgenic mice. Intracerebroventricular injection of 6-hydroxydopamine (50 mu g) in non-transgenic mice produced reductions in the size of striatal area and an enlargement of the cerebral ventricle on both sides of the brains of mice killed two weeks after the injection. In addition, 6-hydroxydopamine caused marked decreases in striatal and nigral [I-125]RTI-121-labelled dopamine transporters not only on the injected side but also on the non-injected side of non-transgenic mice; this was associated with decreased cell number and size of tyrosine hydroxylase-immunoreactive dopamine neurons in the substantia nigra pars compacta on both sides in these mice. In contrast, superoxide dismutase transgenic mice were protected against these neurotoxic effects of 6-hydroxydopamine, with the homozygous transgenic mice showing almost complete protection.
    These results provide further support for a role of superoxide anion in the toxic effects of 6-hydroxydopamine. They also provide further evidence that reactive oxygen species may be the main determining factors in the neurodegenerative effects of catecholamines.

    DOI: 10.1016/S0306-4522(97)00665-9

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  • Superoxide radicals are mediators of the effects of methamphetamine on Zif268 (Egr-1, NGFI-A) in the brain: evidence from using CuZn superoxide dismutase transgenic mice

    H Hirata, M Asanuma, JL Cadet

    MOLECULAR BRAIN RESEARCH   58 ( 1-2 )   209 - 216   1998年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE BV  

    Administration of methamphetamine (METH) to mammals is known to cause deleterious effects to brain monoaminergic systems. These toxic effects are thought to be due to oxidative stress. Acute administration of METH causes activation of immediate-early genes (IEGs) such as c-fos and Zif268 mRNA in rodent brains. However, the exact mechanisms involved in these changes have not been completely clarified. As a first step towards assessing a possible role for free radicals in METH-induced changes in IEGs, we have used CuZn superoxide dismutase (SOD) transgenic (Tg) mice and have quantified the effects of METH on c-fos and Zif268 mRNAs by in situ hybridization techniques. Mice were injected with 25 mg/kg of METH and sacrificed at various time points afterwards. There were significant METH-induced increases in both c-fos and Zif268 mRNAs in the frontal cortex and striatum of both strains of animals. interestingly, the increases in Zif268 were markedly attenuated in the CuZn SOD-Tg mice; the increases in c-fos were also attenuated, but to a significantly lesser degree. These results indicate that superoxide radicals might play an important role in the activation of Zif268 after METH administration. Because IEGs are modulators of gene expression, these results also raise the possibility that oxidative mechanisms might be important factors in neuroadaptive changes caused by stimulant drugs. (C) 1998 Elsevier Science B.V. All rights reserved.

    DOI: 10.1016/S0169-328X(98)00055-2

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  • Protective effects of nicergoline against hydrogen peroxide toxicity in rat neuronal cell line

    E Iwata, Miyazaki, I, M Asanuma, A Iida, N Ogawa

    NEUROSCIENCE LETTERS   251 ( 1 )   49 - 52   1998年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCI IRELAND LTD  

    We examined the effects of nicergoline on hydrogen peroxide (H2O2)-induced neurotoxicity in cultured rat neuronal cell line (B50). H2O2 induced death of B50 cells in a dose-dependent manner. The H2O2-induced neuronal cell death was significantly decreased in B50 cells maintained in the presence of nicergoline. We compared the levels of antioxidants (glutathione, catalase and superoxide dismutase) in nicergoline-treated and untreated B50 cells. Lipid peroxidation products (thiobarbituric acid reactive substances, TEARS) levels were also measured. Cultures treated with nicergoline had higher levels of catalase activity. TEARS level was significantly lower in nicergoline-treated cells than in untreated cells. Our results suggest that nicergoline may induce the up-regulation of intracellular antioxidant defences and protect the neuronal cells against oxidative stress. (C) 1998 Elsevier Science ireland Ltd. All rights reserved.

    DOI: 10.1016/S0304-3940(98)00489-3

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  • Pergolide scavenges both hydroxyl and nitric oxide free radicals in vitro and inhibits lipid peroxidation in different regions of the rat brain

    M Gomez-Vargas, S Nishibayashi-Asanuma, M Asanuma, Y Kondo, E Iwata, N Ogawa

    BRAIN RESEARCH   790 ( 1-2 )   202 - 208   1998年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE BV  

    The free radical hypothesis for the pathogenesis and/or progression of Parkinson's disease (PD) has gained wide acceptance in recent years. Although it is clear that dopamine (DA) agonists cannot completely replace levodopa therapy, they can be beneficial early in the course of PD by reducing the accumulation of DA which undergoes auto-oxidation and generates cytotoxic free radicals. In the present study we demonstrate that pergolide, a widely used DA agonist, has free radical scavenging and antioxidant activities. Using a direct detection system for nitric oxide radical (NO .) by electron spin resonance (ESR) spectrometry in an in vitro . NO-generating system, we examined the quenching effects of pergolide on the amount of NO . generated. Pergolide dose-dependently scavenged NO .. In the competition assay, the IC50 value for pergolide was estimated to be about 30 mu M. Pergolide also dose-dependently attenuated the hydroxyl radical(OH) signal in an in vitro FeSO4-H2O2 ESR system with an approximate IC50 value of 300 mu M. Furthermore, this agent significantly inhibited phospholipid peroxidation of rat brain homogenates in in vitro experiments and after repeated administration (0.5 mg/kg/24 h, i.p. for 7 days). Our findings suggest a neuroprotective role for pergolide on dopaminergic neurons due to its free radical scavenging and antioxidant properties. (C) 1998 Elsevier Science B.V.

    DOI: 10.1016/S0006-8993(97)01521-7

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  • Manda, a fermented natural food, suppresses lipid peroxidation in the senescent rat brain

    M Kawai, S Matsuura, M Asanuma, N Ogawa

    NEUROCHEMICAL RESEARCH   23 ( 4 )   455 - 461   1998年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PLENUM PUBL CORP  

    The level of lipid peroxidation reflects the degree of free radical-induced oxidative damage in brain tissue of the elderly. We examined the effects of Manda, a product prepared by yeast fermentation of several fruits and black sugar, on lipid peroxidation in the senescent rat brain as model of aging. Senescent rats were provided with a diet containing 50 g/100 g Manda for 8 days, supplemented on day 8 with an intragastric administration of Manda (6.0 g/kg body wt.) twice daily. The hydroxyl radical scavenging activity was generated by the FeSO4-H2O2 system and analyzed by electron spin resonance spectrometry. Using this method, the addition of Manda (2.88 mg/ml) to brain homogenates of adult rats (0.06 mg/ml) had an additive inhibitory effect on lipid peroxidation compared with control adult rats not treated with Manda. Incubation of brain homogenates with Manda for 2 h and 3 h, significantly inhibited the increase in Lipid peroxides (malondialdehydes and 4-hydroxyalkenals) levels in aged rats due to auto-oxidation. In addition, oral administration of Manda significantly suppressed the age-related increase in lipid peroxidation in the hippocampus and striatum, although such change was not observed in the cerebral cortex. Although Manda contains trace level of alpha-tocopherol, the level of alpha-tocopherol in Manda did no correlate with its antioxidant effect. Our results suggest that Manda protects against age-dependent oxidative neuronal damage caused by oxidative stress and that this protective effect may be due, in part, to its scavenging activity against free radicals.

    DOI: 10.1023/A:1022475830587

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  • Effects of repeated cyclosporin A administration on iminodipropionitrile-induced dyskinesia and TRE-/CRE-binding activities in rat brain

    K Iida, E Iwata, M Asanuma, SN Asanuma, M Gomez-Vargas, Miyazaki, I, T Nakanishi, N Ogawa

    NEUROSCIENCE RESEARCH   30 ( 2 )   185 - 193   1998年2月

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    記述言語:英語   出版者・発行元:ELSEVIER SCI IRELAND LTD  

    To clarify the involvement of immunophilin ligands in the pathogenesis and pathophysiology of dyskinesia, we examined the effects of repeated administration of cyclosporin A (CsA) on rat dyskinesia induced by repeated injection of iminodipropionitrile (IDPN 100 mg/kg, i.p., for 7 days). The addition of CsA treatment (5 mg/kg, s.c., 1 h before each IDPN injection) exacerbated IDPN-induced dyskinesia. In the group treated with both CsA and IDPN, the concentration of dopamine was significantly increased in the striatum and nucleus accumbens compared with the group treated with IDPN alone. Furthermore, in the electrophoretic mobility shift assay, the injection of CsA + IDPN increased binding activities of transcription factors to the TPA (12-O-tetradecanoylphorbol-13-acetate)-responsive element (TRE) and to the cAMP response element (CRE) in the striatum and nucleus accumbens, compared with those in rats treated with IDPN alone. The levels of D-1-receptor mRNA in the striatum were significantly decreased in the IDPN-treated rats but were at the control level in the rats given CsA + IDPN. These findings suggest that the behavioral aggravation of the IDPN-induced dyskinesia caused by CsA administration may be due to the acceleration of the pre- and post-synaptic dopaminegic systems via activation of transcription factors which bind upstream to tyrosine hydroxylase and D-1-receptor genes, and that the immunophilin binding agents such as CsA are involved in this aggravated dyskinesia. (C) 1998 Elsevier Science Ireland Ltd. All rights reserved.

    DOI: 10.1016/S0168-0102(97)00128-4

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  • ホスホジエステラーゼ

    浅沼幹人

    生体の科学   49   499 - 501   1998年

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  • Parkinson病とNO.

    小川紀雄, 浅沼幹人

    Clinical Neuroscience   16   806 - 808   1998年

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  • Dantrolene sodium reverses the increase in cAMP response element and TPA responsive element DNA-binding activity in the rabbit brain following haloperidol administration and heat stress

    H Tanii, N Taniguchi, Tsujio, I, M Asanuma, E Iwata, T Kudo, N Ogawa, M Takeda

    PSYCHIATRY AND CLINICAL NEUROSCIENCES   51 ( 6 )   415 - 419   1997年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:BLACKWELL SCIENCE  

    Using electrophoretic mobility-shift assay (EMSA), we examined DNA-binding activity of cAMP response element (CKE), onto its responsive element CKE, as well as TPA responsive element (TRE) in the medial hypothalamus and striatum of the experimental rabbits administered with haloperidol under heat stress exposure and studied the effects of dantrolene sodium to the transcriptional factor. In EMSA with nuclear extracts from the rabbit brain, the DNA-binding activities of CKE and TRE in medial hypothalamus and striatum increased following haloperidol and heat stress. These increases were maintained by coadministration with atropine. The treatment with dantrolene sodium markedly reversed such increases. The alterations of activities of these transcriptional factors may reflect the therapeutic effect of dantrolene sodium.

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  • Effects of lecithinized superoxide dismutase on traumatic brain injury in rats

    M Yunoki, M Kawauchi, N Ukita, Y Noguchi, S Nishio, Y Ono, S Asari, T Ohmoto, M Asanuma, N Ogawa

    JOURNAL OF NEUROTRAUMA   14 ( 10 )   739 - 746   1997年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:MARY ANN LIEBERT INC PUBL  

    Only small amounts of superoxide dismutase (SOD) are present in the extracellular space to scavenge excess amounts of superoxide anions (O2(-)) released after traumatic brain injury (TBI). Experiments were performed in rats with cerebral contusion produced by weight-drop technique. We investigated the effects of exogenous lecithinized SOD (PC-SOD) on accumulation of O2(-) produced in our model, by measuring the level of SOD activity (using the NBT-reducing method) and the expression of copper, zinc-SOD (Cu, Zn-SOD) mRNA (by Northern blot analysis). As determined by tissue-specific gravity, administration of PC-SOD reduced brain edema in the periphery of the lesion 6 h after contusion. SOD activity increased in the peripheral region at 30 min after contusion, but returned to normal levels at 6 h after TBI. Administration of PC-SOD increased SOD activity up to 6 h after TBI. The expression of Cu, Zn-SOD mRNA increased in the core region, peripheral portion, and contralateral hemisphere up to 6 h after TBI, then was suppressed in all three regions by PC-SOD. Our results confirm the important role of O2(-) in the development of brain edema after TBI and indicate that PC-SOD diminishes brain edema through a protective effect against O2(-).

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  • Different effects of oxidative stress on activation of transcription factors in primary cultured rat neuronal and glial cells

    E Iwata, M Asanuma, S Nishibayashi, Y Kondo, N Ogawa

    MOLECULAR BRAIN RESEARCH   50 ( 1-2 )   213 - 220   1997年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE BV  

    We compared the cytotoxic effects of oxidative stress on neuronal and glial cells in vitro by examining the cell viability and changes in DNA-binding activities of transcription factors, AP-1 and CREB, using Trypan blue exclusion and electrophoretic mobility shift assay (EMSA), respectively. Neurotoxin 6-hydroxydopamine (6-OHDA) and H2O2 reduced the viability of both types of cells in time- and concentration-dependent manner. Both neurotoxins dose-dependently decreased DNA-binding activities in neuronal cells. The results of cell viability assay suggested that these changes may reflect the reduction in neuronal cell viability. In contrast, both reagents increased DNA-binding activities in glial cells, although they decreased cell numbers. These results suggest that the effects of oxidative stress on transcription factors is different in neuronal and glial cells. We also examined the effect of brain-derived neurotrophic factor (BDNF) on 6-OHDA- or H2O2-induced changes in DNA-binding activities. In neuronal cells, pre-treatment with BDNF prevented the decrease in DNA-binding activities induced by 6-OHDA or H2O2. In glial cells, the effect of BDNF on oxidative stress-induced changes in DNA-binding activities in the 6-OHDA-treated group were opposite to those in H2O2-treated group. Our results suggest that 6-OHDA and H2O2 may exert their cytotoxic mechanisms through different signal transduction systems. (C) 1997 Elsevier Science B.V.

    DOI: 10.1016/S0169-328X(97)00190-3

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  • Late-onset lipid peroxidation and neuronal cell death following transient forebrain ischemia in rat brain

    Y Kondo, M Asanuma, S Nishibayashi, E Iwata, N Ogawa

    BRAIN RESEARCH   772 ( 1-2 )   37 - 44   1997年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE BV  

    We previously reported that iron deposition was seen in the cerebral cortex and hippocampal CA1 area late after transient forebrain rated by four-vessel occlusion in rats. Iron deposition in the hippocampal CA1 area was coupled with delayed pyramidal cell death, while that in the cerebral cortex was not accompanied by neuronal death or atrophy until 6 months after ischemia. Iron is involved in the formation of free radicals, thus contributing to lipid peroxidation. To elucidate whether this iron has deleterious effects on neurons, we investigated changes in the levels of lipid peroxidation and resulting neuronal damage in this ischemia model. The level of malondialdehyde plus 4-hydroxynonenal as major decomposition products of lipid peroxidation, monitored for 6 months beginning just after 30 min of transient forebrain ischemia, was significantly increased in the cerebral cortex at 6 months, and in the striatum from 1 week to 6 months compared to that in sham-operated controls. Histological changes were also examined up to 1 year after reperfusion by immunohistochemical methods. In contrast with the hippocampus and striatum, the cerebral cortex did not develop severe neuronal cell death and atrophy until 1 year after the ischemic insult. We showed that lipid peroxidation took place not only immediately after ischemia-reperfusion but also late after the ischemic insult in regions where iron was deposited, and we showed that neuronal cell death in the cerebral cortex appeared extremely late, suggesting that iron-mediated lipid peroxidation may be of importance in some slowly progressive forms of neurodegeneration. (C) 1997 Elsevier Science B.V.

    DOI: 10.1016/S0006-8993(97)00836-6

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  • Genetic association between susceptibility to Parkinson's disease and alpha(1)-antichymotrypsin polymorphism

    M Yamamoto, Kondo, I, N Ogawa, M Asanuma, Y Yamashita, Y Mizuno

    BRAIN RESEARCH   759 ( 1 )   153 - 155   1997年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE BV  

    The apolipoprotein E (ApoE*) gene is a major risk factor of developing Alzheimer's disease (AD) and the alpha(1)-antichymotrypsin (ACT) polymorphism is likely to modify susceptibility of the ApoE* gene for AD. Because pathogenesis of AD is partly similar to that in idiopathic Parkinson's disease (PD), we investigated the distribution of genotypes of the ApoE and the ACT in patients with PD. The number of individuals with two copies of the ACT-A allele (ACT-AA genotype) in patients with PD increased significantly compared to that in healthy controls (19.9% versus 8.3%, P &lt; 0.02), and the ACT-A allele frequency in patients with PD was significantly higher than that in healthy controls (chi(2) = 5.96, df = 1, P &lt; 0.015). The odds ratio for developing PD in individuals with the ACT-AA genotype was 3.36 compared to individuals with two copies of another allele, the ACT-T allele (ACT-TT genotype). There was no association between ApoE genotypes and susceptibility to PD. These data suggest that the etiological basis of PD might be partly similar to that of AD and the ACT gene might be one of the susceptibility factors for PD.

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  • Thyrotropin releasing hormone prevents abnormalities of cortical acetylcholine and monoamines in mice following head injury

    K Tanaka, N Ogawa, M Asanuma, Y Kondo

    REGULATORY PEPTIDES   70 ( 2-3 )   173 - 178   1997年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE BV  

    We investigated the effects of thyrotropin releasing hormone (TRH) on changes in cortical concentrations of acetylcholine (ACh) and monoamines produced by concussion in mice. Concussion was induced by dropping a metal rod on the head, and the concentration of ACh, norepinephrine (NE), dopamine (DA) and serotonin (5-HT) in the cerebral cortex were measured by HPLC. We also examined the arousal effects of 0.5 mg/kg of TRH and 0.015 mg/kg of L-pyro-2-aminoadipyl-histidyl-thiazolidine-4-carboxamide (MK-771), a TRH analogue, injected intraperitoneally 10 min before concussion, on neurotransmitter concentrations. Mice were sacrificed at 25 (representing the righting reflex time) and 210 s (representing spontaneous movement time). At 25 s after concussion, the concentration of ACh was significantly higher than in control mice, but pretreatment with TRH and MK-771 prevented the rise in ACh. In contrast, head injury significantly reduced NE concentration. TRH and MK-771 also prevented the fall in NE. Concussion did not change cortical concentrations of DA and 5-HT. Our results suggest that disturbances of consciousness produced by concussion may be due to increased ACh and diminished NE in the cerebral cortex. Our findings also suggest that the arousal effects of TRH on concussion-induced disturbances of consciousness are due to normalization of cortical cholinergic and noradrenergic neuronal systems. (C) 1997 Elsevier Science B.V.

    DOI: 10.1016/S0167-0115(97)01013-6

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  • Direct evidence of high DNA binding activity of transcription factor AP-1 in rheumatoid arthritis synovium

    H Asahara, K Fujisawa, T Kobata, T Hasunuma, T Maeda, M Asanuma, N Ogawa, H Inoue, T Sumida, K Nishioka

    ARTHRITIS AND RHEUMATISM   40 ( 5 )   912 - 918   1997年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:LIPPINCOTT-RAVEN PUBL  

    Objective. To investigate the possible activation of transcription factor AP-1 in rheumatoid arthritis (RA) and its involvement in the pathogenesis of RA.
    Methods. Synovial tissues and peripheral blood samples were obtained from 25 patients with RA and 5 patients with osteoarthritis (OA) during arthroplasty and synovectomy. The synovial tissue was digested with collagenase and separated into adherent and nonadherent cells by plastic-adhesion methods, Nuclear extracts obtained from each sample were examined by electrophoretic mobility shift assay to determine the DNA binding activity of AP-1. The expression of c-fos and c-jun messenger RNA (mRNA) was examined by in situ reverse transcription assay.
    Results. A markedly high DNA binding activity of AP-1 was detected in the synovial tissues of RA patients, while virtually no activity or only a little activity was observed in OA patients, Following separation of adherent and nonadherent cells, the AP-1 activity was mainly detected in adherent cells, which consisted of synovial cells and macrophages. However, the activity was significantly higher in the mononuclear cells infiltrating into RA synovium than in RA peripheral blood mononuclear cells, The high DNA binding activity of AP-1 in RA correlated with the expression of c-fos and c-jun mRNA in situ. Furthermore, AP-1 binding activity also correlated with disease activity.
    Conclusion. In RA synovium, AP-1 DNA binding activity was constitutively up-regulated. These findings suggest that AP-1 may play an important role in the pathogenesis of RA, including synoival hyperplasia and abnormal immune responses.

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  • Ketoprofen, a non-steroidal anti-inflammatory drug prevents the late-onset reduction of muscarinic receptors in gerbil hippocampus after transient forebrain ischemia

    M Asanuma, SN Asanuma, M GomezVargas, M Yamamoto, N Ogawa

    NEUROSCIENCE LETTERS   225 ( 2 )   109 - 112   1997年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCI IRELAND LTD  

    Ischemia-induced hippocampal late-onset reduction of muscarinic acetylcholine receptors (LORMAR) begins as late as 7 days after transient forebrain ischemia in the gerbil, but it precedes to completion of neuronal death in the CA1 region. We previously reported that post-ischemic administration of cyclosporin A prevented LORMAR with suppression of astroglial and microglial activation. In the present study, we showed that the chronic post-ischemic administration of a non-steroidal anti-inflammatory drug, ketoprofen (5 mg/kg, subcutaneously, twice a day for 14 days) significantly reduced LORMAR both 14 days and 21 days after the 5-min transient ischemia. This protective effect of ketoprofen against LORMAR suggests that the non-steroidal anti-inflammatory drugs is clinically efficacious in the treatment of LORMAR, a sequela of cerebral ischemia. (C) 1997 Elsevier Science Ireland Ltd.

    DOI: 10.1016/S0304-3940(97)00204-8

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  • Chronic administration of Oren-gedoku-to (TJ15) inhibits ischemia-induced changes in brain indoleamine metabolism and muscarinic receptor binding in the mongolian gerbil

    H Kabuto, M Asanuma, S Nishibayashi, M Iida, N Ogawa

    NEUROCHEMICAL RESEARCH   22 ( 1 )   33 - 36   1997年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PLENUM PUBL CORP  

    We examined the effect of Oren-gedoku-to (TJ15), which is a traditional herbal Kampo prescription used as an anti-cerebral apoplexy agent on these changes. Chronic pre- and post-ischemia TJ15 oral administration almost completely abolished the ischemia-induced muscarinic receptor reduction and 5-hydroxyindoleacetic acid level increase. These results suggest that TJ15 prevents cholinergic synaptic dysfunction and serotonergic presynaptic hyperactivity induced by transient ischemia.

    DOI: 10.1023/A:1027369119224

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  • 神経細胞死と活性酸素・フリーラジカル..

    小川紀雄, 近藤洋一, 岩田恵美, 浅沼幹人, 飯田基之

    フリーラジカルの臨床   11   101 - 106   1997年

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  • Protective effects of FK506 on the late-onset reduction of muscarinic acetylcholine receptors in gerbil hippocampus after transient forebrain ischemia

    S Nishibayashi, Y Kondo, M Asanuma, E Iwata, M GomezVargas, N Ogawa

    JOURNAL OF BRAIN SCIENCE   23 ( 1 )   33 - 40   1997年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:JAPAN BRAIN SCI SOC  

    Late-onset reduction of muscarinic acetylcholine receptors (LORMAR) in the ischemic gerbil hippocampus begins as late as 7 days after a 5-min transient forebrain ischemia and reperfusion. We previously reported that LORMAR is prevented by postadministration of cyclosporin A. In the present study, we aim to elucidate whether the LORMAR can also be prevented by post-ischemic administration of the immunosuppressant FK506 (tacrolimus). We investigated changes in muscarinic acetylcholine receptor binding capacity and histological examination in the transient forebrain ischemic gerbil hippocampus and the effect of this agent on these changes. In the ischemic vehicle-treated group, muscarinic acetylcholine receptors significantly decreased in the hippocampus as the LORMAR with subsequent disruption of the pyramidal cells in the CA1 area. On the other hand, LORMAR is prevented by daily subcutaneous administration of low dose of FK506 (0.5 mg/kg/day) for 10 days after the ischemic insult, although delayed neuronal cell death was not prevented. Thus, we showed that the LORMAR is attenuated by post-administration of FK506.

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  • Effects of lecithinized SOD on contusion injury in rats

    M Yunoki, Y Noguchi, S Nishio, Y Ono, M Kawauchi, S Asai, T Ohmoto, M Asanuma, N Ogawa

    BRAIN EDEMA X   70   182 - 184   1997年

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    記述言語:英語   掲載種別:研究論文(国際会議プロシーディングス)   出版者・発行元:SPRINGER-VERLAG WIEN  

    To analyze the effect of lecithinized superoxide dismutase (SOD) on superoxide accumulation after traumatic injury, the expression of Cu,Zn-SOD mRNA was examined after contusion in rat using Northern blotting. As determined by specific gravity, lecithinized SOD decreased brain edema. The expression of Cu,Zn-SOD mRNA increased at the core, peripheral and contralateral hemisphere of injury. These increases were then suppressed by lecithinized SOD. Our results support the hypothesis that superoxide may play an important role in edema formation after contusion, and that lecithinized SOD appears to prevent brain edema through a protective effect against superoxide injury.

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  • 脳内転写制御因子CREB, AP-1のDNA結合活性に及ぼすドパミンレセプター作用薬の影響.

    浅沼幹人

    Prog. Med.   17   423 - 430   1997年

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  • Aniracetam ameriorates impaired pre-and post-synaptic cholinergic indices in gerbil hippocampus induced by transient forebrain ischemia.

    Kondo, Y, Asanuma, M, Kabuto, H, Iwata, E, Kondo, F, Miyazaki, I, Ogawa, N

    J. Brain Sci.   23   250 - 260   1997年

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  • Scavenging effects of dopamine agonists on nitric oxide radicals

    S Nishibayashi, M Asanuma, R Kohno, M GomezVargas, N Ogawa

    JOURNAL OF NEUROCHEMISTRY   67 ( 5 )   2208 - 2211   1996年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:LIPPINCOTT-RAVEN PUBL  

    It has recently been considered that free radicals are closely involved in the pathogenesis of Parkinson's disease (PD), and the level of nitric oxide radical (. NO), one of the free radicals, is reported to increase in PD brain. In the present study, we established a direct detection system for . NO in an in vitro . NO-generating system using 3-(2-hydroxy-1-methylethyl-2-nitrosohydrazino)-N-methyl-1 -propanamine as an . NO donor and 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl 3-oxide (carboxy-PTIO) by electron spin resonance (ESR) spectrometry acid examined the quenching effects of the dopamine agonists pergolide and bromocriptine on the amount of . NO generated. . NO appeared to be scavenged by pergolide and, to a lesser extent, by bromocriptine. In the competition assay, the 50% inhibitory concentration values for pergolide acid bromocriptine were estimated to be similar to 23 and 200 mu M respectively. It was previously reported that in vivo treatment of pergolide and bromocriptine completely protected against the decrease in levels of striatal dopamine and its metabolites in the B-hydroxydopamine-injected mouse. Considering these findings, pergolide and probably bromocriptine may also protect against dysfunction of dopaminergic neurons because of its multiple effects; not only does it stimulate the presynaptic autoreceptors, but it also directly scavenges . NO radicals and hence protects against . NO-related cytotoxicity. This ESR spectrometry method using carboxy-PnO may be useful for screening other drugs that can quench . NO.

    DOI: 10.1046/j.1471-4159.1996.67052208.x

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  • Alterations of cAMP response element-binding activity in the aged rat brain in response to administration of rolipram, a cAMP-specific phosphodiesterase inhibitor

    M Asanuma, S Nishibayashi, E Iwata, Y Kondo, T Nakanishi, MG Vargas, N Ogawa

    MOLECULAR BRAIN RESEARCH   41 ( 1-2 )   210 - 215   1996年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE BV  

    Transcription factor, cAMP response element-binding protein (CREB), which is phosphorylated by cAMP-dependent kinase via an increase in cAMP, and regulates gene transcription by binding to the cAMP response element (CRE) on target genes. We examined age-dependent alterations in the DNA-binding activity of CREB in rat brain regions, and the effects of rolipram, a cAMP-specific phosphodiesterase (PDE) inhibitor on the CRE-binding activity by electrophoretic mobility-shift assay (EMSA). A marked age-dependent decrease in the CRE-binding activity was shown in all brain regions examined, especially in the basal forebrain, the striatum and the hippocampus. Furthermore, CRE-binding activities in the basal forebrain of both young-adult and aged rats significantly increased 2 h after rolipram administration (1 mg/kg, i.p.), and the rolipram treatment recovered the decreased CRE-binding activity in the aged rats. The saturation experiment in EMSA also revealed that rolipram reversed the decrease in the maximum CRE-bindings in the basal forebrain with aging. Since the 5' upstream region of the rat choline acetyltransferase (ChAT) gene contains CRE, and ChAT-positive neurons in the basal forebrain project to the frontal cortex and the hippocampus, rolipram may exert its previously reported ameliorating effect on the age-related reductions of ChAT activities in the frontal cortex and the hippocampus by phosphorylating CREB in the basal forebrain with activation of cAMP-dependent protein kinase via inhibition of PDE.

    DOI: 10.1016/0169-328X(96)00098-8

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  • Relationship between cholinergic dysfunction and discrimination learning disabilities in Wistar rats following chronic cerebral hypoperfusion

    K Tanaka, N Ogawa, M Asanuma, Y Kondo, M Nomura

    BRAIN RESEARCH   729 ( 1 )   55 - 65   1996年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE BV  

    The effects of chronic hypoperfusion of cerebral blood flow (CBF) on central cholinergic indices and intellectual functions were investigated in rats. Male Wistar rats, aged 9 weeks, were anesthetized with pentobarbital, and the bilateral common carotid arteries were permanently ligated. Cortical CBF in the hypoperfused rats was markedly decreased at 6 weeks after the operation. In the hypoperfused group, cholinergic indices were changed to consist two phases after the operation, before (acute) and after (chronic) 6 weeks after the operation. At 6 weeks, choline acetyltransferase activity was restored to the sham-operated level compared with the changes in the frontal cortex and thalamus + midbrain at 3 weeks. On the other hand, the maximum number of muscarinic acetylcholine receptors was reduced in the frontal cortex, hippocampus and striatum at 6 weeks and thereafter remained at this low level. In discrimination learning task, the percentage of correct responses in the hypoperfused rats was generally reduced in contrast with that of the sham-operated rats, although the number of total responses were not changed. As a consequence, cholinergic dysfunctions correlate with discrimination learning disabilities in the hypoperfused rats. These findings suggest that the hypoperfused rat may be useful for the cerebrovascular type dementia model to clarify pathophysiology.

    DOI: 10.1016/S0006-8993(96)00400-3

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  • Effects of bromocriptine on dopamine turnover with or without levodopa

    N Ogawa, M Asanuma, K Tanaka, K Matsuura, K Iida, M Yamamoto

    JOURNAL OF INTERNATIONAL MEDICAL RESEARCH   24 ( 3 )   271 - 277   1996年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:CAMBRIDGE MED PUBL  

    Bromocriptine, a dopamine agonist, alleviates symptoms of Parkinson's disease, even when administered alone, and is used for its treatment. Better therapeutic effects are, however, achieved when bromocriptine is used in combination with levodopa. In this study, we examined the biochemical changes caused by bromocriptine administration with and without levodopa, and evaluated the effects of the treatments on dopamine turnover in the mouse striatum. Results show that dopamine turnover is suppressed by the administration of bromocriptine alone with a slight decrease in the amount of dopamine, and dopamine turnover is very strongly promoted by the administration of levodopa. When the two drugs are administered together, bromocriptine enhances the levodopa-induced increase in dopamine turnover in the striatum. These findings indicate that bromocriptine therapy in combination with levodopa enhances the dopaminergic function and suggest that the combination therapy of bromocriptine and levodopa shows good efficacy. The results of this study may, thus, provide a theoretical basis for the combination therapy of bromocriptine and levodopa.

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  • Expression of mRNA encoding neurotrophic factors and its regulation in a hybrid neuronal cell line

    T Nakanishi, K Ishii, N Fukushima, M Asanuma, E Iwata, N Ogawa

    BIOCHEMISTRY AND MOLECULAR BIOLOGY INTERNATIONAL   38 ( 4 )   763 - 772   1996年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ACADEMIC PRESS AUST  

    In a cultured hybrid neuronal cell line (BIM) which was produced between human neuroblastoma cells (IMR32) and thymidine auxotrophs (B3T) of rat nerve-like cells (B103), the mRNAs encoding ciliary neurotrophic factor (CNTF) and neurotrophins were detected by the polymerase chain reaction method. The conditioned medium of BIM cells enhanced choline acetyltransferase (ChAT) activity in septal neurons and survival of-ciliary ganglion neurons. The mRNA expression of CNTF and neurotrophins in BIM cells was differently regulated by the stimulation with cAMP, FGF and retinoic acid. These data suggest multiple regulation and collaboration of neurotrophic factors.

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  • Preventive effects of bifemelane hydrochloride on decreased levels of muscarinic acetylcholine receptor and its mRNA in a rat model of chronic cerebral hypoperfusion

    Y Kondo, N Ogawa, M Asanuma, K Matsuura, S Nishibayashi, E Iwata

    NEUROSCIENCE RESEARCH   24 ( 4 )   409 - 414   1996年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCI IRELAND LTD  

    Changes in muscarinic acetylcholine receptor (mACh-R) binding and muscarinic cholinergic ml receptor (ml-R) mRNA levels were determined in a rat model of cerebral hypoperfusion in which hypoperfusion was induced by permanent bilateral occlusion of the common carotid arteries. After 6 weeks of hypoperfusion, mACh-R binding activity was significantly reduced in the frontal cortex (79.0%, P &lt; 0.01), striatum (74.2%, P &lt; 0.01) and hippocampus (78.6%, P &lt; 0.01), and the ml-R mRNA levels in the frontal cortex (86.6%, P &lt; 0.05) and striatum (89.4%, P &lt; 0.05) compared with sham-operated control. Repeated administration of bifemelane hydrochloride (15 mg/kg/day, p.o., once a day from the day of operation for 6 weeks) prevented the hypoperfusion-induced loss of mACh-R binding and ml-R mRNA levels above described. Since the central cholinergic systems play an important role in learning and memory, these findings suggest that bifemelane hydrochloride is useful to treat and/or prevent vascular dementia which is closely related to cerebral hypoperfusion.

    DOI: 10.1016/0168-0102(95)01017-3

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  • Long-term time course of regional changes in cholinergic indices following transient ischemia in the spontaneously hypertensive rat brain

    N Ogawa, M Asanuma, K Tanaka, H Hirata, Y Kondo, M Goto, M Kawauchi, T Ogura

    BRAIN RESEARCH   712 ( 1 )   60 - 68   1996年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE BV  

    Using an animal model of forebrain ischemia in spontaneously hypertensive rats (SHR) by 3-h bilateral carotid occlusion, and various indices of the cerebral cholinergic system were assessed for periods up to 24 weeks. The lesions observed histologically in the hippocampus of SHR 2 weeks after ischemia were less severe than those in the frontal cortex. Marked elevation of acetylcholine concentration was transiently observed in the frontal cortex, hippocampus and thalamus + midbrain at 2 weeks, and in the striatum at 1-4 weeks after ischemia. Choline acetyltransferase activity remained unchanged in all regions throughout the experimental period except for a minimal decrease in the frontal cortex at 4 weeks. Choline esterase (ChE) activity was slightly decreased in the frontal cortex at 2-4 weeks after ischemia but recovered by 8 weeks. A decrease in the hippocampus was seen at 8 weeks. The B-max for the M1-receptor was significantly reduced by 2 weeks in the frontal cortex and by 4 weeks in the hippocampus. Low B-max values in both regions persisted through week 24. These delayed hippocampal changes in the ChE activity and M1-receptor in SHR were similar to those of the very much delayed changes in M1-receptor previously reported in the gerbil model for transient ischemia. In contrast, Wistar-Kyoto rats (WKY), used as normotensive controls, exhibited no histological or biochemical changes for up to 24 weeks. The difference between SHR and WKY may depend on the more severe cerebral blood flow depletion during carotid ligation in the former. The chronic state of SHR after the transient ischemia may be a useful pathophysiological model for human cerebral infarctions with hypertension.

    DOI: 10.1016/0006-8993(95)01446-2

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  • L-DOPA合剤の変更による老齢パーキンソン病患者の問題症状の改善

    浅沼幹人

    老化と疾患   9   521 - 525   1996年

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  • Age-related changes in composition of transcription factor, AP-1 complex in the rat brain

    M Asanuma, Y Kondo, S Nishibayashi, E Iwata, T Nakanishi, N Ogawa

    NEUROSCIENCE LETTERS   201 ( 2 )   127 - 130   1995年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCI IRELAND LTD  

    We examined age-related changes in composition of transcription factor, activator protein-1 (AP-I) which binds to TPA responsive element (TRE) in the non-stimulated rat brain, using electrophoretic mobility-shift assay with immunodepletion/supershift assay. The total TRE-binding activity in the frontal cortex and the hippocampus of the aged rats markedly decreased to 66% and 43%, respectively, and TRE-bindings of AP-1 in both regions also decreased to 82% and 66%, respectively, with aging. Jun-Jun dimers accounted for approximately half of the total TRE-bindings and 80-90% of the AP-1 bindings, while there were fewer Fos-Jun dimers, in both examined regions of the non-stimulated adult. The proportion of active Fos-Jun heterodimers in the frontal cortex increased to up to half of the AP-1 bindings in the aged rats, indicating that cortical AP-1-related transcription may increase with aging even under the non-stimulated condition. In the hippocampus, inactive Jun-Jun homodimers became predominant in AP-1 with aging. This regional diversity of age-related changes in the composition of AP-1 in the brain may be related to changes or dysfunction in neuronal signal transduction in the aged.

    DOI: 10.1016/0304-3940(95)12152-8

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  • High DNA-binding activity of transcription factor NF-κB in synovial membranes of patients with rheumatoid arthritis. arthritis.

    Asahara, H, Asanuma, M, Ogawa, N, Nishibayashi, S, Inoue, H

    Biochem. Mol. Biol. Int.   37 ( 5 )   827 - 832   1995年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

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  • EFFECTS OF SINGLE CYCLOSPORINE-A PRETREATMENT ON PENTYLENETETRAZOL-INDUCED CONVULSION AND ON TRE-BINDING ACTIVITY IN THE RAT-BRAIN

    M ASANUMA, S NISHIBAYASHI, Y KONDO, E IWATA, M TSUDA, N OGAWA

    MOLECULAR BRAIN RESEARCH   33 ( 1 )   29 - 36   1995年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE BV  

    Using electrophoretic mobility-shift assay (EMSA), we examined changes in DNA-binding activities of transcriptional factor-activated protein-1 (AP-1), which is a Fos-Jun protein complex, onto its responsive element TRE in the hippocampus and amygdaloid nucleus of rats stimulated with pentylenetetrazol (PTZ) injection, and also investigated the effects of a single administration of the immunosuppressant cyclosporin A (CsA). In EMSA with nuclear extracts from the rat brain, the TRE-binding activity of AP-1 in the hippocampus and amygdaloid nucleus markedly increased 2 h after the PTZ injection (75 mg/kg, i.p.). These PTZ-induced increases of the TRE-binding protein in these regions were completely suppressed by pretreatment with CsA (5 mg/kg, s.c.) 1 h before the PTZ injection. In addition, the administration of CsA significantly ameliorated PTZ-induced convulsion. This therapeutic effect of single CsA pretreatment may be based, in part, on the effects on the TRE-binding activity of AP-1 ih the brain. Since single pretreatment of CsA in the present study had no effect on the PTZ-induced induction of c-fos mRNA, c-jun mRNA, Fos protein nor Jun protein, the inhibitory effects of single CsA administration an PTZ-induced TRE-binding activity in the brain may be related to the effects of CsA on AP-1 itself. These results suggest that an immune response via activation of transcriptional factor in the brain tissue is involved in the convulsion.

    DOI: 10.1016/0169-328X(95)00102-X

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  • M(1) RECEPTORS IN BLOOD PRESSURE-CONTROLLED ISCHEMIC SPONTANEOUSLY HYPERTENSIVE RATS

    H HIRATA, M ASANUMA, K TANAKA, Y KONDO, N OGAWA

    STROKE   26 ( 7 )   1268 - 1272   1995年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER HEART ASSOC  

    Background and Purpose Hypertension is a primary aggravating factor in cerebral infarction. An acute rise in blood pressure (BP) at the time of a stroke may be harmful to the brain in a hypertensive subject because both cerebral vascular structure and function are altered by hypertension. Muscarinic M(1) receptors are concerned with memory and learning. We aimed to evaluate the effect of controlling BP in hypertensive subjects at the time of stroke with a biochemical index of brain damage.
    Methods We gave a single dose of either the antihyperten sive ct-blocker phentolamine (2 mg/kg IP) or the calcium antagonist nicardipine (2 mg/kg IP) at the start of bilateral carotid artery occlusion to spontaneously hypertensive rats undergoing 3 hours of transient ischemia; we measured the time course of mean BP (MBP) and changes in the M(1) receptor and its mRNA in three brain regions 2 weeks after the transient ischemia.
    Results Administration of phentolamine or nicardipine not only significantly suppressed the ischemia-induced rise of MBP, it actually decreased MBP during ischemia. In an ischemic control group, M(1) receptor binding decreased in the frontal cortex and M(1) receptor mRNA increased in the hippocampus 2 weeks after the ischemia. In contrast, both phentolamine- and nicardipine-treated ischemic rats showed no changes in either index compared with sham-operated controls.
    Conclusions Controlling BP during an ischemic insult attenuates ischemia-induced damage of M(1) receptors in the brain of spontaneously hypertensive rats. These results suggest that a rapid intensive increase of BP at the time of a stroke may exacerbate brain damage in hypertensive individuals.

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  • CHOLECYSTOKININ ALTERATIONS AND EFFECTS OF LEVODOPA ADMINISTRATION IN THE MPTP-TREATED MOUSE-BRAIN

    E IWATA, M ASANUMA, Y KONDO, S NISHIBAYASHI, K MATSUURA, N OGAWA

    RESEARCH COMMUNICATIONS IN MOLECULAR PATHOLOGY AND PHARMACOLOGY   88 ( 1 )   31 - 38   1995年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:P J D PUBLICATIONS LTD  

    To clarify the effects of levodopa administration on MPTP-induced alterations in neuropeptides, we examined the effects of repeated levodopa injections (200 mg/kg i.p.) for 2 weeks starting 4 weeks after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment (30 mg/kg i.p. twice/day for 5 days) on cholecystokinin-octapeptide (CCK-8), substance P (SP) and thyrotropin-releasing hormone (TRH) concentrations at 6 weeks after the MPTP treatment. In the striatum, CCK-8 significantly but slightly decreased in the MPTP-treated mice, coinciding with the MPTP-induced marked reduction of dopamine (DA). This considerable reduction of striatal CCK-8 may result from the selectivity of MPTP since the mesolimbic DA neurons coexisting with CCK-8 are intact with the MPTP treatment. Furthermore, this MPTP-induced decrease in CCK-8 persisted with repeated levodopa administration; therefore, the ineffectiveness of the levodopa treatment may have been be due to the degeneration of the nigrostriatal DA neurons. SP and TRH contents showed little or no change with levodopa treatment in the MPTP-treated mouse brain. The CCK-8 level decreased in the thalamus+midbrain, hippocampus and hindbrain of the MPTP + levodopa-treated group, although there were no changes in the MPTP-treated controls. These results suggest that DAergic neurons, except those in the nigrostriatum, strongly interact with the CCK neurons in these brain regions.

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  • PROTECTIVE EFFECTS OF PERGOLIDE ON DOPAMINE LEVELS IN THE 6-HYDROXYDOPAMINE-LESIONED MOUSE-BRAIN

    M ASANUMA, N OGAWA, S NISHIBAYASHI, M KAWAI, Y KONDO, E IWATA

    ARCHIVES INTERNATIONALES DE PHARMACODYNAMIE ET DE THERAPIE   329 ( 2 )   221 - 230   1995年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ARCH INT PHARMACODYNAMIE  

    Pergolide, along with bromocriptine and lisuride, is one of the most active dopamine receptor agonists. To determine whether or not pergolide protects against dopaminergic neuronal damage, via its activity on monoamine metabolism, we studied the effects of pergolide pretreatment on changes in monoamines and their metabolites in the mouse striatum after intracerebroventricular injection of 6-hydroxydopamine with pretreatment of desipramine. After intracerebroventricular administration of 6-hydroxydopamine (40 mu g) in mice, the levels of dopamine and its metabolites (DOPAC, HVA) in the striatum rapidly decreased to 49%, 29% and 68%, respectively, of the naive controls at week 1 but then gradually recovered to control levels at weeks 2 and 4. Repeated pretreatment with pergolide (0.5 mg/kg, i.p.) for 7 days before administration of 6-hydroxydopamine, almost completely protected against reduction in striatal dopamine and its metabolites 1 week after injection of 6-hydroxydopamine. Therefore, pergolide could normalize the decreased dopamine synthesis or storage, and has a neuroprotective effect against dopaminergic dysfunction induced by the neurotoxin, 6-hydroxydopamine. Although we found that pergolide did not show radical scavenging activity in an in vitro system that generated hydroxyl radicals, it has been reported in vivo that pergolide treatment may induce Cu/Zn superoxide dismutase in the rat striatum. Considering these findings, pergolide may well be protective to dopaminergic neurons, largely because of its effects on presynaptic autoreceptors and on its induction of Cu/Zn superoxide dismutase. Further research on the neuroprotective effects of pergolide in Parkinson disease models, by injection of 6-hydroxydopamine, is needed to clarify its mechanism of action on dopaminergic indices.

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  • CYCLOSPORINE-A PREVENTS ISCHEMIA-INDUCED REDUCTION OF MUSCARINIC ACETYLCHOLINE-RECEPTORS WITH SUPPRESSION OF MICROGLIAL ACTIVATION IN GERBIL HIPPOCAMPUS

    Y KONDO, N OGAWA, M ASANUMA, S NISHIBAYASHI, E IWATA, A MORI

    NEUROSCIENCE RESEARCH   22 ( 1 )   123 - 127   1995年3月

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    記述言語:英語   出版者・発行元:ELSEVIER SCI PUBL IRELAND LTD  

    We previously reported the late onset reduction of muscarinic acetylcholine receptors (LORMAR) which begins 7 days after a 5-min period of experimentally induced forebrain ischemia in the gerbil hippocampus. This study demonstrated that post-ischemic administration of cyclosporin A (CsA) reduced LORMAR 10 days after 5 min of forebrain ischemia in the gerbil hippocampus, suggesting that immunosuppression by CsA may reduce damage to the cholinergic system after ischemia. Microglia positive for HLA-DR class II antigen which presented in the hippocampal CA1 area, the region most vulnerable to ischemia, were also reduced by CsA. CsA may suppress microglial activation especially with regard to the antigen-presenting function, and LORMAR may be attenuated by this modulation of microglial function.

    DOI: 10.1016/0168-0102(95)00878-W

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  • REGIONAL DIFFERENCES IN LATE-ONSET IRON DEPOSITION, FERRITIN, TRANSFERRIN, ASTROCYTE PROLIFERATION, AND MICROGLIAL ACTIVATION AFTER TRANSIENT FOREBRAIN ISCHEMIA IN RAT-BRAIN

    Y KONDO, N OGAWA, M ASANUMA, Z OTA, A MORI

    JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM   15 ( 2 )   216 - 226   1995年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:LIPPINCOTT-RAVEN PUBL  

    With use of iron histochemistry and immunohistochemistry, regional changes in the appearance of iron, ferritin, transferrin, glial fibrillary acidic protein-positive astrocytes, and activated microglia were examined from 1 to 24 weeks after transient forebrain ischemia (four-vessel occlusion model) in rat brain. Expression of the C3bi receptor and the major histocompatibility complex class II antigen was used to identify microglia. Neuronal death was confirmed by hematoxylin-eosin staining only in pyramidal cells of the hippocampal CA, region, which is known as the area most vulnerable to ischemia. Perls' reaction with 3,3'-diaminobenzidine intensification revealed iron deposits in the CA, region after week 4, which gradually increased and formed clusters by week 24. Iron also deposited in layers III-V of the parietal cortex after week 8 and gradually built up as granular deposits in the cytoplasm of pyramidal cells in frontocortical layer V. An increasing astroglial reaction and the appearance of ferritin-immunopositive microglia paralleled the iron accumulation in the hippocampal CA, region, indicating that iron deposition was probably produced in the process of gliosis. Neither neuronal death nor atrophy was found in the cerebral cortex. Nevertheless, an astroglial and ferritin-immunopositive microglial reaction became evident at week 8 in the parietal cortex. On the other hand, the granular iron deposition in the pyramidal neurons of frontocortical layer V was not accompanied by any glial reaction in the chronic stage of ischemia. Three different types of iron deposition in the chronic phase after transient forebrain ischemia were shown in this study. In view of the neuronal damage caused by iron-catalyzed free radical formation, the late-onset iron deposition may be relevant to the pathogenesis of the chronic brain dysfunction seen at a late stage after cerebral ischemia.

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  • ANGIOTENSIN-II INDUCES IN-VIVO C-FOS EXPRESSION FROM RAT RENAL-CORTEX AND MEDULLA

    T OMIYA, T YAMAUCHI, T OGURA, M ASANUMA, Z OTA

    RENAL PHYSIOLOGY AND BIOCHEMISTRY   18 ( 2 )   81 - 88   1995年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:KARGER  

    In order to verify whether angiotensin II (Ang II) induced in vivo protooncogene, c-fos, expression in the rat renal cortex and medulla, we administered various concentrations of Ang II to Wistar rats and measured the c-fos expression from the renal cortex and medulla using the method of Northern hybridization. c-fos expression induced by 1 mu g (1.6 x 10(-6) M) of atrial natriuretic peptide (ANP) was also examined. The result was that the peak expression of c-fos mRNA was observed at approximately 10 min after Ang II administration in both rat renal cortex and medulla. This expression was reduced to the control level at 30 min. The measurement of the concentration of injected-Ang II and c-fos mRNA expression revealed that the peak expression of c-fos mRNA in the renal cortex and medulla was detected at the concentration of 1.0 x 10(-8) M and 1.0 x 10(-9) M Ang II, respectively. Nevertheless, ANP had no significant effect on the increase in c-fos mRNA expression. These data revealed that Ang II transiently increases the in vivo c-fos expression in both rat renal cortex and medulla but ANP does not. This protooncogene expression may induce vascular and mesangial proliferation in the kidney.

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  • NEUROPEPTIDE LEVELS IN DISCRETE BRAIN-REGIONS IN THE IMINODIPROPIONITRILE-INDUCED PERSISTENT DYSKINESIA RAT MODEL

    Y KAWADA, N OGAWA, M ASANUMA, A MORI

    REGULATORY PEPTIDES   55 ( 1 )   103 - 110   1995年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE BV  

    To clarify the role of neuropeptides in dyskinesia induced by iminodipropionitrile (IDPN), the levels of five representative neuropeptides were examined in discrete regions of the rat brain 4 weeks after intraperitoneal injection of IDPN. The five neuropeptides examined were methionine-enkephalin (Met-Enk), substance P (SP) and somatostatin, which are closely related to extrapyramidal function, and thyrotropin-releasing hormone (TRK) and cholecystokinin octapeptide (CCK-8), which are closely related to the neural mechanism of the dopamine system. IDPN pretreatment significantly increased Met-Enk in the basal ganglia but not SP or somatostatin; however, all three neuropeptide levels were increased in the hindbrain. In IDPN-treated rats, TRH and CCK-8 levels were increased in the nucleus accumbens, and the frontal cortical CCK-8 level was extremely increased. These findings, together with previous reports, suggest that neuropeptides in the basal ganglia, hindbrain and cerebral cortex play important roles in the manifestation of dyskinetic symptoms.

    DOI: 10.1016/0167-0115(94)00105-7

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  • EFFECTS OF REPEATED INJECTION OF CYCLOSPORINE-A ON PENTYLENETETRAZOL-INDUCED CONVULSION AND CYCLOPHILIN MESSENGER-RNA LEVELS IN RAT-BRAIN

    M ASANUMA, N OGAWA, S NISHIBAYASHI, Y KONDO, A MORI

    NEUROCHEMICAL RESEARCH   20 ( 1 )   101 - 105   1995年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PLENUM PUBL CORP  

    To investigate the relationship between the immune system and convulsions in an animal model, we examined the effects of repeated administration with the immunosuppressant cycIosporin A on pentylenetetrazol (PTZ)-induced convulsions and the changes in the mRNA expression of its binding protein cyclophilin in the rat brain. The consecutive administration of cyclosporin A (5 mg/kg, s.c., 14 days) significantly aggravated the severity of convulsions induced with PTZ 75 mg/kg, i.p. Furthermore, it down-regulated the levels of cyclophilin mRNA. in several brain regions and inhibited the PTZ-induced increase of hippocampal cyclophilin mRNA. Compared with the group without PTZ pretreatment or the group treated with chronic vehicle administration after the PTZ-preinjection, chronic cyclosporin A administration after the initial injection of PTZ apparently aggravated convulsions after the second PTZ injection. Interestingly, the increase in hippocampal cyclophilin mRNA observed after a single PTZ injection was not found after the second PTZ injection in the group with PTZ pretreatment. Therefore, these findings suggest that cyclosporin A administered peripherally can affect the central nervous system, and that an immune response associated with the first convulsive episode plays a key role in severity during subsequent attacks.

    DOI: 10.1007/BF00995159

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  • 脳の老化と生化学

    浅沼幹人, 小川紀雄

    臨床と研究   72   2654 - 2658   1995年

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  • 神経変性過程における免疫制御薬シクロスポリンAの効果

    小川紀雄, 浅沼幹人

    Dementia   9   153 - 161   1995年

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  • 老齢ラット脳内における転写制御因子AP-1のFos-Jun/Jun dimer比の変化

    浅沼幹人, 近藤洋一, 西林佐紀子, 岩田恵美, 松浦弘治, 小川紀雄, 森 昭胤

    Neurosciences   21   125 - 128   1995年

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  • CHRONIC EFFECTS OF TRANSIENT FOREBRAIN ISCHEMIA ON MONOAMINES IN THE SPONTANEOUSLY HYPERTENSIVE RAT-BRAIN

    S NISHIBAYASHI, M ASANUMA, Y KONDO, E IWATA, K MATSUURA, T OGURA, N OGAWA

    BIOGENIC AMINES   11 ( 2 )   187 - 194   1995年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:VSP BV  

    Using the 3-hr common carotid occlusion model in spontaneously hypertensive rats (SHRs), we investigated the changes in monoamines and their metabolites up to the chronic phase, 6 mouths after the transient forebrain ischemia, in various brain regions. In the striatum, the levels of dopamine (DA) at the 3rd week and serotonin (5-HT) at the 2nd week were 1.6-fold and 2.4-fold higher than the levels in the respective sham-operated controls coinciding with increases in their metabolites, homovanillic acid and 5-hydroxyindoleacetic acid. However, these marked increases in both transmitters were transient aid their levels recovered to the sham-operated levels. This transient increase in DA release in the striatum may be caused by ischemia-induced disruption of nerve endings, and may aggravate tissue damage in the striatum at the chronic phase after ischemia. Transient or lasting changes in noradrenaline, DA, 5-HT and their metabolites were also observed in other brain regions, the thalamus+midbrain and the hippocampus of SHRs after transient ischemia. These ischemia-induced alterations in monoamines at the chronic phase may be partly involved in the late-onset sequelae seen in the cerebrovascular disorders.

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  • 中枢神経における転写制御因子結合活性に対する酸化的ストレスの影響

    岩田恵美, 浅沼幹人, 西林佐紀子, 近藤洋一, 松浦弘治, 小川紀雄, 森 昭胤

    Neurosciences   21   77 - 80   1995年

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  • ラット脳血流慢性低潅流時におけるアセチルコリン系の変化

    西林佐紀子, 浅沼幹人, 近藤洋一, 岩田恵美, 松浦弘治, 飯田享子, 小川紀雄, 森 昭胤

    Neurosciences   21   109 - 112   1995年

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  • REGIONAL CHANGES IN ALPHA-TUBULIN AND BETA-ACTIN MESSENGER-RNA ACCUMULATIONS AFTER TRANSIENT ISCHEMIA IN SPONTANEOUSLY HYPERTENSIVE RAT BRAINS

    Y KONDO, N OGAWA, M ASANUMA, H HIRATA, S NISHIBAYASHI, A MORI

    RESEARCH COMMUNICATIONS IN MOLECULAR PATHOLOGY AND PHARMACOLOGY   86 ( 2 )   139 - 153   1994年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:P J D PUBLICATIONS LTD  

    Regional changes in the mRNA accumulations for cytoskeletal proteins alpha-tubulin and beta-actin were examined by in situ hybridization and Northern blot analysis in spontaneously hypertensive rat brains at chronic stages after 3 hours of transient ischemia. alpha-Tubulin mRNA accumulations showed no significant change at 2 weeks after transient ischemia except for a significant decrease in the frontal cortex (9.7%, p &lt; 0.01) coinciding with ischemia induced histological changes. beta-Actin mRNA level was significantly increased in the parietal cortex (8.5%), septum (10.0%), amygdala (11.0%), CA4 area (5.8%) and the dentate gyrus (7.5%) of the hippocampus at 2 weeks after recirculation compared with a sham-operated control group (p&lt;0.01). The ischemic areas of hippocampal and frontocortical lesions receive afferent neurons from those regions where beta-actin mRNA was increased, suggesting that ischemia-induced increases in beta-actin mRNA may reflect actin synthesis in these neurons to compensate for lost synaptic connections. Two cytoskeletal mRNA concentrations reacted differently to cerebral ischemia, and did not parallel histological signs of ischemia either temporally or spatially.

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  • CHRONIC ADMINISTRATION OF ACETYLCHOLINESTERASE INHIBITOR IN THE SENESCENT RAT-BRAIN

    K TANAKA, N OGAWA, M ASANUMA, Y KONDO, A MORI

    NEUROBIOLOGY OF AGING   15 ( 6 )   721 - 725   1994年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE INC  

    The effects of chronic administration of ENA-713, an acetylcholinesterase (AChE) inhibitor, on pre- and postsynaptic cholinergic indices were examined in the senescent rat brain. in the senescent group, the acetylcholine (ACh) level was markedly reduced in the frontal cortex, hippocampus, striatum and thalamus + midbrain, but these reductions were completely prevented by ENA-713. Moreover, although choline acetyltransferase (ChAT) activity was also significantly decreased in these four regions, it recovered in the frontal cortex, hippocampus and thalamus + midbrain after ENA-713 treatment. In contrast, cholinesterase (ChE) activity was not changed in any experimental groups. The maximum number (B-max) of muscarinic M(1) receptor (M1-R) binding site in the frontal cortex in the senescent group was decreased without any change in affinity, but this decrease was also inhibited by ENA-713. Thus, these findings suggest that ENA-713 may have protective, neurotrophic and therapeutic effects on aging-induced cholinergic dysfunction and be useful for the treatment of aging-related dementia, such as the Alzheimer-type dementia.

    DOI: 10.1016/0197-4580(94)90054-X

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  • TUBULIN AND ACTIN MESSENGER-RNAS IN THE YOUNG-ADULT AND THE AGED RAT-BRAIN - EFFECTS OF REPEATED ADMINISTRATION WITH BIFEMELANE HYDROCHLORIDE

    S NISHIBAYASHI, N OGAWA, M ASANUMA, Y KONDO, A MORI

    ARCHIVES OF GERONTOLOGY AND GERIATRICS   19 ( 3 )   265 - 272   1994年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCI PUBL IRELAND LTD  

    In an attempt to identify the age-dependent changes in the potential synthesis of cytoskeletal proteins, we investigated changes in messenger RNA (mRNA) of alpha-tubulin and beta-actin in the young-adult and the aged rat brain using Northern blot analysis. alpha-Tubulin mRNA levels in the frontal cortex and hippocampus, and beta-actin mRNA levels in the hippocampus were significantly decreased in the aged rat brain. Age-dependent decreases in these mRNAs may be related to the neuronal dysfunction associated with aging, in addition to the reduction of several kinds of receptors previously reported. Repeated administration of bifemelane hydrochloride (4-(2-benzylphenoxy)-N-methylbutylamine hydrochloride) for 14 days increased the levels of beta-actin mRNA in the frontal cortex and the striatum of both young-adult and aged rats,although the effect of bifemelane treatment was smaller and not significant in the aged group, These results suggest that bifemelane treatment may enhance the synthesis of cytoskeletal protein and promote neural plasticity by inducing neurite growth or synapse formation.

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  • BROMOCRIPTINE PROTECTS MICE AGAINST 6-HYDROXYDOPAMINE AND SCAVENGES HYDROXYL FREE-RADICALS IN-VITRO

    N OGAWA, K TANAKA, M ASANUMA, M KAWAI, T MASUMIZU, M KOHNO, A MORI

    BRAIN RESEARCH   657 ( 1-2 )   207 - 213   1994年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE BV  

    Pretreatment with bromocriptine (5 mg/kg, i.p., 7 days) completely protected against the decrease in mouse striatal dopamine and its metabolites induced by intraventricular injection of 6-hydroxydopamine after intraperitoneal administration of desipramine, but similar pretreatment with L-DOPA/carbidopa (75/7.5 mg/kg, i.p., 7 days) showed only partial protective effect. Furthermore, in an in vitro system that generated .OH from FeSO4-H2O2, bromocriptine dose-dependently reduced the number of. OH radicals. These findings indicate that bromocriptine has a neuroprotective effect against neurotoxins such as 6-hydroxydopamine, probably due, in part, to its hydroxyl radical scavenging activity and inhibiting effect on dopamine turnover rate. This suggests that early introduction of bromocriptine in the therapy of Parkinson's disease may be superior to treatment with L-DOPA alone.

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  • REDUCED CHOLINE-ACETYLTRANSFERASE ACTIVITY AND MUSCARINIC M1 RECEPTOR LEVELS IN AGED FISHER-344 RAT BRAINS DID NOT PARALLEL THEIR RESPECTIVE MESSENGER-RNA LEVELS

    N OGAWA, M ASANUMA, Y KONDO, S NISHIBAYASHI, A MORI

    BRAIN RESEARCH   658 ( 1-2 )   87 - 92   1994年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE BV  

    Differences in the acetylcholine (ACh)-mediated neuronal system of the brain between aged and young rats were studied by measuring choline acetyltransferase (ChAT) activity, muscarinic M1 receptor (M1-R) and their respective mRNA levels. In aged rats, ChAT activity and the M1-R level were significantly reduced in the cerebral cortex, hippocampus and striatum compared with that in young rats. On the other hand, there was no difference in the ChAT mRNA level in the striatum and the basal forebrain, or the M1-R mRNA level in the cerebral cortex, hippocampus and striatum between aged and young rats. The effects of chronic administration of bifemelane (4-(2-benzylphenoxy)-N-methylbutylamine hydrochloride), which is used for the treatment of sequelae of cerebrovascular diseases, were also evaluated. In aged rats chronically administered bifemelane, the ChAT activity recovered to the level in the young rats in the cerebral cortex and hippocampus, and the M1-R revel recovered completely in the cerebral cortex, hippocampus and striatum. However, the ChAT mRNA level and the M1-R mRNA level were not affected by bifemelane administration. Thus, the decreases and recoveries in ChAT activity and M1-R level did not parallel the changes in their respective mRNAs. These results suggest that the age-related impairments in ACh-mediated neuronal system are considered to be caused primarily by disorders of post-transcriptional events.

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  • EFFECTS OF REPEATED IMMUNOSUPPRESSANT TREATMENT ON RAT PENTYLENETETRAZOL-INDUCED CONVULSION

    M ASANUMA, Y KONDO, N OGAWA, A MORI

    JAPANESE JOURNAL OF PSYCHIATRY AND NEUROLOGY   48 ( 2 )   281 - 284   1994年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:FOLIA PUBL SOC  

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  • CHANGES IN LIPID-PEROXIDATION, CU/ZN SUPEROXIDE-DISMUTASE AND ITS MESSENGER-RNA FOLLOWING AN INTRACEREBROVENTRICULAR INJECTION OF 6-HYDROXYDOPAMINE IN MICE

    N OGAWA, M ASANUMA, Y KONDO, H HIRATA, S NISHIBAYASHI, A MORI

    BRAIN RESEARCH   646 ( 2 )   337 - 340   1994年5月

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    記述言語:英語   出版者・発行元:ELSEVIER SCIENCE BV  

    A single i.c.v. injection of 6-hydroxydopamine (6-OHDA) in mice resulted in a biphasic increase in lipid peroxidation as assayed by the level of thiobarbituric acid-reacting substances (TBARS). An increase in Cu/Zn-superoxide dismutase (SOD) activity was temporally related with the first peak of TBARS but remained unchanged during the second TBARS peak. This suggests that a free radical species other than O-2(-) may be involved in the late onset increase in TBARS. The level of Cu/Zn-SOD mRNA did not immediately reflect the change in Cu/Zn-SOD activity but rather increased gradually reaching significantly higher levels only 8 weeks after i.c.v. an injection of 6-OHDA. This increase in Cu/Zn-SOD mRNA likely occurs in response to a consumption of intrinsic SOD. Thus, short- and long-term increases in lipid peroxidation likely occur by different mechanisms and studies of both are needed to elucidate the neurodegenerative process.

    DOI: 10.1016/0006-8993(94)90102-3

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  • DIFFERENTIAL-EFFECTS OF CHRONIC L-DOPA TREATMENT ON LIPID-PEROXIDATION IN THE MOUSE-BRAIN WITH OR WITHOUT PRETREATMENT WITH 6-HYDROXYDOPAMINE

    N OGAWA, M ASANUMA, Y KONDO, Y KAWADA, M YAMAMOTO, A MORI

    NEUROSCIENCE LETTERS   171 ( 1-2 )   55 - 58   1994年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCI IRELAND LTD  

    Whether or not chronic L-DOPA treatment (100 mg/kg, intraperitoneally (i.p.), twice daily for 4 weeks) alters Lipid peroxidation in the brain as an indicator of neuronal damage was examined in normal mice and mice in which catecholamine (CA) neurons had been injured previously by the administration of B-hydroxydopamine (6-OHDA), followed by recovery. In normal mice, chronic L-DOPA treatment reduced the thiobarbituric acid reacting substances (TBARS) level, an indicator of lipid peroxidation, in the cerebral cortex. In contrast, in mice with CA neuronal injury induced by pretreatment with 6-OHDA, the chronic L-DOPA treatment markedly increased the TBARS in the striatum and frontal cortex, despite recovery of the striatal dopamine levels similar to those in the control mice. These findings suggest that the long-term high-dose administration of L-DOPA enhances the progression of neuronal damage in patients with injured CA neurons such as those with Parkinson's disease.

    DOI: 10.1016/0304-3940(94)90603-3

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  • ACETYLCHOLINESTERASE INHIBITOR ENA-713 PROTECTS AGAINST ISCHEMIA-INDUCED DECREASE IN PRESYNAPTIC AND POSTSYNAPTIC CHOLINERGIC INDEXES IN THE GERBIL BRAIN FOLLOWING TRANSIENT ISCHEMIA

    K TANAKA, N OGAWA, K MIZUKAWA, M ASANUMA, Y KONDO, S NISHIBAYASHI, A MORI

    NEUROCHEMICAL RESEARCH   19 ( 2 )   117 - 122   1994年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPRINGER/PLENUM PUBLISHERS  

    The effects of pre-treatment with ENA-713, an acetylcholinesterase (AChE) inhibitor, on changes in pre- and postsynaptic cholinergic indices in gerbil brain following transient ischemia were studied at 4 and 14 days after recirculation. In the ischemic group, hippocampal acetylcholine (ACh) level was significantly reduced (to 23% of sham-operated controls) at 4 days post-ischemia, but this reduction was completely prevented by ENA-713 treatment. Choline acetyltransferase (ChAT) and cholinesterase (ChE) activities were not significantly changed at 4 and 14 days post-ischemia. Although the maximum number (Bmax) of muscarinic ACh receptor (mACh-R) binding in the hippocampus was decreased (to 44%) without any change in affinity at 14 days post-ischemia, this decrease was also inhibited by ENA-713 treatment. In addition, histological experiment indicated that ENA-713 inhibited ischemia-induced pyramidal cell loss in the hippocampal CA1 regions. Thus, these findings suggest that ENA-713 has protective, neurotrophic and therapeutic effects on cerebrovascular type dementia due to cerebral ischemia.

    DOI: 10.1007/BF00966804

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  • EFFECT OF VAGOTOMY ON HYPERACTIVITY AND INCREASED DOPAMINE TURNOVER INDUCED BY INTRAPERITONEAL ADMINISTRATION OF THYROTROPIN-RELEASING-HORMONE

    N OGAWA, M ASANUMA, Y KONDO, H HIRATA, N NAKAYAMA, A MORI

    BRAIN RESEARCH   633 ( 1-2 )   167 - 170   1994年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE BV  

    Thyrotropin-releasing hormone (TRH) injected intraperitoneally at doses of 10 mg/kg and 20 mg/kg induced marked hyperactivity in rats. Although regional levels of brain dopamine and its metabolites (DOPAC and HVA) in vagotomized rats did not differ from those in sham-operated controls, the (DOPAC + HVA)/dopamine ratio, an indicator of dopamine turnover, was significantly higher in the nucleus accumbens of TRH-treated sham-operated rats than that in untreated sham-operated controls. TRH injection induced hyperactivity only in sham-operated rats and not in subdiaphragmatic bilaterally vagotomized rats. Similarly, bilateral vagotomy completely abolished the TRH-induced increase in dopaminergic turnover in the nucleus accumbens. These results suggest that the dopaminergic system in the nucleus accumbens is involved in hyperactivity induced by TRH, and that TRH mainly affects peripheral receptors. The vagal nerve may be the major pathway from the visceral organs to the brain involved in the etiology of hyperactivity.

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  • Amantadine(Symmetrel)の使い方と問題点

    浅沼幹人, 小川紀雄

    内科   73   868 - 870   1994年

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  • 脳障害過程での免疫系の関与-免疫抑制薬cyclosporine Aを用いた実験的研究-

    小川紀雄, 浅沼幹人, 近藤洋一

    日本神経精神薬理学会雑誌   14   377 - 381   1994年

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  • Pitfalls in Assessment of c-fos mRNA Expression in the Brain: Effects of Animal Handling

    Masato Asanuma, Norio Ogawa

    Reviews in the Neurosciences   5 ( 2 )   171 - 178   1994年

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    記述言語:英語  

    Immediate early genes are rapidly and transiently induced by many stimuli and produce their transcription factors. Of the immediate early genes, the proto-oncogene c-fos and its product Fos play a role in cell proliferation, differentiation and general signal transmission as the 'third messenger’ regulating the transcription of other genes. Even minute stimuli such as the attachment of electrodes, needle injection and saline administration increase the level of c-fos mRNA expression in animal brains. It is, therefore, necessary to investigate the effects of using anesthetics and solvents for drug administration on c-fos expression in order to accurately assess net c-fos induction after stimulation. Furthermore, experimental procedures might themselves affect c-fos mRNA expression in the brain after in vivo stimulation. In this review, we discuss technical pitfalls in assessing in vivo c-fos expression. Rough handling with repeated saline administration enhanced cortical c-fos mRNA expression in the rat brain after a single saline injection by increasing baseline c-fos mRNA levels. In contrast, gentle handling with repeated saline administration diminished c-fos mRNA expression after a single injection by decreasing baseline c-fos mRNA levels. These two types of handling with the repeated injection led to diametrically opposite results on c-fos mRNA expression after a single stimulation. Our results suggest that c-fos mRNA induction after a single stimulation might be affected by the types or intensities of animal handling and that effects of animal handling must be considered when estimating c-fos mRNA induction. © 1994, Freund Publishing House Ltd.

    DOI: 10.1515/REVNEURO.1994.5.2.171

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  • 虚血と神経毒による晩発性脳障害

    小川紀雄, 浅沼幹人, 水川公直

    老年期痴呆研究会誌   6   16 - 19   1994年

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  • Iminodipropionitrile投与によって発症させたジスキネジアモデルラットの脳内神経ペプチドの変化

    河田義郎, 小川紀雄, 浅沼幹人, 森 昭胤

    Neurosciences   20   41 - 44   1994年

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  • ALTERATIONS IN THE BINDING OF THE PHOSPHODIESTERASE INHIBITOR, ROLIPRAM, AFTER TRANSIENT ISCHEMIA IN THE GERBIL BRAIN

    M ASANUMA, N OGAWA, H HIRATA, Y KONDO, S NISHIBAYASHI, M YAMAMOTO, A MORI

    RESEARCH COMMUNICATIONS IN CHEMICAL PATHOLOGY AND PHARMACOLOGY   82 ( 3 )   279 - 285   1993年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:P J D PUBLICATIONS LTD  

    To determine ischemia-induced changes in phosphodiesterase (PDE), changes in the membranous binding sites of rolipram, a cAMP-selective PDE inhibitor, were examined in the gerbil brain following transient 5 min forebrain ischemia. Coinciding with the delayed neuronal death (DND) in the hippocampal CA1 region, affinities for cerebral rolipram bindings decreased on Day 4, when intrinsic cAMP, substrate for PDE, might increase. The number of rolipram binding sites was significantly reduced in the hippocampus on Day 14, despite the lack of change on Day 4. This reduction in rolipram binding was in agreement with the previously reported late onset reduction of muscarinic receptors, progressing more slowly than DND. Slowly progressive mechanisms may be involved in the ischemia-induced reduction of the hippocampal rolipram binding sites which may be PDEs

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  • ABNORMALITIES IN MUSCARINIC CHOLINERGIC RECEPTORS AND THEIR G-PROTEIN COUPLING SYSTEMS IN THE CEREBRAL FRONTAL-CORTEX IN ALZHEIMERS-DISEASE

    N OGAWA, K MIZUKAWA, M ASANUMA, KANAZAWA, I

    ARCHIVES OF GERONTOLOGY AND GERIATRICS   17 ( 2 )   77 - 89   1993年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCI IRELAND LTD  

    Receptor binding assays and in vitro macroautoradiography were used to analyze muscarinic cholinergic receptors (MCR) in the cerebral frontal cortex of Alzheimer's disease (AD), senile dementia of Alzheimer type (SDAT), and age-matched control brains at autopsy. Total MCR binding, detected by [H-3]quiniclinidyl benzilate binding, did not differ significantly between the 3 groups. The concentrations of M1 subtype (M1-R), detected by [H-3]pirenzepine binding, and high affinity state MCRs, however, were significantly lower in AD than in control and SDAT frontal cortices. No differences were detected in the affinity of these receptors for their ligands. The MCRs in AD frontal cortex were more sensitive to the agonist carbachol than were control MCRs. Autoradiography revealed a complete destruction of the laminar distribution of MCR and M1-R in AD and SDAT frontal cortices. Forskolin and phorbol ester binding sites, used to analyze second messenger systems, were significantly and markedly reduced in AD frontal cortex. In addition, coupling between MCR and second messenger systems was supersensitive in AD frontal cortex. Our findings that there are alterations in the structural distribution of MCR as well as reductions and abnormalities in second messenger systems in AD cerebral frontal cortex, suggest that drug therapy with acetylcholine precursors, choline esterase inhibitors and muscarinic agonists cannot eliminate symptoms in dementia patients. Furthermore, they point out the need for techniques to diagnose the disease prior to disintegration of the neuronal network, and the need for therapies to delay or prevent the progression of structural changes.

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  • RAPID RESPONSE OF STRIATAL MUSCARINIC M(1)-RECEPTOR MESSENGER-RNA TO MUSCARINIC CHOLINERGIC AGENTS IN RAT-BRAIN

    HH CHOU, N OGAWA, M ASANUMA, H HIRATA, Y KONDO, A MORI

    MOLECULAR BRAIN RESEARCH   19 ( 3 )   211 - 214   1993年8月

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    記述言語:英語   出版者・発行元:ELSEVIER SCIENCE BV  

    The effects of a single administration of muscarinic cholinergic agents on the level of muscarinic M1-receptor messenger RNA (M1-R mRNA) in the rat striatum were studied. Carbachol increased the M1-R mRNA expression rapidly and transiently, while trihexyphenidyl decreaSed it. These results suggest that muscarinic cholinergic agents participate in the positive regulation of muscarinic receptor mRNA in the early stage after treatment, contrary to the negative regulation in the chronic stage.

    DOI: 10.1016/0169-328X(93)90028-N

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  • EFFECTS OF THE ACETYLCHOLINESTERASE INHIBITOR ENA-713 ON ISCHEMIA-INDUCED CHANGES IN ACETYLCHOLINE AND AROMATIC AMINE LEVELS IN THE GERBIL BRAIN

    K TANAKA, N OGAWA, M ASANUMA, H HIRATA, Y KONDO, N NAKAYAMA, A MORI

    ARCHIVES INTERNATIONALES DE PHARMACODYNAMIE ET DE THERAPIE   323   85 - 96   1993年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ARCH INT PHARMACODYNAMIE  

    The effects of a new acetylcholinesterase inhibitor, ENA-713, on ischemia-induced changes in acetylcholine, monoamines, and their metabolites, were studied in the gerbil. ENA-713 (0.2 mg/kg) or saline was administered intraperitoneally to gerbils 30 min before induction of cerebral ischemia by bilateral carotid occlusion. Pretreatment with ENA-713 mitigated the ischemia-induced abnormalities of the cholinergic, dopaminergic and serotoninergic systems in the gerbil brain, although it had virtually no effect on acetylcholine, monoamines, or their metabolites in any region of the normal gerbil brain. These findings suggest that ENA-713 has beneficial effects against ischemia-induced cerebral disorders. Thus, ENA-713 seems to be promising as a preventive or therapeutic agent for cerebrovascular dementia due to cerebral ischemia and might be useful for the treatment of Alzheimer-type dementia which is associated with multiple neurotransmitter abnormalities in the brain.

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  • THE PREVENTIVE EFFECT OF CYCLOSPORINE-A, AN IMMUNOSUPPRESSANT, ON THE LATE ONSET REDUCTION OF MUSCARINIC ACETYLCHOLINE-RECEPTORS IN GERBIL HIPPOCAMPUS AFTER TRANSIENT FOREBRAIN ISCHEMIA

    N OGAWA, K TANAKA, Y KONDO, M ASANUMA, K MIZUKAWA, A MORI

    NEUROSCIENCE LETTERS   152 ( 1-2 )   173 - 176   1993年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCI IRELAND LTD  

    We previously reported that a late onset reduction of muscarinic acetylcholine receptors (LORMAR) occurs in the gerbil hippocampus after 5 min of transient ischemia. This reduction begins as late as 7 days post-ischemia and accompanies the accumulation of glia, but is subsequent to completion of the disappearance of CA1 pyramidal cells. In the present study, we showed that this LORMAR was prevented by daily post-ischemic administration of the immunosuppressant cyclosporin A (CsA). The effectiveness of CsA against the LORMAR indicates that an immune mechanism may be involved in the progressive brain damage occurring after transient ischemia.

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  • CHOLINERGIC DEFICITS IN AGED RAT-BRAIN ARE CORRECTED WITH NICERGOLINE

    N OGAWA, M ASANUMA, H HIRATA, Y KONDO, Y KAWADA, A MORI

    ARCHIVES OF GERONTOLOGY AND GERIATRICS   16 ( 2 )   103 - 110   1993年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCI IRELAND LTD  

    Choline acetyltransferase (CAT) and muscarinic cholinergic receptor (MCR) activities are markedly reduced in aged as compared with young-adult rat brain. Nicergoline was found to correct these reduced activities in most regions of the brain, especially in the cerebral cortex and hippocampus. Chronic administration of nicergoline had no effect on CAT activity or MCR binding in young-adult rat brain. Nicergoline thus appears to have a specific therapeutic effect on cholinergic functions in aged rat brain, where it acts both pre-synaptically and post-synaptically.

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  • EFFECTS OF REPEATED ADMINISTRATION OF ROLIPRAM, A CAMP-SPECIFIC PHOSPHODIESTERASE INHIBITOR, ON ACETYLCHOLINERGIC INDEXES IN THE AGED RAT-BRAIN

    M ASANUMA, N OGAWA, Y KONDO, H HIRATA, A MORI

    ARCHIVES OF GERONTOLOGY AND GERIATRICS   16 ( 2 )   191 - 198   1993年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCI IRELAND LTD  

    The effects of repeated treatment of rolipram, a cAMP specific phosphodiesterase inhibitor (0.1 mg/kg/day i.p., 14 days), on several neuronal cholinergic indices, especially on those in aged rats were examined. In young-adult rats, rolipram treatment increased choline acetyltransferase (ChAT) activity (V(max) value) in the striatum as well as in thalamus + midbrain, whereas it decreased choline esterase activity in the hippocampus. The ChAT activity (V(max) value) and the M1-R binding (B(max) value) in the aged control rats were significantly reduced in all the brain regions examined, compared with the young-adult rats, but consecutive rolipram treatment ameliorated the reductions of both indices in the frontal cortex and the hippocampus to approximately the young-adult control levels. Since high membrane binding site concentrations for rolipram itself were revealed in the frontal cortex and the hippocampus, where the rolipram treatment showed ameliorating effects on the ChAT activity and the M1-R binding, the present findings indicate that repeated rolipram administration easily affects these two brain regions. Thus, repeated rolipram administration could restore both the presynaptic ChAT activity and the postsynaptic muscarinic cholinergic M1-R binding which are decreased with aging.

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  • EFFECT OF CHRONIC CERULETIDE TREATMENT ON DOPAMINERGIC NEUROTRANSMITTERS, RECEPTORS AND THEIR MESSENGER-RNAS IN THE STRIATUM OF RATS WITH DYSKINESIA INDUCED BY IMINODIPROPIONITRILE

    H HIRATA, N OGAWA, M ASANUMA, Z OTA, A MORI

    BRAIN RESEARCH   604 ( 1-2 )   197 - 204   1993年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE BV  

    To clarify the mechanism of long-lasting ceruletide action, an analogue of cholecystokinin, in relieving the dyskinesia induced by the iminodipropionitrile (IDPN), we investigated the changes in dopaminergic neuronal system in the striatum. In the control rats, ceruletide had no significant effect on the concentrations of dopamine (DA), DOPAC or HVA or on the turnover of DA in the striatum. The concentration of DA was decreased and the turnover of DA [(DOPAC + HVA)/DA] was increased in the striatum of IDPN-treated rats. Chronic administration of ceruletide (160 mug . kg-1 . day-1 x 10 days) increased DA concentration and decreased DA turnover only transiently. Both D1 and D2 receptors and their mRNAs were decreased in the striatum of rats given IDPN. After chronic ceruletide treatment, D1 receptor rose to the control level for 3 days, while the D2 receptor rose to a level 1.5 times the control level for 3 days. Even at the 7 days after chronic ceruletide treatment, D2-R rose significantly as compared with the IDPN-treated rats. Both D1 and D2 receptor mRNAs were significantly increased for 3 days in the IDPN-treated Tats. These observations indicate that the synthesis of DA receptors is increased by ceruletide treatment in the striatum of IDPN-treated rats. These changes in DA receptors and their mRNAs closely paralleled the changes in dyskinetic movement of the IDPN-treated rats after repeated daily administration of ceruletide, as previously reported. The parallel changes between the DA receptors and dyskinetic movement suggest that an up-regulation of DA receptors in the striatum corresponds with an improvement of dyskinesia in the IDPN-treated rats. Thus, the efficacy of ceruletide in treating the dyskinesia induced by IDPN may be related to the up-regulation of DA receptors in the striatum.

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  • ISCHEMIA-INDUCED CHANGES IN ALPHA-TUBULIN AND BETA-ACTIN MESSENGER-RNA IN THE GERBIL BRAIN AND EFFECTS OF BIFEMELANE HYDROCHLORIDE

    M ASANUMA, N OGAWA, H HIRATA, HH CHOU, Y KONDO, A MORI

    BRAIN RESEARCH   600 ( 2 )   243 - 248   1993年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE BV  

    Using in situ hybridization histochemistry, we examined changes in the cytoskeletal protein alpha-tubulin and beta-actin mRNAs in the gerbil brain 14 days after transient ischemia. In an attempt to identify the changes induced in the synthesis of cytoskeletal protein by ischemia, we also evaluated the effects of post-ischemia administration of bifemelane on these cytoskeletal proteins. Alpha-tubulin and beta-actin mRNAs were decreased in the CA1 region 14 days after transient ischemia. These decreases coincided with the loss of CA1 pyramidal cells, suggesting that they may have been related to delayed neuronal death. The beta-actin mRNA level in ischemic controls was significantly increased in the dentate gyrus, habenular nucleus, and medial and lateral thalamic nuclei, where some afferent nerves project into the hippocampal pyramidal cells. The increased beta-actin mRNA suggests that there may be a compensatory enhancement of actin synthesis in the afferent neurons that restores loosened synaptic connections with the ischemic cells in the CA1-4 fields. Administration of bifemelane just after recirculation prevented most of the ischemia-induced mRNA reductions in the CA1 field. Bifemelane's effect may be related to inhibition of Ca2+ influx and its radical scavenging activity. When bifemelane was administered to the ischemic group, alpha-tubulin mRNA levels significantly increased in the dentate gyrus and amygdaloid nucleus, and beta-actin mRNAs showed a tendency to increase in the CA3 and CA4 fields, dentate gyrus, and medial and lateral thalamic nuclei. These findings suggest that bifemelane may enhance synthesis of cytoskeletal protein, especially in the ischemic brain, inducing axon outgrowth or synapse formation.

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  • 脳血管障害総論/脳神経化学の進歩

    小川紀雄, 浅沼幹人, 近藤洋一

    日本臨床   51(1993年増刊上巻)   61 - 68   1993年

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  • ニユーロトランスミッターのレセプター結合実験法

    浅沼幹人, 小川紀雄

    実験医学   11   216 - 223   1993年

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  • 脳に対するカルシウム拮抗薬の功罪-カルシウム拮抗薬のドーパミン受容体に対する作用-

    浅沼幹人

    Clinical Calcium   3   97 - 102   1993年

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  • 脊髄小脳変性症/生化学的な進歩

    浅沼幹人, 小川紀雄

    Clinical Neuroscience   11   626 - 629   1993年

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  • 脳血管障害後遺症に対する塩酸ビフェメラン長期投与の効果

    浅沼幹人, 平田 洋, 近藤洋一, 小川紀雄

    臨床と研究   70   572 - 576   1993年

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  • REGIONAL CHANGES IN NEUROPEPTIDE LEVELS AFTER 5,7-DIHYDROXYTRYPTAMINE-INDUCED SEROTONIN DEPLETION IN THE RAT-BRAIN

    Y KONDO, N OGAWA, M ASANUMA, H HIRATA, K TANAKA, Y KAWADA, A MORI

    JOURNAL OF NEURAL TRANSMISSION-GENERAL SECTION   92 ( 2-3 )   151 - 157   1993年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPRINGER-VERLAG WIEN  

    The levels of five neuropeptides (substance-P, somatostatin, cholecystokinin octapeptide, methionin-enkephalin and dynorphin) were examined in the brain and the spinal cord of rats 2 weeks after intracerebroventricular injection of 5,7-dihydroxytryptamine (5,7-DHT). 5,7-DHT injection caused a significant reduction of the serotonin level in all regions of the brain. The level of each neuropeptide except dynorphin significantly increased in specific regions of the brain after 5,7-DHT treatment without any decrease in their levels in any region. Since, coexistence and interaction between classical neurotransmitters and neuropeptides in the same neurons have been reported, both are indispensable for evaluating pathophysiological state of the brain function associated with abnormal neural transmission. The present findings together with previous reports suggest that neuropeptides act as neurotransmitters and compensate for the impaired function of the serotonergic systems.

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  • DEGENERATION OF DOPAMINERGIC-NEURONS AND FREE-RADICALS - POSSIBLE PARTICIPATION OF LEVODOPA

    N OGAWA, R EDAMATSU, K MIZUKAWA, M ASANUMA, M KOHNO, A MORI

    PARKINSONS DISEASE : FROM BASIC RESEARCH TO TREATMENT   60   242 - 250   1993年

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    記述言語:英語   掲載種別:研究論文(国際会議プロシーディングス)   出版者・発行元:RAVEN PRESS  

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  • 大腸ファイバー検査直後よりwearing off現象の著明な改善のみられたParkinson病

    近藤洋一, 平田 洋, 浅沼幹人, 小川紀雄, 太田善介

    神経内科   38   291 - 292   1993年

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  • 塩酸ビフェメラン投与にて前頭葉の血流改善と感情失禁の改善を認めた脳梗塞の一例

    山本光利, 浅沼幹人, 小川紀雄

    日本老年医学会雑誌   30 ( 1 )   70 - 73   1993年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.3143/geriatrics.30.70

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  • ドキサゾシン投与において脳血流増加を認めた脳梗塞合併高血圧症の一例

    山本光利, 浅沼幹人, 小川紀雄

    臨床と研究   70   2975 - 2978   1993年

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  • Amytriptyline投与により無動・姿勢保持障害・歩行障害等の症状改善と同時に前頭葉脳血流低下の著明な改善を認めた進行性核上麻痺の一例

    浅沼幹人, 平田 洋, 近藤洋一, 小川紀雄

    臨床神経学   33   317 - 321   1993年

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  • 一過性脳虚血後の晩発性ムスカリン性受容体減少に対する免疫抑制剤Cyclosporin Aの阻止効果

    小川紀雄, 浅沼幹人, 近藤洋一, 水川公直, 森 昭胤

    Neurosciences   19   81 - 84   1993年

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  • POSTISCHEMIC ADMINISTRATION OF BIFEMELANE HYDROCHLORIDE PROHIBITS ISCHEMIA-INDUCED DEPLETION OF THE MUSCARINIC M(1)-RECEPTOR AND ITS MESSENGER-RNA IN THE GERBIL HIPPOCAMPUS

    N OGAWA, M ASANUMA, K MIZUKAWA, H HIRATA, H CHOU, A MORI

    BRAIN RESEARCH   591 ( 1 )   171 - 175   1992年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE BV  

    Parallel determinations of muscarinic cholinergic M1 receptor (M1-R) binding and of M1-R mRNA levels were carried out in the gerbil hippocampus 14 days after 5 min of transient ischemia. Both were reduced in the ischemic tissue to about 50% of the levels found in sham-operated controls, indicating that the late loss of M1-R is probably dependent on decreased synthesis. Three administrations of bifemelane hydrochloride (15 mg/kg, i.p., just after ischemia and 6 and 12 h later) completely prevented neuronal death in the hippocampus and ischemia-induced losses of hippocampal M1-R and its mRNA. Since vascular dementia may depend upon the ischemia-induced losses in cholinergic communication in the hippocampus, these findings suggest that it may be possible to prevent its occurrence by post-ischemic treatment with bifemelane hydrochloride.

    DOI: 10.1016/0006-8993(92)90993-J

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  • EFFECTS OF CHRONIC CODERGOCRINE MESYLATE ADMINISTRATION ON THE BRAIN SOMATOSTATINERGIC SYSTEM IN AGED RATS

    K TANAKA, N OGAWA, M ASANUMA, H HIRATA, Y KONDO, HH CHOU, A MORI

    ARCHIVES OF GERONTOLOGY AND GERIATRICS   15 ( 2 )   133 - 139   1992年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCI IRELAND LTD  

    Codergocrine mesylate (dihydroergotoxine; DHET), which is an ergot derivative, has been reported to counteract some age-induced impairments in brain function, but the mechanism of these effects is not known. We examined the effect of chronic DHET administration on the somatostatinergic system in the brains of aged rats. Intraperitoneal injections of DHET (1 mg/kg per day) or of vehicle were given to aged rats for 14 days, and resulted in a significant increase in somatostatin (SOM) receptor binding in all six brain regions examined except the hindbrain. DHET had no effect on SOM receptor binding in the brains of young-adult rats. However, the SOM concentration in aged rats was nearly identical to that in young-adult rats and the SOM concentration in different brain areas did not change after chronic administration of DHET. Thus, the present results suggest that chronic administration of DHET can ameliorate at least one of the age-induced impairments of brain somatostatinergic function.

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  • EFFECTS OF CHRONIC CATECHOLAMINE DEPLETIONS ON MUSCARINIC M1-RECEPTOR AND ITS MESSENGER-RNA IN RAT-BRAIN

    M ASANUMA, N OGAWA, K HABA, H HIRATA, A MORI

    JOURNAL OF THE NEUROLOGICAL SCIENCES   110 ( 1-2 )   205 - 214   1992年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE BV  

    In order to compare the effects of total catecholamine (CA) or noradrenaline (NA) depletions on cholinergic systems, and the mechanisms of receptor regulation in various brain regions, the regional changes in the levels of acetylcholine (ACh), M1-receptor (M1-R) binding, and Ml-R messenger RNA (mRNA) were mainly examined in rats which had received either repeated reserpine treatment or a single injection of the selective noradrenergic neurotoxin N-2-chloroethyl-N-ethyl-2-bromo-benzylamine (DSP-4). The levels of dopamine (DA), its metabolites, NA, binding to both DI and D2 sites, and the mRNA encoding the D2 receptor were also measured. Administration of reserpine (0.5 mg/kg/day, s.c.) for 2, 7 and 14 days depleted DA and NA in virtually all brain regions, while the short-term treatment increased DA metabolites in the striatum (at 2 days) and basal forebrain (at both 2 and 7 days). Administration of DSP-4 (50 mg/kg, i.p.) resulted in a specific loss of NA in the brain 10 days after the injection. These DSP-4 treated rats showed no change in the levels of ACh or M1-R except for an increase in ACh in the frontal cortex. In contrast, numerous changes in cholinergic indices were seen in the reserpine treated groups, and these changes varied from region to region of brain and with the length of drug treatment. In the striatum, ACh levels were increased in rats treated for 2 or 7 days but were normal after 14 days. M1-Rs were decreased at 14 days. These changes suggest that striatal DA, initially released by reserpine, inhibits the release of ACh from striatal cholinergic interneurons, while prolonged depletion of DA relieves this inhibition, leading to a subsequent down-regulation of M1-Rs. In the frontal cortex, ACh and M1-R levels were all decreased by reserpine treatment for 2 or 7 days, and the M1-Rs remained depressed at 14 days. In the basal forebrain, which contains the cholinergic cells that project to the cortex, DA metabolism was increased by 2 or 7 day reserpine treatment. This increased DAergic activity in the basal forebrain may facilitate cholinergic neurons, causing increased release of ACh in the frontal cortex. This, in turn, may lead to a down-regulation of the M1-Rs in that region. The levels of mRNAs encoding M1-Rs were increased in the striatum and frontal cortex by reserpine treatment, despite the decreases in the M1-Rs themselves. This indicates that the down-regulation of M1-Rs in both regions may be due to an increase in receptor degradation rather than a decrease in receptor production. This contrasts with the mechanism of up-regulation of the striatal D2 receptor in reserpinized rats which correlates with increased expression of its mRNA. The present results indicate that cholinergic neurons in the striatum and basal forebrain are both regulated by DAergic neurons, but in different fashions.

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  • EFFECTS OF DIHYDROERGOTOXINE ON CENTRAL CHOLINERGIC NEURONAL SYSTEMS AND DISCRIMINATION-LEARNING TEST IN AGED RATS

    N OGAWA, M NOMURA, K HABA, M ASANUMA, K TANAKA, K HORI, A MORI

    BRAIN RESEARCH   586 ( 2 )   229 - 234   1992年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE BV  

    We evaluated changes in the cholinergic neuronal system and learning ability with aging. Choline acetyltransferase (ChAT) activity, a presynaptic index of the cholinergic system, was decreased in the cerebral cortex. hippocampus. striatum, and hypothalamus in the brain of aged rats compared with young adults. Muscarinic cholinergic binding sites (receptors. MCR), a postsynaptic index of the cholinergic system, were markedly decreased in all areas of the brain. However, intraperitoneal injection of 1 mg/kg of dihydroergotoxine (DHET) for 14 days normalized both ChAT and MCR in the cerebral cortex and hippocampus. In the striatum, ChAT was normalized, but MCR did not recover. Aged rats showed marked learning impairment in a 30-day operant type brightness discrimination learning test. Daily DHET administration restored the discrimination ability in the aged rats to nearly the young adult level. DHET had no effects on central cholinergic indices or learning test results in young adult rats. These findings suggest that learning is impaired in aged rats due to impairment in the central cholinergic neuronal system, and that DHET normalizes the decreased function in this system, restoring the learning ability.

    DOI: 10.1016/0006-8993(92)91631-N

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  • EFFECTS OF CHRONIC BIFEMELANE HYDROCHLORIDE ADMINISTRATION ON RECEPTORS FOR N-METHYL-D-ASPARTATE IN THE AGED-RAT BRAIN

    N OGAWA, K MIZUKAWA, K HABA, M ASANUMA, A MORI

    NEUROCHEMICAL RESEARCH   17 ( 7 )   687 - 691   1992年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PLENUM PUBL CORP  

    We assayed N-methyl-D-aspartate (NMDA) receptors [H-3]3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid ([H-3]CPP) bindings) and evaluated their distribution in the brain by quantitative autoradiography in young adult and aged rats. In the young adult rats, NMDA receptors were present at relatively high concentrations in the cerebral cortex and hippocampus. In the aged rats, NMDA receptors were decreased in the nealy all areas of the brain, especially in the cerebral cortex and hippocampus. Chronic administration of bifemelane hydrochloride, a drug for sequela of cerebrovascular diseased, at a dose of 15 mg/kg/day for 14 days, markedly attenuated these decrease in NMDA receptors. Since NMDA receptors are considered to be involved in memory and learning processes, our results suggest that bifemelane hydrochloride may be applicable to the treatment of disturbed memory and learning.

    DOI: 10.1007/BF00968006

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  • Age-related changes in cerebrospinal fluid γ-aminobutyric acid concentration.

    Takayama, H, Ogawa, N, Yamamoto, M, Asanuma, M, Hirata, H, Ota, Z

    Eur. J. Clin. Chem. Clin. Biochem.   30 ( 5 )   271 - 274   1992年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

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  • LATE ONSET AND LONG-LASTING SUPPRESSIVE EFFECTS OF CERULETIDE, AN ANALOG OF CHOLECYSTOKININ, ON C-FOS MESSENGER-RNA EXPRESSION IN THE RAT STRIATUM

    M ASANUMA, N OGAWA, H HIRATA, K HABA, HH CHOU, A MORI

    NEUROSCIENCE LETTERS   138 ( 2 )   233 - 236   1992年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCI IRELAND LTD  

    C-fos mRNA expression by stimulation with subcutaneous (s.c.) administration of saline or cycloheximide (CHX) was examined in the rat striatum with or without pretreatment with ceruletide, an analogue of cholecystokinin. The c-fos mRNA induction 1 h after CHX stimulation (25 mg/kg, s.c.) was significantly suppressed by ceruletide pretreatment (80-mu-g/kg, s.c.) 2 h before CHX stimulation in the striatum, and tended to be suppressed by ceruletide pretreatment 4 h before saline or CHX stimulation. Long-lasting and inhibitory effects of ceruletide on dyskinesia and on dopaminergic (DAergic) neuronal systems, and c-fos mRNA expression by activation of the DAergic system have been reported. The present findings together with previous reports suggest that ceruletide might have late onset and long-lasting suppressive effects on the expression of c-fos mRNA in the striatum and that these effects might be related to its effects on DAergic neuronal transmission.

    DOI: 10.1016/0304-3940(92)90922-T

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  • EFFECT OF PROPENTOFYLLINE ON ISCHEMIA-INDUCED LOSS OF MUSCARINIC CHOLINERGIC RECEPTOR-BINDING IN THE GERBIL HIPPOCAMPUS

    H HIRATA, N OGAWA, K HABA, M ASANUMA, H CHOU, A MORI

    RESEARCH COMMUNICATIONS IN CHEMICAL PATHOLOGY AND PHARMACOLOGY   75 ( 3 )   365 - 368   1992年3月

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    記述言語:英語   出版者・発行元:P J D PUBLICATIONS LTD  

    Super-delayed loss of muscarinic-1 (M1) receptors and the protective effect of propentofylline on these changes were examined in the gerbil hippocampus after transient ischemia with radioactive pirenzepine. M1 receptors were markedly decreased in the gerbil hippocampus 14 days after transient ischemia. Single administration of propentofylline (20mg/kg, ip) just after transient ischemia almost completely prevented the ischemia-induced decrease in the number of M1 receptors, and had no effect in sham-operated controls. These findings suggest that one of the therapeutic efficacies of propentofylline is the result of the normalization of the dysfunction of the acetylcholine neuronal system in cerebrovascular disease.

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  • CHANGES OF NEUROPEPTIDES AND THEIR RECEPTORS IN EXPERIMENTAL STROKE GERBIL BRAINS

    K HABA, N OGAWA, M ASANUMA, H HIRATA, YH SORA, A MORI

    JOURNAL OF THE NEUROLOGICAL SCIENCES   108 ( 1 )   88 - 92   1992年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE BV  

    Eight kinds of neuropeptides and four kinds of neuropeptide receptors were examined in the right and left hemispheres of mongolian gerbils after unilateral carotid ligation-induced stroke and in normal controls. Five hours after ligation of the right common carotid artery, beta-endorphin concentration in the right hemisphere (ischemic side) of the stroke group was significantly increased compared with that in the contralateral hemisphere (non-ischemic side), but there were no differences between sides in other neuropeptides either with or without stroke. Furthermore, although there were no differences in [H-3]naloxone binding, [H-3]thyrotropin-releasing hormone binding or I-125-vasoactive intestinal polypeptide binding in the brain in this model of stroke, [H-3]enkephalin binding was significantly lower on the ischemic side than on the non-ischemic side in the stroke group. These results suggest that increased activity in the beta-endorphinergic system in the brain might bc partly caused by ischemic brain failure.

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  • DEVELOPMENT OF A SIMPLE SPASTICITY QUANTIFICATION METHOD - EFFECTS OF TIZANIDINE ON SPASTICITY IN PATIENTS WITH SEQUELAE OF CEREBROVASCULAR-DISEASE

    N OGAWA, M ASANUMA, H HIRATA, Z OTA, Y YAMAWAKI, M YAMAMOTO

    JOURNAL OF INTERNATIONAL MEDICAL RESEARCH   20 ( 1 )   78 - 86   1992年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:CAMBRIDGE MED PUBL  

    A simple method that can be performed at the bedside using a spring balance was developed in order to quantify spasticity. The effects of tizanidine on spasticity were evaluated in 30 patients with sequelae of cerebrovascular disease using this method. Treatment with tizanidine was effective in 60% of the patients; there were high correlations between spasticity before and after tizanidine administration and the severity of symptoms and also between the degree of improvement in spasticity and in that of the symptoms. Atonic seizures, due to overdose of tizanidine, were observed in only one patient. The simple spasticity quantification method developed was useful for monitoring tizanidine administration in order to prevent drug overdose. The method appears to be very useful for evaluating the degree of spasticity at the bedside and in measuring the effects of antispastic drugs.

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  • EFFECTS OF CHRONIC ADMINISTRATION OF LISURIDE HYDROGEN MALEATE ON AROMATIC AMINE AND METABOLITE LEVELS IN THE GERBIL BRAIN FOLLOWING BILATERAL COMMON CAROTID LIGATION

    H HIRATA, N OGAWA, K HABA, M ASANUMA, H CHOU, A MORI

    ARCHIVES INTERNATIONALES DE PHARMACODYNAMIE ET DE THERAPIE   315   5 - 15   1992年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ARCH INT PHARMACODYNAMIE  

    Cerebral monoaminergic neurotransmitters and their metabolites show various concentration changes in gerbils following bilateral carotid ligation. The present study evaluated the effect of chronic administrations of lisuride hydrogen maleate (lisuride) on these changes. Lisuride (0.01 mg/kg or 0.05 mg/kg) or vehicle was intraperitoneally administered to gerbils for 14 consecutive days before the induction of a 30 min ischemia by bilateral carotid ligation. Animals were sacrified immediately and the levels of dopamine, DOPAC, homovanillic acid, noradrenaline, serotonin and 5-hydroxyindoleacetic acid determined by HPLC in the striatum, cortex, hippocampus and diencephalon/midbrain. Lisuride itself had no effect on any compound determined in any region. In the carotid-ligated gerbil brain, however, lisuride corrected the reduction of dopamine in the striatum, normalized or reduced increases in the (DOPAC + homovanillic acid)/dopamine ratio in the striatum, hippocampus and diencephalon/midbrain, and increased the levels of serotonin in all four regions. The present study, together with previous reports, indicate that lisuride may interfere with ischemia-induced cerebrovascular disturbances and, in such a way, improve some pathological sequelae of cerebrovascular disease.

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  • EFFECTS OF BIFEMELANE HYDROCHLORIDE ON LOSS OF N-METHYL-D-ASPARTATE RECEPTOR AND MUSCARINIC CHOLINERGIC RECEPTOR-BINDING IN THE GERBIL HIPPOCAMPUS AFTER TRANSIENT ISCHEMIA

    M ASANUMA, N OGAWA, K HABA, H HIRATA, H CHOU, A MORI

    ARCHIVES INTERNATIONALES DE PHARMACODYNAMIE ET DE THERAPIE   315   16 - 21   1992年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ARCH INT PHARMACODYNAMIE  

    The effects of bifemelane hydrochloride on changes of N-methyl-D-aspartate receptors and muscarinic cholinergic receptors were examined in the gerbil hippocampus after transient ischemia with radioactive-specific ligands. There were marked reductions in both these receptors in the gerbil hippocampus 14 days after transient ischemia, without changes in the respective affinities. Post-ischemia bifemelane treatment almost completely prevented the ischemia-induced decreases in the numbers of these receptors, and had no effect in sham-operated controls. The results of the present study suggest that this drug prevents postsynaptic dysfunction induced by transient ischemia, and may be useful in the therapy of both the chronic and the acute stage of cerebrovascular disease.

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  • 薬物療法-L-DOPAを中心に

    浅沼幹人, 小川紀雄

    MEDICO   23   9997 - 10001   1992年

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  • Distinction between declarative memory and procedural memory using 8-arm radial maze task : Biphasic effects of thyrotropin reloading hormone on scopolamine-induced amnesia.

    Ogawa, N, Asanuma, M, Hirata, H, Chou, H, Kondo, Y, Ogawa, S, Mori, A

    Res. Commun. Psychiat. Behav.   17   1 - 15   1992年

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  • 脳梗塞後遺症における脳循環改善薬の有効症状スペクトラムの比較

    小川紀雄, 浅沼幹人, 平田 洋, 近藤洋一

    Prog. Med.   12   1337 - 1344   1992年

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  • 多発性脳梗塞におけるnicergolineの臨床効果と<sup>123</sup>I-IMP SPECT上の脳血流改善

    小川紀雄, 浅沼幹人, 平田 洋, 太田善介

    臨床と研究   69   949 - 957   1992年

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  • Lisuride hydrogen maleateによる老齢ラット脳ムスカリン性アセチルコリンレセプターの改善-定量的レセプター・オートラジオグラフィー法による検討-

    高山晴彦, 浅沼幹人, 水川公直, 平田 洋, 佐藤博彦, 太田善介, 小川紀雄

    日本老年医学会雑誌   29 ( 1 )   24 - 28   1992年

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.3143/geriatrics.29.24

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  • 超高齢者の脳血管障害後遺症に対する脳代謝改善薬の有効症状のプロフィールの相違

    浅沼幹人, 平田 洋, 高山晴彦, 更井哲夫, 小川紀雄

    臨床と研究   69   265 - 275   1992年

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  • 長期パーキンソン病患者に対するタンパク質摂取制限療法の効果,副作用および適応に関する検討

    平田 洋, 浅沼幹人, 近藤洋一, 小川紀雄

    臨床神経学   32   973 - 978   1992年

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  • OPPOSITE EFFECTS OF ROUGH AND GENTLE HANDLING WITH REPEATED SALINE ADMINISTRATION ON C-FOS MESSENGER-RNA EXPRESSION IN THE RAT-BRAIN

    M ASANUMA, N OGAWA, H HIRATA, H CHOU, K TANAKA, A MORI

    JOURNAL OF NEURAL TRANSMISSION-GENERAL SECTION   90 ( 3 )   163 - 169   1992年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPRINGER-VERLAG WIEN  

    The rough handling with repeated saline administration (1.2 ml/kg s.c. for 7 days) enhanced cortical c-fos mRNA expression in the rat brain after a single saline stimulation (1.2 ml/kg s.c.) due to increasing baseline c-fos mRNA levels, whereas the gentle handling with repeated saline administration declined c-fos mRNA expression after a single injection due to decreasing the baseline of c-fos mRNA levels. These two types of handling with the repeated injection led to diametrically opposite results on c-fos mRNA expression after a single stimulation. Neither two types of handling with repeated saline injections affected the net increment of c-fos mRNA induction after a single stimulation, therefore, the effects of handling with repeated treatment on c-fos mRNA expression might be independent of the effects of a single saline stimulation. The present study suggests that c-fos mRNA induction after a single stimulation might be affected by the types or intensities of handling and that care must be taken to estimate c-fos mRNA induction.

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  • MUSCARINIC CHOLINERGIC RECEPTOR-MEDIATED MODULATION ON STRIATAL C-FOS MESSENGER-RNA EXPRESSION INDUCED BY LEVODOPA IN RAT-BRAIN

    H CHOU, N OGAWA, M ASANUMA, H HIRATA, A MORI

    JOURNAL OF NEURAL TRANSMISSION-GENERAL SECTION   90 ( 3 )   171 - 181   1992年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPRINGER-VERLAG WIEN  

    To clarify the interactions between dopamine receptors and muscarinic cholinergic receptors by which neurotransmitters may affect genetic responses, we studied the effects of the muscarinic cholinergic agonist, carbachol, and the muscarinic cholinergic antagonist, trihexyphenidyl, on levodopa-induced c-fos messenger RNA (mRNA) expression in rat striatum. Animals were administered levodopa (levodopa with one-tenth dosage of carbidopa), carbachol or thrihexyphenidyl alone or administered in combination as levodopa (100 mg/kg) + carbachol, or levodopa + trihexyphenidyl given as a single bolus. Levodopa given alone increase the expression of c-fos mRNA. Although carbachol or trihexyphenidyl alone was ineffective in inducing c-fos mRNA, the combination of levodopa and carbachol (greater-than-or-equal-to 0.1 mg/kg) significantly suppressed the induction of c-fos mRNA as compared with levodopa given alone. The combined administration of levodopa and trihexyphenidyl showed a trend toward an additive effect on the induction of c-fos mRNA vs levodopa alone. These findings suggest that the muscarinic cholinergic system may modulate the levodopa-induced c-fos mRNA expression which then regulates the expression of other mRNAs.

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  • COMPARISON OF THE EFFECTS OF BIFEMELANE HYDROCHLORIDE, IDEBENONE AND INDELOXAZINE HYDROCHLORIDE ON ISCHEMIA-INDUCED CHANGES IN BRAIN MONOAMINES AND THEIR METABOLITES IN GERBILS

    K HABA, N OGAWA, M ASANUMA, H HIRATA, A MORI

    JOURNAL OF NEURAL TRANSMISSION-GENERAL SECTION   88 ( 3 )   187 - 198   1992年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPRINGER-VERLAG WIEN  

    Bifemelane hydrochloride (bifemelane), idebenone and indeloxazine hydrochloride (indeloxazine) are used clinically to reduce apathy and other emotional disturbances in patients with cerebrovascular disease. In gerbil brains, ischemia affects many monoaminergic neurotransmitters and their metabolites. In the present study, the effects of treatment with bifemelane, idebenone and indeloxazine on ischemia-induced changes in monoamines and their metabolites were studied in ischemic gerbil brains. Although these drugs had no effect on the monoaminergic neurotransmitters or their metabolites in sham-operated animals, in the ischemic brains both dopamine and serotonin turnovers were abnormal after idebenone or indeloxazine treatment. Bifemelane, in contrast, tended to correct the ischemia-induced changes in the dopaminergic and serotonergic systems in the cerebral cortex, hippocampus and thalamus + midbrain. From the present results and those in previous reports, we conclude that bifemelane is more appropriate than idebenone or indeloxazine as a treatment for the ischemia-induced changes in monoaminergic neurotransmitter systems.

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  • DISTRIBUTION OF THE BETA-2 ADRENERGIC-RECEPTOR MESSENGER-RNA IN THE RAT-BRAIN BY INSITU HYBRIDIZATION HISTOCHEMISTRY - EFFECTS OF CHRONIC RESERPINE TREATMENT

    M ASANUMA, N OGAWA, K MIZUKAWA, K HABA, H HIRATA, A MORI

    NEUROCHEMICAL RESEARCH   16 ( 12 )   1253 - 1256   1991年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PLENUM PUBL CORP  

    We studied the distribution of the rat brain beta-2 adrenergic receptor (AR) mRNA, and the effects of monoamine depletions by chronic reserpine treatment using in situ hybridization histochemistry. In the control group, high level signals of beta-2 AR mRNA were observed in the parietal, frontal and piriform cortices, the medial septal nuclei, the olfactory tubercle, and the midbrain. Moderate signals were found in the striatum, the retrosplenial cortex, the hippocampus, and the thalamic nuclei. After chronic reserpine treatment, beta-2 AR mRNA levels were increased in many brain regions. The large increases were seen in the hippocampus, all thalamic nuclei, the amygdaloid nuclei, and the midbrain, followed by the striatum and the occipital cortex. The receptor up-regulation resulting from chronic monoamine depletion may be due to these increases in beta-2 AR mRNA, indicating that this up-regulation may be caused by increased receptor production rather than decreased receptor degradation.

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  • CALCIUM-ANTAGONIST FLUNARIZINE HYDROCHLORIDE AFFECTS STRIATAL D2 DOPAMINE-RECEPTORS IN THE YOUNG-ADULT AND AGED RAT-BRAIN

    M ASANUMA, N OGAWA, K HABA, H HIRATA, A MORI

    ARCHIVES OF GERONTOLOGY AND GERIATRICS   13 ( 3 )   271 - 278   1991年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCI IRELAND LTD  

    The calcium (Ca) antagonist flunarizine hydrochloride (FNZ) has been reported to induce parkinsonism, especially in the elderly, The effects of FNZ on dopamine receptors in rat striatal membranes, especially in aged rats, were studied using radiolabeled receptor assay. Similar displacing potencies in [H-3]spiperone bindings were exhibited for FNZ and the Ca antagonists verapamil and nicardipine. FNZ was found to directly and competitively effect D2 receptors (D2-Rs) as an antagonist, without effecting D1 receptors. Furthermore, the washing of preoccupied membranes revealed that FNZ has a long-acting potent effect on D2-Rs. The comparative study of FNZ and sulpiride in young-adult and aged rats showed that the effect of FNZ on D2-Rs was more marked in aged rats. These results might be related to FNZ-induced parkinsonism and its high incidence in the elderly.

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  • EFFECTS OF BETA-ADRENERGIC BLOCKING-AGENTS ON SPECIFIC BINDING OF [H-3] D-ALA2-MET5-ENKEPHALINAMIDE AND [H-3] NALOXONE

    H TAKAYAMA, N OGAWA, M ASANUMA, H HIRATA, T OGURA, Z OTA

    ACTA MEDICA OKAYAMA   45 ( 5 )   295 - 299   1991年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:OKAYAMA UNIV MED SCHOOL  

    To gain further insight into the central nervous system (CNS)-action of beta-adrenergic blocking agents (beta-blockers), we examined the effects of various kinds of beta-blockers on opioid receptors (Op-Rs) using radiolabeled receptor assay (RRA). We demonstrated that beta-blockers are competitively bound to Op-Rs in the CNS. Sodium index of beta-blockers in [H-3]naloxone binding study indicated that beta-blockers had the mixed agonist-antagonist activity of opiates. The relative potency of beta-blockers in opioid RRA was negatively correlated with their membrane stabilizing activity. Neither beta-blocking activity nor intrinsic sympathomimetic activity was correlated with IC50 values of beta-blockers in opioid RRA. While it is widely accepted that beta-blockers have a tranquilizing activity, a part of the tranquilizing action of beta-blockers may be mediated through Op-Rs in the CNS. Although beta-blockers may have effects on their own receptors (beta-receptors) in the CNS, the more precise mechanisms of central action of these drugs must be further investigated.

    DOI: 10.18926/AMO/32199

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  • DOPAMINE DEFICIENCY IN THE WEAVER MUTANT MOUSE - AN ANIMAL-MODEL OF OLIVOPONTOCEREBELLAR ATROPHY

    H CHOU, N OGAWA, M ASANUMA, H HIRATA, A MORI

    RESEARCH COMMUNICATIONS IN CHEMICAL PATHOLOGY AND PHARMACOLOGY   74 ( 1 )   117 - 120   1991年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:P J D PUBLICATIONS LTD  

    The dopamine system in weaver mutant mice, a model of cerebellar atrophy, was studied. Dopamine levels of 6-week-old weaver mice were 37%, 44%, 34%, and 41% of levels in age-matched controls in the cerebral cortex, hippocampus, septal region and striatum, respectively. Noradrenaline levels did not differ from controls. This study shows that weaver mice have specific deficiencies in the dopamine system.

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  • LONG-LASTING EFFECT OF CERULETIDE ON DYSKINESIA AND MONOAMINERGIC NEURONAL PATHWAYS IN RATS TREATED WITH IMINODIPROPIONITRILE

    N OGAWA, K HABA, M ASANUMA, A MORI

    BRAIN RESEARCH   556 ( 2 )   271 - 279   1991年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE BV  

    In a model of dyskinesia induced by the administration of iminodipropionitrile (IDPN) in the rat, we evaluated the effects of ceruletide, an analogue of cholecystokinin, on behavioral abnormalities and monoaminergic neuronal function. Vertical head twitching in the IDPN-treated animals was inhibited for over 5 h following a single subcutaneous dose of 160-mu-g/kg ceruletide. In animals dosed daily for 2 or 3 days, the number of head twitches at 24 h after the last dose was about one-third of the number before treatment. After repeated daily doses of ceruletide for 6 days, the number of head twitches was reduced to low levels and remained significantly below pretreatment levels until the 4th posttreatment day. These results indicate that the inhibition of dyskinesia by ceruletide was long-lasting. Assays of monoaminergic neurotransmitters and their metabolites in various brain regions indicate that an imbalance between dopaminergic and serotonergic neuronal systems plays a major role in the pathogenesis of the IDPN-induced dyskinesia, i.e. the ratio of (DOPAC+HVA)/5-HIAA was significantly greater in the striatum but significantly smaller in the hippocampus of the IDPN-treated vs normal animals. This initially abnormal ratio of (DOPAC+HVA)/5-HIAA in the striatum and hippocampus of IDPN-treated animals returned to normal following treatment with ceruletide, corresponding with the reduction of the head twitching. The alterations in monoaminergic neuronal function induced by repeated administration of ceruletide persisted for at least 3 days, even though its plasma half-life is several minutes. Ceruletide also exerted a marked effect on monoaminergic neuronal function in the IDPN-treated rats, in contrast to only a slight effect in normal animals. The observed beneficial effect of ceruletide on impaired neuronal pathways indicates that it acts as a 'neuro-normalizer' in the animal model of IDPN-induced dyskinesia.

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  • CHRONIC LISURIDE HYDROGEN MALEATE ADMINISTRATION ENHANCES MUSCARINIC RECEPTOR-BINDING IN SENESCENT RAT-BRAIN

    H HIRATA, N OGAWA, K MIZUKAWA, K HABA, M ASANUMA, A MORI, Z OTA

    JOURNAL OF INTERNATIONAL MEDICAL RESEARCH   19 ( 4 )   318 - 325   1991年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:CAMBRIDGE MED PUBL  

    Changes in the regional density of muscarinic-1 (M1) receptors and the effect of lisuride hydrogen maleate on these changes were studied in senescent rat brain by in vitro autoradiography. In young adult controls, M1 receptor binding was most dense in the striatum and hippocampus, followed by the cerebral cortex and amygdala. Binding to M1 receptors was markedly lower in these areas of the senescent brain compared with the young adult brain. These decreases were reversed by intraperitoneal administration of 50-mu-g/kg.day lisuride for 14 days. The present results indicate that the therapeutic efficacy of lisuride depends on normalization of not only monoamine systems but also acetylcholine systems.

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  • LOSS OF N-METHYL-D-ASPARTATE (NMDA) RECEPTOR-BINDING IN RAT HIPPOCAMPAL AREAS AT THE CHRONIC STAGE AFTER TRANSIENT FOREBRAIN ISCHEMIA - HISTOLOGICAL AND NMDA RECEPTOR-BINDING STUDIES

    N OGAWA, K HABA, K MIZUKAWA, M ASANUMA, H HIRATA, A MORI

    NEUROCHEMICAL RESEARCH   16 ( 5 )   519 - 524   1991年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PLENUM PUBL CORP  

    Although neuronal death following brain ischemia was originally considered to be due to an energy deficiency resulting from an impaired respiratory chain, the observation of "delayed neuronal death" indicated some other factor. It is believed that delayed neuronal death after transient forebrain ischemia appears as a result of release of glutamate, an excitatory amino acid. In the present study, transient ischemia for 20 minutes in a rat four-vessel occlusion model was induced, and serial changes in histology and N-methyl-D-aspartate receptor (NMDA-R) binding were evaluated up to the chronic stage. Destruction of pyramidal cells and extensive astrocytic proliferation in the CA1 area of the hippocampus was completed by 10 days after cerebral ischemia followed by cerebral blood recirculation. However, the glutamate receptor subtype, NMDA-R, showed no change in all brain regions until after 10 days, but decreased in the hippocampus to 50% after 21 days despite no evidence of histological progression of neuronal death. The results show that the time course for appearance of light microscopic damage in the hippocampal region does not parallel that for depletion of NMDA-R binding sites.

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  • 神経伝達物質とパーキンソン病

    浅沼幹人, 小川紀雄

    臨床成人病   21   1191 - 1199   1991年

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  • パーキンソン病

    浅沼幹人, 小川紀雄

    Brain Medical   3   351 - 358   1991年

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  • ソマトスタチン減少剤

    浅沼幹人, 小川紀雄

    生体の科学   42   505 - 506   1991年

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  • SUPER-DELAYED CHANGES OF MUSCARINIC ACETYLCHOLINE-RECEPTOR IN THE GERBIL HIPPOCAMPUS FOLLOWING TRANSIENT ISCHEMIA

    N OGAWA, K HABA, M ASANUMA, K MIZUKAWA, A MORI

    NEURORECEPTOR MECHANISMS IN BRAIN   287   343 - 347   1991年

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    記述言語:英語   掲載種別:研究論文(国際会議プロシーディングス)   出版者・発行元:PLENUM PRESS DIV PLENUM PUBLISHING CORP  

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  • イブジラストの脳梗塞症例における脳血流改善作用-SPECTを用いて-

    高山晴彦, 浅沼幹人, 佐藤博彦, 平田 洋, 太田善介, 小川紀雄

    臨床と研究   68   1857 - 1862   1991年

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  • 老齢ラット脳におけるソマトスタチン・レセプターの減少と塩酸bifemelane投与による増加作用-レセプター・オートラジオグラフィー法による検討-

    佐藤博彦, 水川公直, 小川紀雄, 浅沼幹人, 太田善介

    日本老年医学会誌   28 ( 1 )   18 - 23   1991年

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.3143/geriatrics.28.18

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  • レセルピン慢性投与のアセチルコリン系神経機構に及ぼす影響

    浅沼幹人, 羽場久美子, 小川紀雄, 森 昭胤

    Neurosciences   17   87 - 90   1991年

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  • 脳血管障害後遺症における意欲低下・問題行動に対する塩酸インデロキサジンの改善効果

    浅沼幹人, 平田 洋, 高山晴彦, 更井哲夫, 小川紀雄

    Prog. Med.   11   1527 - 1530   1991年

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  • CHRONIC BIFEMELANE HYDROCHLORIDE ADMINISTRATION ENHANCES MUSCARINIC CHOLINERGIC RECEPTOR-BINDING IN THE SENESCENT RAT-BRAIN

    N OGAWA, K MIZUKAWA, K HABA, M ASANUMA, A MORI

    JOURNAL OF MEDICINE   22 ( 1 )   17 - 27   1991年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:P J D PUBLICATIONS LTD  

    In senescent rats, the binding ability of muscarinic cholinergic receptors (MCR) was markedly decreased in the cerebral cortex, hippocampus, thalamus, and the striatum compared with young adult rats. This decrease was markedly improved by chronic administration of bifemelane hydrochloride (bifemelane). In view of the findings that bifemelane markedly inhibits the decrease in acetylcholine (ACh) associated with cerebral ischemia, and that it improves amnesia induced by scopalamine, it may be inferred that bifemelane between in situ malignant melanoma and other melanin-containing in situ malignancies has been presented. All types of malignant melanoma which originate within the epidermis or epithelium have an in situ phase and show horizontal growth, and small early forms defy classification. The classification of the most common types of malignant melanoma has been revised. Although the level of invasion and tumor thickness are useful prognostic and therapeutic parameters, their determination is crude and subject to several shortcomings.

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  • REGIONAL RESPONSES OF RAT-BRAIN OPIOID RECEPTORS UPON CASTRATION AND TESTOSTERONE REPLACEMENT

    H TAKAYAMA, N OGAWA, M ASANUMA, Z OTA

    RESEARCH COMMUNICATIONS IN CHEMICAL PATHOLOGY AND PHARMACOLOGY   70 ( 3 )   355 - 358   1990年12月

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    記述言語:英語   出版者・発行元:P J D PUBLICATIONS LTD  

    Regional responses of rat brain opioid receptors (Op-Rs) upon castration and testosterone replacement were studied using [H-3]naloxone (NAL) binding for u-type and [H-3]D-Ala2-methionine-enkephalin (ENK) binding for delta-type Op-R. Castration itself produced an increase in specific NAL and ENK binding in the olfactory bulb and thalamus+midbrain. In the hypothalamus, specific ENK binding was increased without any change in NAL binding. After the testosterone replacement in castrated rats, specific NAL binding was decreased and returned to the control level in the thalamus+midbrain, but remained high in the olfactory bulb. Specific ENK binding was decreased and returned to the control level in the olfactory bulb, hypothalamus and thalamus+midbrain. These results indicated that there are regional differences between u- and delta-type Op-R responses to castration and testosterone replacement. Op-R subtypes were regulated differentially by endogenous hormonal changes, such as testosterone.

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  • ALTERATIONS OF SOMATOSTATIN AND ITS MODULATION BY LEVODOPA IN MPTP-TREATED MOUSE-BRAIN

    M ASANUMA, N OGAWA, YH SORA, K PONGDHANA, K HABA, A MORI

    JOURNAL OF THE NEUROLOGICAL SCIENCES   100 ( 1-2 )   155 - 160   1990年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE BV  

    We examined the changes in the concentrations of neuropeptides in various regions of the mouse brain 1, 2 or 6 weeks after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment (30 mg/kg i.p. twice/day for 5 days) and further examined the effects of levodopa injections (200 mg/kg i.p.) for 14 days starting 4 weeks after MPTP treatment on regional somatostatin (SRIF) concentrations. Substance P, cholecystokinin-octapeptide and thyrotropin-releasing hormone did not show any significant changes up to 6 weeks after MPTP treatment, whereas the SRIF concentration increased 1 week after MPTP treatment but decreased thereafter, showing a marked decrease in the striatum and hippocampus after 6 weeks. In the striatum, the decreased concentration of SRIF recovered to the normal level with levodopa injections. This SRIF depletion could be a change secondary to dopamine depletion. On the other hand, in the cerebral cortex, while showing no change in the SRIF concentration after MPTP treatment, the concentration decreased significantly with levodopa injections. In the hippocampus, the decreased SRIF levels were still low after levodopa treatment. Since it has been reported that SRIF concentrations are significantly reduced in the frontal cortex and hippocampus of demented parkinsonians and patients with senile dementia of the Alzheimer type and that levodopa treatment induced various psychiatric side effects, the results of the present study suggest some relationship among levodopa treatment, SRIF depletion and the demented state.

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  • EFFECTS OF CHRONIC ADMINISTRATION OF MERGOCRYPTINE ON CHANGES IN NEUROTRANSMITTER LEVELS IN THE ISCHEMIC GERBIL BRAIN

    N OGAWA, K HABA, M ASANUMA, M KAWATA, A MORI

    ARCHIVES INTERNATIONALES DE PHARMACODYNAMIE ET DE THERAPIE   308   21 - 31   1990年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ARCH INT PHARMACODYNAMIE  

    Changes in various neurotransmitter systems of the gerbil brain during ischemia and the effects of administration of mergocryptine, a new ergot derivative, were studied. Gerbils intraperitoneally administered 0.5 mg/kg of mergocryptine or the vehicle once a day for 14 days were used. The administration of mergocryptine to control animals had no effect on the contents of neurotransmitters or their metabolites in various regions of the brain, but it corrected abnormalities in the neurotransmitter systems caused by ischemia. These results suggest the usefulness of mergocryptine against the deleterious effects of brain ischemia.

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  • COMPARISON OF FORMALDEHYDE PREPERFUSED FROZEN AND FRESHLY FROZEN TISSUE-PREPARATION FOR THE INSITU HYBRIDIZATION FOR ALPHA-TUBULIN MESSENGER-RNA IN THE RAT-BRAIN

    M ASANUMA, N OGAWA, K MIZUKAWA, K HABA, A MORI

    RESEARCH COMMUNICATIONS IN CHEMICAL PATHOLOGY AND PHARMACOLOGY   70 ( 2 )   183 - 192   1990年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:P J D PUBLICATIONS LTD  

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  • ニューロトランスミッターとドプス-パーキンソン病治療薬としての基礎と臨床-

    小川紀雄, 浅沼幹人

    薬の知識   41   3 - 8   1990年

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  • 老齢ラットにおけるNMDAレセプターの減少とBifemelane Hydrochloride投与による回復

    小川紀雄, 水川公直, 羽場久美子, 浅沼幹人

    (老年医学) Geriat. Med.   28   1845 - 1849   1990年

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  • 塩酸フルナリジンの線条体D2ドーパミンレセプターに対する作用

    小川紀雄, 浅沼幹人, 高山晴彦, 佐藤博彦, 貫名 至

    臨床神経学   30   1221 - 1226   1990年

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  • 老齢ラット脳におけるアセチルコリン系神経機構障害とnicergolineによる補正

    小川紀雄, 水川公直, 羽場久美子, 浅沼幹人

    (老年医学) Geriat. Med.   27   1198 - 1204   1989年

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  • 脳内環境辞典 Nrf2.

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  • 脳内環境-維持機構と破綻がもたらす疾患研究

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  • 平成25年度厚生労働科学研究費補助金(医療品・医療機器等レギュラトリーサイエンス総合研究事業)「違法ドラッグの構造類似性に基づく有害性評価法の確立と乱用実態把握に関する研究」課題番号:H24-医薬-一般-008研究報告書

    平成25年度厚生労働科学研究費補助金(医薬品・医療機器等レギュラトリーサイエンス総合研究事業)  2014年 

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  • 平成24年度厚生労働科学研究費補助金(医療品・医療機器等レギュラトリーサイエンス総合研究事業)「違法ドラッグの構造類似性に基づく有害性評価法の確立と乱用実態把握に関する研究」課題番号:H24-医薬-一般-008研究報告書

    平成24年度厚生労働科学研究費補助金(医薬品・医療機器等レギュラトリーサイエンス総合研究事業)  2013年 

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  • 平成23年度厚生労働科学研究費補助金(医薬品・医療機器等レギュラトリーサイエンス総合研究事業)「違法ドラッグの精神依存並びに精神障害の発症機構と乱用実態把握に関する研究」課題番号:H21-医薬-一般-031研究報告書

    平成23年度厚生労働科学研究費補助金(医薬品・医療機器等レギュラトリーサイエンス総合研究事業)  2012年 

     詳細を見る

  • 平成22年度厚生労働科学研究費補助金(医薬品・医療機器等レギュラトリーサイエンス総合研究事業)「違法ドラッグの精神依存並びに精神障害の発症機構と乱用実態把握に関する研究」課題番号:H21-医薬-一般-031研究報告書

    平成22年度厚生労働科学研究費補助金(医薬品・医療機器等レギュラトリーサイエンス総合研究事業)  2011年 

     詳細を見る

  • 平成21年度厚生労働科学研究費補助金(医薬品・医療機器等レギュラトリーサイエンス総合研究事業)「違法ドラッグの精神依存並びに精神障害の発症機構と乱用実態把握に関する研究」課題番号:H21-医薬-一般-031研究報告書

    平成21年度厚生労働科学研究費補助金(医薬品・医療機器等レギュラトリーサイエンス総合研究事業)  2010年 

     詳細を見る

  • 腎とフリーラジカル第10集

    東京医学社  2010年 

     詳細を見る

  • 平成20年度両備てい園記念財団研究助成金による研究報告 生物学に関する試験研究論叢,25巻

    両備てい園記念財団  2010年 

     詳細を見る

  • 実践行動薬理学

    金芳堂  2010年 

     詳細を見る

  • Handbook of Free Radicals: Formation, Types and Effects

    Nova Science Publishers  2010年 

     詳細を見る

  • 厚生労働科学研究費補助金 難治性疾患克服研究事業 「新規抗パーキンソン病薬ゾニサミドの神経保護作用に関する臨床研究」 平成18-20年度総合研究報告書

    厚生労働科学研究費補助金 難治性疾患克服研究事業  2009年 

     詳細を見る

  • パーキンソン病 病因病態と治療,うつ・衝動制御障害

    中外医学社  2008年 

     詳細を見る

  • 平成19年度厚生労働科学研究費補助金(医薬品・医療機器等レギュラトリーサイエンス総合研究事業)「違法ドラッグの薬物依存形成メカニズムとその乱用実態把握に関する研究」課題番号:H18-医薬-一般-018研究報告書

    2008年 

     詳細を見る

  • パーキンソン病 病因病態と治療,うつ・衝動制御障害

    中外医学社  2008年 

     詳細を見る

  • 平成17年度-平成19年度科学研究費補助金(基盤研究(C)) 研究成果報告書

    2008年 

     詳細を見る

  • 厚生労働科学研究費補助金 難治性疾患克服研究事業「新規抗パーキンソン病薬ゾニサミドの神経保護作用に関する臨床研究」平成19年度総括・分担研究報告書

    2008年 

     詳細を見る

  • 平成18年度厚生労働科学研究費補助金(医薬品・医療機器等レギュラトリーサイエンス総合研究事業)「違法ドラッグの薬物依存形成メカニズムとその乱用実態把握に関する研究」課題番号:H18-医薬-一般-018研究報告書

    2007年 

     詳細を見る

  • 厚生労働科学研究費補助金 難治性疾患克服研究事業「新規抗パーキンソン病薬ゾニサミドの神経保護作用に関する臨床研究」平成18年度分担研究報告書

    2007年 

     詳細を見る

  • 厚生労働科学研究費補助金 難治性疾患克服研究事業「日本発の新しい抗パーキンソン作用薬ゾニサミドの臨床研究班」平成15-17年度総合研究報告書

    2006年 

     詳細を見る

  • 平成17年度厚生労働科学研究費補助金(厚生労働科学特別研究事業)「脱法ドラッグの構造修飾特性とその依存性および神経毒性発現の関連性」課題番号:H17-特別-033研究報告書

    2006年 

     詳細を見る

  • 酸化ストレス─フリーラジカル医学生物学の最前線 Ver.2

    医歯薬出版  2006年 

     詳細を見る

  • 厚生労働科学研究費補助金 難治性疾患克服研究事業「日本発の新しい抗パーキンソン作用薬ゾニサミドの臨床研究班」平成17年度総括・分担研究報告書

    2006年 

     詳細を見る

  • 岡山大学教育研究プロジェクト「脱法ドラッグの乱用防止にむけた融合的研究機構」

    2005年 

     詳細を見る

  • 厚生労働科学研究費補助金 医薬安全総合研究事業 「規制薬物の依存及び神経毒性の発現にかかわる仕組みの分子生物学的解明に関する研究」平成15年度 総括・分担研究報告書

    2004年 

     詳細を見る

  • 厚生労働科学研究費補助金こころの健康科学研究事業 「パーキン蛋白の機能解析と黒質変性及びその防御(H13-こころ-012)」平成15年度 総括・分担研究報告書

    2004年 

     詳細を見る

  • 平成15年度厚生労働科学研究費補助金(厚生労働科学特別研究事業)総括・分担研究報告書

    2004年 

     詳細を見る

  • 厚生労働科学研究費補助金 医薬安全総合研究事業 「規制薬物の依存及び神経毒性の発現にかかわる仕組みの分子生物学的解明に関する研究」平成13-15年度 総括研究報告書

    2004年 

     詳細を見る

  • 厚生科学研究費補助金(医薬安全総合研究事業)規制薬物の依存及び神経毒性の発現にかかわる仕組みの分子生物学的解明に関する研究 平成14年度総括報告

    2003年 

     詳細を見る

  • Immunosuppressant Analogs in Neuroprotection

    Humana Press  2003年 

     詳細を見る

  • 厚生科学研究費補助金特定疾患対策研究事業 神経変性疾患に関する研究班2001年度研究報告書

    2002年 

     詳細を見る

  • 厚生科学研究費補助金(医薬安全総合研究事業)規制薬物の依存及び神経毒性の発現にかかわる仕組みの分子生物学的解明に関する研究 平成13年度総括報告

    2002年 

     詳細を見る

  • 酸化ストレス─フリーラジカル医学生物学の最前線

    医歯薬出版  2001年 

     詳細を見る

  • 生物学に関する試験研究論叢第16集 平成11年度両備てい園記念財団研究助成金による研究報告

    2001年 

     詳細を見る

  • 厚生省厚生科学研究費補助金特定疾患対策研究事業「神経変性疾患に関する研究班」2000年度研究報告書

    2001年 

     詳細を見る

  • 酸化ストレスによる神経障害とその防御、酸化ストレス-フリーラジカル医学生物学の最前線

    医歯薬出版、東京  2001年 

     詳細を見る

  • 脊髄小脳変性症の臨床

    新興医学出版社  1999年 

     詳細を見る

  • Free radicals in brain physiology and disorders.

    Academic Press, San Diego  1996年 

     詳細を見る

  • 新しいSCDの臨床、脊髄小脳変性症の臨床

    新興医学出版社、東京  1996年 

     詳細を見る

  • 活性酸素とバイオシグナル

    講談社サイエンティフィック、東京  1996年 

     詳細を見る

  • レセプター:基礎と臨床

    朝倉書店、東京  1993年 

     詳細を見る

  • 痴呆の基礎研究、高年期の痴呆シリーズ

    中央法規出版、東京  1993年 

     詳細を見る

  • Parkinson's Disease. From Aspects to Molecular Basis., Key Topics in Brain Research

    Springer-Verlag, Wien  1991年 

     詳細を見る

  • 内分泌学の進歩

    トプコ出版部  1991年 

     詳細を見る

  • Neuroreceptor Mechanisms in Brain

    Plenum Publishing Corporation, New York  1991年 

     詳細を見る

▼全件表示

MISC

  • ドパミン神経毒による酸化ストレスに対するアストロサイトの分子発現および神経保護作用の部位特異性

    浅沼 幹人, 奥村 菜央, 鳥越, 育子, 村上 真樹, 北村 佳久, 千堂 年昭

    パーキンソン病・運動障害疾患コングレスプログラム・抄録集   13回   118 - 118   2019年7月

     詳細を見る

    記述言語:日本語   出版者・発行元:Movement Disorder Society of Japan (MDSJ)  

    researchmap

  • 部位特異的アストロサイト機能不全がもたらすロテノン誘発ドパミン神経障害

    宮崎 育子, 浅沼 幹人, 村上 真樹, 菊岡 亮, 磯岡 奈未, 十川 千春, 十川 紀夫, 北村 佳久

    パーキンソン病・運動障害疾患コングレスプログラム・抄録集   13回   118 - 118   2019年7月

     詳細を見る

    記述言語:日本語   出版者・発行元:Movement Disorder Society of Japan (MDSJ)  

    researchmap

  • 大学院生が期待するウェットからドライな薬学研究の未来 抗がん剤投与による不安症状の発症機序解明とその治療・予防に向けたアプローチ

    住吉 佑介, 内藤 七海, 中村 優花, 菅 詩歩, 牛尾 聡一郎, 宮崎 育子, 浅沼 幹人, 北村 佳久, 千堂 年昭

    日本薬学会年会要旨集   139年会 ( 1 )   329 - 329   2019年3月

     詳細を見る

    記述言語:日本語   出版者・発行元:(公社)日本薬学会  

    researchmap

  • ロチゴチンによるアストロサイトのセロトニン1Aレセプターを標的としたドパミン神経保護

    宮崎 育子, 磯岡 奈未, 菊岡 亮, 和田 晃一, 中山 恵利香, 進 浩太郎, 山本 大地, 北村 佳久, 浅沼 幹人

    パーキンソン病・運動障害疾患コングレスプログラム・抄録集   12回   117 - 117   2018年7月

     詳細を見る

    記述言語:日本語   出版者・発行元:Movement Disorder Society of Japan (MDSJ)  

    researchmap

  • 医療のさらなる安心・安全を志向する若手研究者のイノベーティブチャレンジ 抗がん剤投与による不安症状発症の病態機序解明 セロトニン神経系の関与

    中村 優花, 住吉 佑介, 内藤 七海, 牛尾 聡一郎, 宮崎 育子, 浅沼 幹人, 北村 佳久, 千堂 年昭

    日本薬学会年会要旨集   138年会 ( 1 )   333 - 333   2018年3月

     詳細を見る

    記述言語:日本語   出版者・発行元:(公社)日本薬学会  

    researchmap

  • 医療のさらなる安心・安全を志向する若手研究者のイノベーティブチャレンジ 抗がん剤投与による不安症状発症の病態機序解明 セロトニン神経系の関与

    中村 優花, 住吉 佑介, 内藤 七海, 牛尾 聡一郎, 宮崎 育子, 浅沼 幹人, 北村 佳久, 千堂 年昭

    日本薬学会年会要旨集   138年会 ( 1 )   333 - 333   2018年3月

     詳細を見る

    記述言語:日本語   出版者・発行元:(公社)日本薬学会  

    researchmap

  • 農薬ロテノン暴露による腸管神経障害とコーヒー成分による神経保護効果

    宮崎 育子, 磯岡 奈未, 菊岡 亮, 和田 晃一, 北村 佳久, 浅沼 幹人

    パーキンソン病・運動障害疾患コングレスプログラム・抄録集   11回   99 - 99   2017年10月

     詳細を見る

    記述言語:日本語   出版者・発行元:Movement Disorder Society of Japan (MDSJ)  

    researchmap

  • 農薬ロテノンによるアストロサイト機能異常がもたらすドパミン神経障害

    宮崎 育子, 菊岡 亮, 磯岡 奈未, 北村 佳久, 浅沼 幹人

    日本生物学的精神医学会・日本神経精神薬理学会合同年会プログラム・抄録集   39回・47回   158 - 158   2017年9月

     詳細を見る

    記述言語:日本語   出版者・発行元:日本生物学的精神医学会・日本神経精神薬理学会  

    researchmap

  • アストロサイトを介したミルタザピンのドパミン神経保護効果に関する検討

    菊岡 亮, 宮崎 育子, 久保田 菜月, 前田 恵実, 香川 大樹, 守山 雅晃, 粂 明日香, 北村 佳久, 浅沼 幹人

    日本生物学的精神医学会・日本神経精神薬理学会合同年会プログラム・抄録集   39回・47回   193 - 193   2017年9月

     詳細を見る

    記述言語:日本語   出版者・発行元:日本生物学的精神医学会・日本神経精神薬理学会  

    researchmap

  • 農薬ロテノンによる非細胞自律性ドパミン神経障害

    宮崎 育子, 村上 真樹, 菊岡 亮, 磯岡 奈未, 北村 佳久, 浅沼 幹人

    The Journal of Toxicological Sciences   42 ( Suppl. )   S321 - S321   2017年6月

     詳細を見る

    記述言語:日本語   出版者・発行元:(一社)日本毒性学会  

    researchmap

  • Influence of nicotine on doxorubicin and cyclophosphamide combination treatment-induced spatial cognitive impairment and anxiety-like behavior in rats

    Yoshihisa Kitamura, Erika Kanemoto, Misaki Sugimoto, Ayumi Machida, Yuka Nakamura, Nanami Naito, Hirotaka Kanzaki, Ikuko Miyazaki, Masato Asanuma, Toshiaki Sendo

    NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY   390 ( 4 )   369 - 378   2017年4月

     詳細を見る

    記述言語:英語   出版者・発行元:SPRINGER  

    In the present study, we examined the effects of nicotine on cognitive impairment, anxiety-like behavior, and hippocampal cell proliferation in rats treated with a combination of doxorubicin and cyclophosphamide. Combined treatment with doxorubicin and cyclophosphamide produced cognitive impairment and anxiety-like behavior in rats. Nicotine treatment reversed the inhibition of novel location recognition induced by the combination treatment. This effect of nicotine was blocked by methyllycaconitine, a selective alpha 7 nicotinic acetylcholine receptor (nAChR) antagonist, and dihydro-beta-erythroidine, a selective alpha 4 beta 2 nAChR antagonist. In addition, nicotine normalized the amount of spontaneous alternation seen during the Y-maze task, which had been reduced by the combination treatment. This effect of nicotine was inhibited by dihydro-beta-erythroidine. In comparison, nicotine did not affect the anxiety-like behavior induced by the combination treatment. Furthermore, the combination treatment reduced the number of proliferating cells in the subgranular zone of the hippocampal dentate gyrus, and this was also prevented by nicotine. Finally, the combination of doxorubicin and cyclophosphamide significantly reduced hippocampal alpha 7 nAChR mRNA expression. These results suggest that nicotine inhibits doxorubicin and cyclophosphamide-induced cognitive impairment via alpha 7 nAChR and alpha 4 beta 2 nAChR, and also enhances hippocampal neurogenesis.

    DOI: 10.1007/s00210-016-1338-z

    Web of Science

    researchmap

  • 革新的創薬・育薬を目指す若手研究者によるトランスレーショナルリサーチの最前線 パーキンソン病モデルマウスにおけるミルタザピンの神経保護効果に関する検討

    菊岡 亮, 宮崎 育子, 浅沼 幹人, 北村 佳久, 千堂 年昭

    日本薬学会年会要旨集   137年会 ( 1 )   284 - 284   2017年3月

     詳細を見る

    記述言語:日本語   出版者・発行元:(公社)日本薬学会  

    researchmap

  • Identification of transcription factors activated by methylmercury in mouse brain.

    Kim, M.S, Takahashi, T, Lee, J.Y, Miura, N, Asanuma, M, Hwang, G.W, Naganuma, A

    Fundam. Toxicol. Sci.   4 ( 1 )   37 - 39   2017年

     詳細を見る

    記述言語:英語   掲載種別:書評論文,書評,文献紹介等  

    DOI: 10.2131/fts.4.37

    researchmap

  • Therapeutic strategy of targeting astrocytes for neuroprotection in parkinson’s disease

    Ikuko Miyazaki, Masato Asanuma

    Current Pharmaceutical Design   23 ( 33 )   4936 - 4947   2017年

     詳細を見る

    記述言語:英語   掲載種別:書評論文,書評,文献紹介等   出版者・発行元:Bentham Science Publishers B.V.  

    Parkinson’s disease (PD) is one of common neurodegenerative diseases, which shows motor symptoms including tremor, bradykinesia, rigidity and postural instability. It also involves non-motor symptoms such as cognitive impairment, mental manifestation, autonomic disorder and sensory disturbance. Although treatments to improve the motor disability in PD are being assessed at present, the main challenge remains that is the development of neuroprotective or disease-modifying treatments. Therefore, it is desirable to find approaches that can inhibit the progression of dopaminergic neurodegeneration. Astrocytes are known to play an important role in the maintenance of the neuronal environment and exert neuroprotective effects. Additionally, astrocyte dysfunction increases the susceptibility of neurons to cytotoxicity. We have demonstrated neuroprotective approaches in parkinsonian models in various studies targeting astrocytes. In this article, we summarize the neuroprotective function of astrocytes in the brain, involvement of astrocyte dysfunction in neurodegeneration, and experimental approaches to dopaminergic neuroprotection. We review findings reported in several papers including our own studies. We also address target molecules and pivotal pathways in astrocytes for dopaminergic neuroprotection. The review discusses new promising therapeutic strategies to prevent dopaminergic neurodegeneration in PD.

    DOI: 10.2174/1381612823666170710163731

    Scopus

    researchmap

  • Effect of alteration of glutathione content on cell viability in a-synuclein-transfected SH-SY5Y cells.

    Tanaka, K, Sonoda, K, Asanuma, M

    Advances in Parkinson's Disease   6   93 - 100   2017年

     詳細を見る

    記述言語:英語   掲載種別:書評論文,書評,文献紹介等  

    DOI: 10.4236/apd.2017.63010

    researchmap

  • ALSモデルの運動障害および運動神経変性に対するセロトニン1Aアゴニストの抑制効果

    浅沼幹人, 宮崎育子, 村上真樹, 村上真樹, 鳥越菜央, 中野剛志, 菊岡亮, 北村佳久, 千堂年昭

    パーキンソン病・運動障害疾患コングレスプログラム・抄録集   10th   68 - 68   2016年10月

     詳細を見る

    記述言語:日本語   出版者・発行元:Movement Disorder Society of Japan (MDSJ)  

    J-GLOBAL

    researchmap

  • 農薬ロテノン暴露によるドパミン神経障害におけるアストロサイトの関与

    宮崎育子, 村上真樹, 村上真樹, 菊岡亮, 磯岡奈未, 北村佳久, 浅沼幹人

    パーキンソン病・運動障害疾患コングレスプログラム・抄録集   10th   69 - 69   2016年10月

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    記述言語:日本語   出版者・発行元:Movement Disorder Society of Japan (MDSJ)  

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  • L-Theanine protects against excess dopamine-induced neurotoxicity in the presence of astrocytes

    Mika Takeshima, Ikuko Miyazaki, Shinki Murakami, Taizo Kita, Masato Asanuma

    JOURNAL OF CLINICAL BIOCHEMISTRY AND NUTRITION   59 ( 2 )   93 - 99   2016年9月

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    記述言語:英語   掲載種別:書評論文,書評,文献紹介等   出版者・発行元:JOURNAL CLINICAL BIOCHEMISTRY & NUTRITION  

    L-Theanine (gamma-glutamylethylamide), a component of green tea, is considered to have regulatory and neuroprotective roles in the brain. The present study was designed to determine the effect of L-theanine on excess dopamine-induced neurotoxicity in both cell culture and animal experiments. The primary cultured mesencephalic neurons or co-cultures of mesencephalic neurons and striatal astrocytes were pretreated with L-theanine for 72 h, and then treated with excess dopamine for further 24 h. The cell viability of dopamine neurons and levels of glutathione were evaluated. Excess dopamine-induced neurotoxicity was significantly attenuated by 72 h preincubation with L-theanine in neuron-astrocyte co-cultures but not in neuron-rich cultures. Exposure to L-theanine increased the levels of glutathione in both astrocytes and glial conditioned medium. The glial conditioned medium from L-theanine-pretreated striatal astrocytes attenuated dopamine-induced neurotoxicity and quinoprotein formation in mesencephalic neurons. In addition, replacement of L-glutamate with L-theanine in an in vitro cell-free glutathione-synthesis system produced glutathione-like thiol compounds. Furthermore, L-theanine administration (4 mg/kg, p.o.) for 14 days significantly increased glutathione levels in the striatum of mice. The results suggest that L-theanine provides neuroprotection against oxidative stress-induced neuronal damage by humoral molecules released from astrocytes, probably including glutathione.

    DOI: 10.3164/jcbn.16-15

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  • 3-O-Methyldopa inhibits astrocyte-mediated dopaminergic neuroprotective effects of L-DOPA

    Masato Asanuma, Ikuko Miyazaki

    BMC NEUROSCIENCE   17   52   2016年7月

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    記述言語:英語   掲載種別:書評論文,書評,文献紹介等   出版者・発行元:BIOMED CENTRAL LTD  

    Background: We evaluated the effects of 3-O-methyldopa (3-OMD), a metabolite of L-DOPA which is formed by catechol-O-methyltransferase (COMT), on the uptake, metabolism, and neuroprotective effects of L-DOPA in striatal astrocytes. We examined changes in the numbers of dopaminergic neurons after treatment with L-DOPA and 3-OMD or entacapone, a peripheral COMT inhibitor, using primary cultured mesencephalic neurons and striatal astrocytes.
    Results: The number of tyrosine hydroxylase-positive dopaminergic neurons was not affected by L-DOPA treatment in mesencephalic neurons alone. However, the increase in viability of dopaminergic neurons in the presence of astrocytes was further enhanced after methyl-L-DOPA treatment (25 mu M) in mixed cultured mesencephalic neurons and striatal astrocytes. The neuroprotective effect of 25 mu M L-DOPA was almost completely inhibited by simultaneous treatment with 3-OMD (10 or 100 mu M), and was enhanced by concomitant treatment with entacapone (0.3 mu M). The uptake of L-DOPA into and the release of glutathione from striatal astrocytes after L-DOPA treatment (100 mu M) were inhibited by simultaneous exposure to 3-OMD (100 mu M).
    Conclusions: These data suggest that L-DOPA exerts its neuroprotective effect on dopaminergic neurons via astrocytes and that 3-OMD competes with L-DOPA by acting on target molecule(s) (possibly including glutathione) released from astrocytes. Since some amount of entacapone can cross the blood-brain barrier, this reagent may enhance L-DOPA transportation by inhibiting COMT and increase the astrocyte-mediated neuroprotective effects of L-DOPA on dopaminergic neurons.

    DOI: 10.1186/s12868-016-0289-0

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  • パーキンソン病モデルマウスにおけるミルタザピンの神経保護効果に関する検討(Neuroprotective effects of mirtazapine in parkinsonian mice)

    菊岡 亮, 宮崎 育子, 久保田 菜月, 前田 恵実, 香川 大樹, 守山 雅晃, 粂 明日香, 村上 真樹, 北村 佳久, 浅沼 幹人

    日本神経精神薬理学会年会プログラム・抄録集   46回   232 - 232   2016年7月

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    記述言語:英語   出版者・発行元:(一社)日本神経精神薬理学会  

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  • 抗うつ薬ミルタザピンのアストロサイトを標的としたドパミン神経保護(Astrocyte-targeted neuroprotection of antidepressant mirtazapine)

    宮崎 育子, 菊岡 亮, 久保田 菜月, 前田 恵実, 香川 大樹, 守山 雅晃, 粂 明日香, 村上 真樹, 北村 佳久, 浅沼 幹人

    日本神経精神薬理学会年会プログラム・抄録集   46回   232 - 232   2016年7月

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    記述言語:英語   出版者・発行元:(一社)日本神経精神薬理学会  

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  • 筋萎縮性側索硬化症モデルにおける運動障害および運動神経変性に対する8-OH-DPATの抑制効果(8-OH-DPAT ameliorates motor dysfunction and motor neuron degeneration in mouse model of amyotrophic lateral sclerosis)

    浅沼 幹人, 宮崎 育子, 村上 真樹, 鳥越 奈央, 中野 剛志, 菊岡 亮, 北村 佳久, 千堂 年昭

    日本神経精神薬理学会年会プログラム・抄録集   46回   232 - 232   2016年7月

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    記述言語:英語   出版者・発行元:(一社)日本神経精神薬理学会  

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  • In vitro quantitative determination of the concentration of the polymerization agent methyl 2-benzoylbenzoate in intravenous injection solution and the cytotoxic effects of the chemical on normal human peripheral blood mononuclear cells

    Chiaki Tsuboi, Yoichi Kawasaki, Kei Yoshitome, Kenta Yagi, Taro Miura, Satoru Esumi, Ikuko Miyazaki, Masato Asanuma, Yoshihisa Kitamura, Toshiaki Sendo

    ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH   23 ( 10 )   10262 - 10269   2016年5月

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    記述言語:英語   掲載種別:書評論文,書評,文献紹介等   出版者・発行元:SPRINGER HEIDELBERG  

    In previous studies, we detected the photoinitiators 1-hydroxycyclohexyl phenyl ketone (1-HCHPK) and 2-methyl-4'-(methylthio)-2-morpholinopropiophenone (MTMP) in an intravenous injection solution. Importantly, 1-HCHPK and MTMP have been demonstrated to be cytotoxic to normal human peripheral blood (PB) mononuclear cells (MNC). Cell death (apoptosis) pathways can be classified into two modes, caspase-dependent and -independent pathways. However, it is unclear whether methyl 2-benzoylbenzoate (MBB) induces the caspase-dependent and/or -independent pathway in normal human PBMNC. In the present in vitro study, we examined the levels of MBB in a solution from an intravenous fluid bag and the cytotoxicity of MBB towards normal human PBMNC via the caspase-8-, caspase-9-, or apoptosis-inducing factor (AIF)-mediated apoptosis pathways. We found that extracts from the injection solution had been contaminated with approximately 80 mu M of the photoinitiator MBB. In addition, MBB induced apoptosis in the high concentration range in normal human PBMNC in vitro. Moreover, we found that MBB-induced apoptosis occurs via the caspase-9 pathway, but not the AIF pathway. In conclusion, we suggest that MBB has cytotoxic effects on normal human PBMNC in vitro, which are mediated via the caspase-dependent pathway.

    DOI: 10.1007/s11356-016-6332-y

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  • Neuroprotective effects of levetiracetam target xCT in astrocytes in parkinsonian mice

    Ikuko Miyazaki, Shinki Murakami, Nao Torigoe, Yoshihisa Kitamura, Masato Asanuma

    JOURNAL OF NEUROCHEMISTRY   136 ( 1 )   194 - 204   2016年1月

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    記述言語:英語   掲載種別:書評論文,書評,文献紹介等   出版者・発行元:WILEY-BLACKWELL  

    Astrocytes but not neurons express cystine/glutamate exchange transporter (xCT), which takes up cystine, and consequently supplies the substrate for GSH synthesis in neurons. It is recognized that GSH synthesis in neurons is dependent on the expression of xCT in astrocytes. Previous studies reported that levetiracetam (LEV), an anti-epileptic drug, increased xCT expression invivo. The purpose of this study was to examine neuroprotective effects of LEV in parkinsonian models and demonstrate xCT in astrocytes as a target of neuroprotection against dopaminergic neurodegeneration. We identified striatal astrocytes cultured with LEV showed significant increase in xCT expression and GSH levels. Preincubation of primary cultured mesencephalic dopamine neurons with conditioned media from LEV-treated astrocytes protected against 6-hydroxydopamine (6-OHDA)-induced neurotoxicity. These protective effects were canceled by xCT inhibitor. Furthermore, reduction of nigrostriatal dopaminergic neurons in 6-OHDA-lesioned parkinsonian mice was significantly abrogated by repeated injections of LEV. Treatment with LEV significantly increased the expression of xCT in striatal astrocytes in the hemi-parkinsonian mice. In conclusion, LEV exerts neuroprotective effects against neurodegeneration via up-regulation of xCT and GSH in astrocytes. Thus, xCT in astrocytes could be a potential target in novel neuroprotective approaches to prevent degeneration of dopaminergic neurons.

    DOI: 10.1111/jnc.13405

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  • Changes in Metallothionein Isoform Expression in the Bones of Ovariectomized Rats

    Chiharu Sogawa, Mika Ikegame, Ikuko Miyazaki, Toshiaki Ara, Yasuhiro Imamura, Yuka Okusha, Kazumi Ohyama, Masato Asanuma, Norio Sogawa, Toshio Yamamoto, Ken-ichi Kozaki

    JOURNAL OF HARD TISSUE BIOLOGY   25 ( 1 )   21 - 26   2016年1月

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    記述言語:英語   掲載種別:書評論文,書評,文献紹介等   出版者・発行元:JOURNAL HARD TISSUE BIOLOGY  

    Metal-binding proteins, metallothioneins (MTs), may play important roles in bone metabolism. However, the contribution of MTs to bone metabolism remains obscure. In the present study, we investigated the expression of MT isoforms in bone cells and mRNA for MT isoforms in the tibiae following ovariectomy (OVX). The results obtained showed that MT-I/II and MT-III were expressed in osteoblasts, osteoclasts, and osteocytes 4 weeks after OVX. Peaks in the mRNA expression ratios (OVX/Sham) of MT-I/II and MT-III changed following OVX. The expression ratio of MT-I/II increased after 1 week, whereas that of MT-III increased 4 weeks after OVX. These results suggest that the contribution of MTs to bone metabolism may depend on the isoforms in the cell types and the stage after OVX.

    DOI: 10.2485/jhtb.25.21

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  • Anti-high mobility group box 1 antibody exerts neuroprotection in a rat model of Parkinson's disease

    Tatsuya Sasaki, Keyue Liu, Takashi Agari, Takao Yasuhara, Jun Morimoto, Mihoko Okazaki, Hayato Takeuchi, Atsuhiko Toyoshima, Susumu Sasada, Aiko Shinko, Akihiko Kondo, Masahiro Kameda, Ikuko Miyazaki, Masato Asanuma, Cesario V. Borlongan, Masahiro Nishibori, Isao Date

    EXPERIMENTAL NEUROLOGY   275   220 - 231   2016年1月

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    記述言語:英語   掲載種別:書評論文,書評,文献紹介等   出版者・発行元:ACADEMIC PRESS INC ELSEVIER SCIENCE  

    The high mobility group box-1 (HMGB1) exists as an architectural nuclear protein in the normal state, but displays an inflammatory cytokine-like activity in the extracellular space under pathological condition. Inflammation in the pathogenesis of Parkinson's disease (PD) has been documented. In this study, we investigated the involvement of HMGB1 in the pathology and the neuroprotective effects of neutralizing anti-HMGB1 monoclonal antibody (mAb) on an animal model of PD. Adult female Sprague-Dawley rats were initially injected with 6-hydroxydopmaine (6-OHDA, 20 mu g/4 mu l) into the right striatum, then anti-HMGB1 mAb (1 mg/kg), or control mAb was intravenously administered immediately, at 6 and 24 h after 6-OHDA injection. The treatment with anti-HMGB1 mAb significantly preserved dopaminergic neurons in substantia nigra pars compacta and dopaminergic terminals inherent in the striatum, and attenuated PD behavioral symptoms compared to the control mAb-treated group. HMGB1 was retained in the nucleus of neurons and astrocytes by inhibiting the proinflammation-induced oxidative stress in the anti-HMGB1 mAb-treated group, whereas HMGB1 translocation was observed in neurons at 1 day and astrocytes at 7 days after 6-OHDA injection in the control mAb-treated group. Anti-HMGB1 mAb inhibited the activation of microglia, disruption of blood-brain-barrier (BBB), and the expression of inflammation cytokines such as IL-1 beta. and IL-6. These results suggested that HMGB1 released from neurons and astrocytes was at least partly involved in the mechanism and pathway of degeneration of dopaminergic neurons induced by 6-0HDA exposure. Intravenous administration of anti-HMGB1 mAb stands as a novel therapy for PD possibly acting through the suppression of neuroinflammation and the attenuation of disruption of BOB associated with the disease. (C) 2015 Elsevier Inc. All rights reserved.

    DOI: 10.1016/j.expneurol.2015.11.003

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  • Serotonin-1A agonist 8-OH-DPAT alleviates motor dysfunction and motor neuron degeneration in a model of amyotrophic lateral sclerosis.

    Miyazaki I, Murakami S, Nakano T, Torigoe N, Kikuoka R, Kitamura Y, Sendo T, Asanuma M

    Ann. Pharmacol. Pharmaceut.   1 ( 1 )   1003 - 1003   2016年

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    記述言語:英語   掲載種別:書評論文,書評,文献紹介等  

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  • Neuroprotective effect of fermented papaya preparation by activation of Nrf2 pathway in astrocytes.

    Murakami S, Miyazaki I, Asanuma M

    Nutr. Neurosci.   1 - 9   2016年

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    記述言語:英語   掲載種別:書評論文,書評,文献紹介等  

    DOI: 10.1080/1028415X.2016.1253171

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  • Serotonin 1A receptors on astrocytes as a potential target for treatment of Parkinson's disease.

    Miyazaki I, Asanuma M

    Curr. Med. Chem.   23 ( 7 )   686 - 700   2016年

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    記述言語:英語   掲載種別:書評論文,書評,文献紹介等  

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  • Doxorubicin and cyclophosphamide treatment produces anxiety-like behavior and spatial cognition impairment in rats: Possible involvement of hippocampal neurogenesis via brain-derived neurotrophic factor and cyclin D1 regulation

    Yoshihisa Kitamura, Sayo Hattori, Saori Yoneda, Saori Watanabe, Erika Kanemoto, Misaki Sugimoto, Toshiki Kawai, Ayumi Machida, Hirotaka Kanzaki, Ikuko Miyazaki, Masato Asanuma, Toshiaki Sendo

    BEHAVIOURAL BRAIN RESEARCH   292   184 - 193   2015年10月

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    記述言語:英語   掲載種別:書評論文,書評,文献紹介等   出版者・発行元:ELSEVIER SCIENCE BV  

    Many patients who have received chemotherapy to treat cancer experience depressive- and anxiety-like symptoms or cognitive impairment. However, despite the evidence for this, the underlying mechanisms are still not understood. This study investigated behavioral and biochemical changes upon treatment with doxorubicin and cyclophosphamide, focusing on mental and cognitive systems, as well as neurogenesis in male rats. Doxorubicin (2 mg/kg), cyclophosphamide (50 mg/kg), and the combination of doxorubicin and cyclophosphamide were injected intraperitoneally once per week for 4 weeks. In particular, the co-administration of doxorubicin and cyclophosphamide produced anhedonia-like, anxiety-like, and spatial cognitive impairments in rats. It also reduced both the number of proliferating cells in the subgranular zone of the hippocampal dentate gyrus and their survival. Serum brain-derived neurotrophic factor (BDNF) levels were decreased along with chemotherapy-induced decreases in platelet levels. However, hippocampal BDNF levels and Bdnf mRNA levels were not decreased by this treatment. On the other hand, hippocampal cyclin D1 levels were significantly decreased by chemotherapy. These results suggest that the co-administration of doxorubicin and cyclophosphamide induces psychological and cognitive impairment, in addition to negatively affecting hippocampal neurogenesis, which may be related to hippocampal cyclin D1 levels, but not hippocampal BDNF levels. (C) 2015 Elsevier B.V. All rights reserved.

    DOI: 10.1016/j.bbr.2015.06.007

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  • パーキンソン病モデルマウスにおけるアストロサイトの5‐HT1Aレセプターを標的とした神経保護

    宮崎育子, 宮崎育子, 菊岡亮, 久保田菜月, 前田恵実, 香川大樹, 村上真樹, 村上真樹, 北村佳久, 浅沼幹人, 浅沼幹人

    パーキンソン病・運動障害疾患コングレスプログラム・抄録集   9th   67 - 67   2015年10月

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    記述言語:日本語   出版者・発行元:Movement Disorder Society of Japan (MDSJ)  

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  • ミルタザピンのアストロサイトを標的としたドパミン神経保護効果

    宮崎育子, 菊岡亮, 久保田菜月, 前田恵実, 香川大樹, 村上真樹, 村上真樹, 北村佳久, 浅沼幹人, 浅沼幹人

    日本神経精神薬理学会プログラム・抄録集   45th   185 - 185   2015年9月

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    記述言語:日本語   出版者・発行元:日本生物学的精神医学会・日本神経精神薬理学会  

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  • Long-Term Systemic Exposure to Rotenone Induces Central and Peripheral Pathology of Parkinson's Disease in Mice

    Shinki Murakami, Ikuko Miyazaki, Ko Miyoshi, Masato Asanuma

    NEUROCHEMICAL RESEARCH   40 ( 6 )   1165 - 1178   2015年6月

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    記述言語:英語   掲載種別:書評論文,書評,文献紹介等   出版者・発行元:SPRINGER/PLENUM PUBLISHERS  

    Parkinson's disease (PD) is a progressive neurodegenerative disease with motor and non-motor symptoms that precede the onset of motor symptoms. Rotenone is often used to induce PD-like pathology in the central nervous system (CNS) and enteric nervous system (ENS). However, there is little or no information on the temporal changes in other neural tissues and the spread of pathology throughout the entire body organs. Here, we recorded the serial immunohistochemical changes in neurons and glial cells of the striatum, substantia nigra (SN), olfactory bulb (OB), thoracic cord (ThC) and ascending colon (AC) induced by 1-, 3- and 6-week administration of rotenone (50 mg/kg/day) infused subcutaneously in C57BL mice using an osmotic pump. Rotenone exposure for 3 or 6 weeks caused neurodegeneration in the striatum, whereas neuronal damage was seen in the SN and OB only after 6 weeks. Moreover, rotenone induced neurodegeneration in the myenteric plexus of AC but not in ThC. Rotenone also activated glial cells before any apparent neurodegeneration in the CNS but not in the ENS. Our results demonstrated that subcutaneous administration of rotenone can cause progressive neurodegeneration in the OB and AC, in addition to the nigrostriatal pathway, and temporal differential glial activation, and that these changes do not spread retrogradely from OB or ENS to nigrostriatal pathway. The results suggested that the different vulnerability of neurons to the neurotoxic effects of rotenone administrated subcutaneously are due to glial activation in these neural tissues.

    DOI: 10.1007/s11064-015-1577-2

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  • ALSモデルマウスにおけるセロトニン1Aアゴニストによる神経保護効果の検討

    中野剛志, 鳥越菜央, 村上真樹, 宮崎育子, 浅沼幹人, 北村佳久, 千堂年昭

    日本薬学会年会要旨集(CD-ROM)   135th ( 3 )   ROMBUNNO.28PB-PM242 - 191   2015年3月

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    記述言語:日本語   出版者・発行元:(公社)日本薬学会  

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  • Possible involvement of iron-induced oxidative insults in neurodegeneration

    Takeshi Asano, Masato Koike, Shin-ichi Sakata, Yukiko Takeda, Tomoko Nakagawa, Taku Hatano, Satoshi Ohashi, Manabu Funayama, Kenji Yoshimi, Masato Asanuma, Shinya Toyokuni, Hideki Mochizuki, Yasuo Uchiyama, Nobutaka Hattori, Kazuhiro Iwai

    NEUROSCIENCE LETTERS   588   29 - 35   2015年2月

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    記述言語:英語   掲載種別:書評論文,書評,文献紹介等   出版者・発行元:ELSEVIER IRELAND LTD  

    Involvement of iron in the development of neurodegenerative disorders has long been suggested, and iron that cannot be stored properly is suggested to induce iron toxicity. To enhance iron uptake and suppress iron storage in neurons, we generated transgenic (Tg) mice expressing iron regulatory protein 2 (IRP2), a major regulator of iron metabolism, in a neuron-specific manner. Although very subtle, IRP2 was expressed in all regions of brain examined. In the Tg mice, mitochondrial oxidative insults were observed including generation of 4-hydroxynonenal modified proteins, which appeared to be removed by a mitochondrial quality control protein Parkin. Inter-crossing of the Tg mice to Parkin knockout mice perturbed the integrity of neurons in the substantia nigra and provoked motor symptoms. These results suggest that a subtle, but chronic increase in IRP2 induces mitochondrial oxidative insults and accelerates neurodegeneration in a mouse model of Parkinson's disease. Thus, the IRP2 Tg may be a useful tool to probe the roles of iron-induced mitochondrial damages in neurodegeraration research. (C) 2014 Elsevier Ireland Ltd. All rights reserved.

    DOI: 10.1016/j.neulet.2014.12.052

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  • ハルミンの薬物依存性ならびに細胞毒性の評価:植物由来幻覚成分の有害作用について.

    舩田正彦, 竹林美佳, 宮崎育子, 浅沼幹人, 青尾直也, 和田 清

    精神保健研究   61 ( 28 )   61 - 72   2015年

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    記述言語:英語   掲載種別:書評論文,書評,文献紹介等  

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  • Visualization of Astrocytic Primary Cilia in the Mouse Brain by Immunofluorescent Analysis Using the Cilia Marker Arl13b

    Kyosuke Kasaharaa, Ko Miyoshi, Shinki Murakami, Ikuko Miyazaki, Masato Asanuma

    ACTA MEDICA OKAYAMA   68 ( 6 )   317 - 322   2014年12月

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    記述言語:英語   掲載種別:書評論文,書評,文献紹介等   出版者・発行元:OKAYAMA UNIV MED SCHOOL  

    In vertebrates, almost all somatic cells extend a single immotile cilium, referred to as a primary cilium. Increasing evidence suggests that primary cilia serve as cellular antennae in many types of tissues by sensing chemical or mechanical stimuli in the milieu surrounding the cells. In rodents an antibody to adenylyl cyclase 3 (AC3) has been widely used to label the primary cilia of neurons in vivo by immunostaining, whereas the lack of markers for the primary cilia of astrocytes has made it difficult to observe astrocytic primary cilia in vivo. Here, we obtained a visualization of astrocytic primary cilia in the mouse brain. In the somatosensory cortex, a large portion of neurons and astrocytes at postnatal day 10 (P10), and of neurons at P56 had AC3-positive primary cilia, whereas only approx. one-half of the astrocytes in the P56 mice carried primary cilia weakly positive for AC3. In contrast, the majority of astrocytes had ADP-ribosylation factor-like protein 13B (Arl13b)-positive primary cilia in the somatosensory cortex and other brain regions of P56 mice. The lengths of astrocytic primary cilia positive for Arl13b varied among the brain regions. Our data indicate that Arl13b is a noteworthy marker of astrocytic primary cilia in the brain.

    DOI: 10.18926/AMO/53020

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  • Methylphenidate improves learning impairments and hyperthermia-induced seizures caused by an Scn1a mutation

    Iori Ohmori, Nozomi Kawakami, Sumei Liu, Haijiao Wang, Ikuko Miyazaki, Masato Asanuma, Hiroyuki Michiue, Hideki Matsui, Tomoji Mashimo, Mamoru Ouchida

    EPILEPSIA   55 ( 10 )   1558 - 1567   2014年10月

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    記述言語:英語   掲載種別:書評論文,書評,文献紹介等   出版者・発行元:WILEY-BLACKWELL  

    ObjectiveDevelopmental disorders including cognitive deficit, hyperkinetic disorder, and autistic behaviors are frequently comorbid in epileptic patients with SCN1A mutations. However, the mechanisms underlying these developmental disorders are poorly understood and treatments are currently unavailable. Using a rodent model with an Scn1a mutation, we aimed to elucidate the pathophysiologic basis and potential therapeutic treatments for developmental disorders stemming from Scn1a mutations.MethodsWe conducted behavioral analyses on rats with the N1417H-Scn1a mutation. With high-performance liquid chromatography, we measured dopamine and its metabolites in the frontal cortex, striatum, nucleus accumbens, and midbrain. Methylphenidate was administered intraperitoneally to examine its effects on developmental disorder-like behaviors and hyperthermia-induced seizures.ResultsBehavioral studies revealed that Scn1a-mutant rats had repetitive behavior, hyperactivity, anxiety-like behavior, spatial learning impairments, and motor imbalance. Dopamine levels in the striatum and nucleus accumbens in Scn1a-mutant rats were significantly lower than those in wild-type rats. In Scn1a-mutant rats, methylphenidate, by increasing dopamine levels in the synaptic cleft, improved hyperactivity, anxiety-like behavior, and spatial learning impairments. Surprisingly, methylphenidate also strongly suppressed hyperthermia-induced seizures.SignificanceDysfunction of the mesolimbic dopamine reward pathway may contribute to the hyperactivity and learning impairments in Scn1a-mutant rats. Methylphenidate was effective for treating hyperactivity, learning impairments, and hyperthermia-induced seizures. We propose that methylphenidate treatment may ameliorate not only developmental disorders but also epileptic seizures in patients with SCN1A mutations.

    DOI: 10.1111/epi.12750

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  • Neuroprotective Effects of Metallothionein Against Rotenone-Induced Myenteric Neurodegeneration in Parkinsonian Mice

    Shinki Murakami, Ikuko Miyazaki, Norio Sogawa, Ko Miyoshi, Masato Asanuma

    NEUROTOXICITY RESEARCH   26 ( 3 )   285 - 298   2014年10月

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    記述言語:英語   掲載種別:書評論文,書評,文献紹介等   出版者・発行元:SPRINGER  

    Parkinson's disease (PD) is a neurodegenerative disease with motor symptoms as well as non-motor symptoms that precede the onset of motor symptoms. Mitochondrial complex I inhibitor, rotenone, has been widely used to reproduce PD pathology in the central nervous system (CNS) and enteric nervous system (ENS). We reported previously that metallothioneins (MTs) released from astrocytes can protect dopaminergic neurons against oxidative stress. The present study examined the changes in MT expression by chronic systemic rotenone administration in the striatum and colonic myenteric plexus of C57BL mice. In addition, we investigated the effects of MT depletion on rotenone-induced neurodegeneration in CNS and ENS using MT-1 and MT-2 knockout (MT KO) mice, or using primary cultured neurons from MT KO mice. In normal C57BL mice, subcutaneous administration of rotenone for 6 weeks caused neurodegeneration, increased MT expression with astrocytes activation in the striatum and myenteric plexus. MT KO mice showed more severe myenteric neuronal damage by rotenone administration after 4 weeks than wild-type mice, accompanied by reduced astroglial activation. In primary cultured mesencephalic neurons from MT KO mice, rotenone exposure induced neurotoxicity in dopaminergic neurons, which was complemented by addition of recombinant protein. The present results suggest that MT seems to provide protection against neurodegeneration in ENS of rotenone-induced PD model mice.

    DOI: 10.1007/s12640-014-9480-1

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  • Striatal Astrocytes Act as a Reservoir for L-DOPA

    Masato Asanuma, Ikuko Miyazaki, Shinki Murakami, Francisco J. Diaz-Corrales, Norio Ogawa

    PLOS ONE   9 ( 9 )   e106362   2014年9月

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    記述言語:英語   掲載種別:書評論文,書評,文献紹介等   出版者・発行元:PUBLIC LIBRARY SCIENCE  

    L-DOPA is therapeutically efficacious in patients with Parkinson's disease (PD), although dopamine (DA) neurons are severely degenerated. Since cortical astrocytes express neutral amino acid transporter (LAT) and DA transporter (DAT), the uptake and metabolism of L-DOPA and DA in striatal astrocytes may influence their availability in the dopaminergic system of PD. To assess possible L-DOPA-and DA-uptake and metabolic properties of striatal astrocytes, we examined the expression of L-DOPA, DA and DAT in striatal astrocytes of hemi-parkinsonian model rats after repeated L-DOPA administration, and measured the contents of L-DOPA, DA and their metabolite in primary cultured striatal astrocytes after L-DOPA/DA treatment. Repeated injections of L-DOPA induced apparent L-DOPA-and DA-immunoreactivities and marked expression of DAT in reactive astrocytes on the lesioned side of the striatum in hemi-parkinsonian rats. Exposure to DA for 4 h significantly increased the levels of DA and its metabolite DOPAC in cultured striatal astrocytes. L-DOPA was also markedly increased in cultured striatal astrocytes after 4-h L-DOPA exposure, but DA was not detected 4 or 8 h after L-DOPA treatment, despite the expression of aromatic amino acid decarboxylase in astrocytes. Furthermore, the intracellular level of L-DOPA in cultured striatal astrocytes decreased rapidly after removal of extracellular L-DOPA. The results suggest that DA uptaken into striatal astrocytes is rapidly metabolized and that striatal astrocytes act as a reservoir of L-DOPA that govern the uptake or release of L-DOPA depending on extracellular L-DOPA concentration, but are less capable of converting L-DOPA to DA.

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  • Effects of (+)-8-OH-DPAT on the duration of immobility during the forced swim test and hippocampal cell proliferation in ACTH-treated rats

    Ayaka Miyake, Yoshihisa Kitamura, Ikuko Miyazaki, Masato Asanuma, Toshiaki Sendo

    PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR   122   240 - 245   2014年7月

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    記述言語:英語   掲載種別:書評論文,書評,文献紹介等   出版者・発行元:PERGAMON-ELSEVIER SCIENCE LTD  

    In the present study, we examined the effect of ACTH on the immobilization of rats in the forced swim test and hippocampal cell proliferation after administration of the 5-HT1A receptor agonist, R-(+)-8-hydroxy-2-di-n-propylamino tetralin ((+)-8-OH-DPAT). Chronic treatment with (+)-8-OH-DPAT (0.01-0.1 mg/kg, s.c.) significantly decreased the duration of immobility in saline- and ACTH-treated rats. Chronic administration of ACTH caused a significant decrease in hippocampal cell proliferation. However, (+)-8-OH-DPAT significantly normalized cell proliferation in ACTH-treated rats. We then investigated the effects of (+)-8-OH-DPAT on the expression of brain-derived neurotrophic factor (BDNF) and cyclin D1 (elements of cyclic adenosine monophosphate response element-binding protein (CREB)-BDNF and Wnt signaling pathways, respectively) in the hippocampus of saline- and ACTH-treated rats. ACTH treatment significantly decreased the expression of cyclin D1, while treatment with (+)-8-OH-DPAT normalized the expression of cyclin D1 in ACTH-treated rats. However, the expression of BDNF did not change in either saline- or ACTH-treated rats. These findings suggest that the antidepressant effects of (+)-8-OH-DPAT in treatment-resistant animals may be attributed to an enhancement of hippocampal cell proliferation, at least in part due to an enhancement of cyclin D1 expression. (C) 2014 Elsevier Inc All rights reserved.

    DOI: 10.1016/j.pbb.2014.04.003

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  • Lack of Dopaminergic Inputs Elongates the Primary Cilia of Striatal Neurons

    Ko Miyoshi, Kyosuke Kasahara, Shinki Murakami, Mika Takeshima, Natsuko Kumamoto, Asako Sato, Ikuko Miyazaki, Shinsuke Matsuzaki, Toshikuni Sasaoka, Taiichi Katayama, Masato Asanuma

    PLOS ONE   9 ( 5 )   e97918   2014年5月

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    記述言語:英語   掲載種別:書評論文,書評,文献紹介等   出版者・発行元:PUBLIC LIBRARY SCIENCE  

    In the rodent brain, certain G protein-coupled receptors and adenylyl cyclase type 3 are known to localize to the neuronal primary cilium, a primitive sensory organelle protruding singly from almost all neurons. A recent chemical screening study demonstrated that many compounds targeting dopamine receptors regulate the assembly of Chlamydomonas reinhardtii flagella, structures which are analogous to vertebrate cilia. Here we investigated the effects of dopaminergic inputs loss on the architecture of neuronal primary cilia in the rodent striatum, a brain region that receives major dopaminergic projections from the midbrain. We first analyzed the lengths of neuronal cilia in the dorsolateral striatum of hemi-parkinsonian rats with unilateral lesions of the nigrostriatal dopamine pathway. In these rats, the striatal neuronal cilia were significantly longer on the lesioned side than on the non-lesioned side. In mice, the repeated injection of reserpine, a dopamine-depleting agent, elongated neuronal cilia in the striatum. The combined administration of agonists for dopamine receptor type 2 (D2) with reserpine attenuated the elongation of striatal neuronal cilia. Repeated treatment with an antagonist of D2, but not of dopamine receptor type 1 (D1), elongated the striatal neuronal cilia. In addition, D2-null mice displayed longer neuronal cilia in the striatum compared to wild-type controls. Reserpine treatment elongated the striatal neuronal cilia in D1-null mice but not in D2-null mice. Repeated treatment with a D2 agonist suppressed the elongation of striatal neuronal cilia on the lesioned side of hemi-parkinsonian rats. These results suggest that the elongation of striatal neuronal cilia following the lack of dopaminergic inputs is attributable to the absence of dopaminergic transmission via D2 receptors. Our results provide the first evidence that the length of neuronal cilia can be modified by the lack of a neurotransmitter's input.

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  • アストロサイトを介したレベチラセタムのドパミン神経保護効果に関する検討

    宮崎育子, 村上真樹, 鳥越菜央, 北村佳久, 浅沼幹人

    日本薬理学会近畿部会プログラム・要旨集   125th   37   2014年5月

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  • Protective Effects of Phytochemical Antioxidants Against Neurotoxin-Induced Degeneration of Dopaminergic Neurons

    Taizo Kita, Masato Asanuma, Ikuko Miyazaki, Mika Takeshima

    JOURNAL OF PHARMACOLOGICAL SCIENCES   124 ( 3 )   313 - 319   2014年3月

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    記述言語:英語   掲載種別:書評論文,書評,文献紹介等   出版者・発行元:JAPANESE PHARMACOLOGICAL SOC  

    The specific toxicity to dopaminergic neurons of psychostimulants and neurotoxins has been extensively studied in vivo and in vitro, and findings have been used to establish animal models of amphetamine psychosis or Parkinson's disease. The multiple mechanisms of neurotoxicity operating in these disorders are known to involve oxidative stress or neuroinflammation, producing the characteristic behavioral and neuropathlogical changes arising from injured dopaminergic neurons and glial cells. A number of studies have shown that glia-targeting antioxidants play important roles in protecting against the neurotoxicity caused by psychostimulants or neurotoxins. Phytochemicals, which are non-nutritive plant chemicals, protect dopaminergic neurons and glial cells from damage caused by psychostimulants or neurotoxins. The objective of this review was to evaluate the involvement of glial cells in dopaminergic neuron specific toxicity and to explore the neuroprotective activity of phytochemicals in terms of anti-inflammatory and antioxidant action.

    DOI: 10.1254/jphs.13R19CP

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  • ACTH反復投与ラットにおけるketamineの抗うつ効果に関する検討

    中村紘子, 米田紗緒里, 野白有里子, 宮崎育子, 浅沼幹人, 北村佳久, 千堂年昭

    日本薬学会年会要旨集(CD-ROM)   134th ( 3 )   ROMBUNNO.28PMM-105 - 151   2014年3月

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    記述言語:日本語   出版者・発行元:(公社)日本薬学会  

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  • Effects of Bupropion and Pramipexole on Cell Proliferation in the Hippocampus of Adrenocorticotropic Hormone-Treated Rats

    Yuka Onoue, Keiko Kuwatsuka, Ikuko Miyazaki, Masato Asanuma, Yoshihisa Kitamura, Toshiaki Sendo

    BIOLOGICAL & PHARMACEUTICAL BULLETIN   37 ( 2 )   327 - 330   2014年2月

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    記述言語:英語   掲載種別:書評論文,書評,文献紹介等   出版者・発行元:PHARMACEUTICAL SOC JAPAN  

    The dopamine reuptake inhibitor bupropion and dopamine D2/3 receptor agonist pramipexole have been clinically proven to improve both depression and treatment-resistant depression. We examined its influence on the duration of immobility during the forced swim test in adrenocorticotropic hormone (ACTH)-treated rats and further analyzed the possible role of the dopamine nerve system in this effect. Bupropion and pramipexole significantly decreased the duration of immobility in normal and ACTH-treated rats. We previously demonstrated that the chronic administration of ACTH caused a significant decrease in hippocampal cell proliferation and neurogenesis. In this study, we used the mitotic marker 5-bromo-2'-deoxyridine to investigate the effects of bupropion and pramipexole on cell proliferation in the subgranular zone of the hippocampal dentate gyms following chronic treatment with ACTH. The ACTH treatment for 14 d decreased adult hippocampal cell proliferation. The chronic administration of bupropion for 14 d blocked the loss of cell proliferation resulting from the chronic treatment with ACTH, whereas pramipexole did not. The administration of bupropion may have treatment-resistant antidepressive properties, which may be partly attributed to the normalization of hippocampal cell proliferation.

    DOI: 10.1248/bpb.b13-00749

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  • Metallothionein deficiency exacerbates diabetic nephropathy in streptozotocin-induced diabetic mice

    Hiromi Tachibana, Daisuke Ogawa, Norio Sogawa, Masato Asanuma, Ikuko Miyazaki, Naoto Terami, Takashi Hatanaka, Chikage Sato Horiguchi, Atsuko Nakatsuka, Jun Eguchi, Jun Wada, Hiroshi Yamada, Kohji Takei, Hirofumi Makino

    AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY   306 ( 1 )   F105 - F115   2014年1月

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    記述言語:英語   出版者・発行元:AMER PHYSIOLOGICAL SOC  

    Oxidative stress and inflammation play important roles in diabetic complications, including diabetic nephropathy. Metallothionein (MT) is induced in proximal tubular epithelial cells as an antioxidant in the diabetic kidney; however, the role of MT in renal function remains unclear. We therefore investigated whether MT deficiency accelerates diabetic nephropathy through oxidative stress and inflammation. Diabetes was induced by streptozotocin injection in MT-deficient (MT-/-) and MT+/+ mice. Urinary albumin excretion, histological changes, markers for reactive oxygen species (ROS), and kidney inflammation were measured. Murine proximal tubular epithelial (mProx24) cells were used to further elucidate the role of MT under high-glucose conditions. Parameters of diabetic nephropathy and markers of ROS and inflammation were accelerated in diabetic MT-/- mice compared with diabetic MT+/+ mice, despite equivalent levels of hyperglycemia. MT deficiency accelerated interstitial fibrosis and macrophage infiltration into the interstitium in the diabetic kidney. Electron microscopy revealed abnormal mitochondrial morphology in proximal tubular epithelial cells in diabetic MT-/- mice. In vitro studies demonstrated that knockdown of MT by small interfering RNA enhanced mitochondrial ROS generation and inflammation-related gene expression in mProx24 cells cultured under high-glucose conditions. The results of this study suggest that MT may play a key role in protecting the kidney against high glucose-induced ROS and subsequent inflammation in diabetic nephropathy.

    DOI: 10.1152/ajprenal.00034.2013

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  • アストロサイトによる神経機能修飾とパーキンソン病での神経保護

    浅沼幹人

    岡山医学会雑誌   126 ( 3 )   203 - 208   2014年

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    記述言語:英語   掲載種別:書評論文,書評,文献紹介等  

    DOI: 10.4044/joma.126.203

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  • Neuroprotective effects of levetiracetam in parkinsonian model mice

    Ikuko Miyazaki, Shinki Murakami, Nao Torigoe, Yoshihisa Kitamura, Masato Asanuma

    JOURNAL OF PHARMACOLOGICAL SCIENCES   124   150P - 150P   2014年

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:JAPANESE PHARMACOLOGICAL SOC  

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  • ALSモデルマウスにおけるセロトニン1Aアゴニストによる神経保護効果の検討

    中野剛志, 鳥越菜央, 村上真樹, 宮崎育子, 浅沼幹人, 北村佳久, 千堂年昭

    日本生物学的精神医学会誌   154   2014年

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  • 抗がん剤投与ラットにおける精神機能および海馬神経新生に関する検討

    米田紗緒里, 服部紗代, 中村紘子, 宮崎育子, 浅沼幹人, 北村佳久, 千堂年昭

    日本薬学会年会要旨集(CD-ROM)   134th   ROMBUNNO.GS02-7   2014年

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  • Targeting 5-HT1A receptors in astrocytes to protect dopaminergic neurons in parkinsonian models

    Ikuko Miyazaki, Masato Asanuma, Shinki Murakami, Mika Takeshima, Nao Torigoe, Yoshihisa Kitamura, Ko Miyoshi

    Neurobiology of Disease   59 ( 59 )   244 - 256   2013年11月

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    記述言語:英語   掲載種別:書評論文,書評,文献紹介等  

    Astrocytes are abundant neuron-supporting glial cells that harbor a powerful arsenal of neuroprotective antioxidative molecules and neurotrophic factors. Here we examined whether enrichment with healthy striatal astrocytes can provide neuroprotection against progressive dopaminergic neurodegeneration. Serotonin 1A (5-HT1A) agonist 8-OH-DPAT induced astrocyte proliferation and increased metallothionein-1/-2 (MT-1/-2), antioxidative molecules, in cultured astrocytes and the striatum of mice. Primary cultured mesencephalic dopamine neurons were protected against oxidative stress by preincubation with conditioned media from 8-OH-DPAT-treated astrocytes. These protective effects were canceled by 5-HT1A antagonist or MT-1/-2-specific antibody. Furthermore, reduction of nigrostriatal dopaminergic neurons in 6-hydroxydopamine-lesioned parkinsonian model mice was significantly abrogated by repeated injections of 8-OH-DPAT. Treatment with 8-OH-DPAT markedly increased the expression of MT in striatal astrocytes in the hemi-parkinsonian mice. Our study provides a promising therapeutic strategy of neuroprotection against oxidative stress and progressive dopaminergic neurodegeneration by demonstrating the efficacy of targeting 5-HT1A receptors in astrocytes. © 2013 Elsevier Inc.

    DOI: 10.1016/j.nbd.2013.08.003

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  • 線条体アストロサイトが酸化ストレスに対して発現誘導する因子の網羅的解析

    鳥越 菜央, 宮崎 育子, 村上 真樹, 北村 佳久, 千堂 年昭, 浅沼 幹人

    日本臨床精神神経薬理学会・日本神経精神薬理学会合同年会プログラム・抄録集   23回・43回   250 - 250   2013年10月

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    記述言語:日本語   出版者・発行元:日本臨床精神神経薬理学会・日本神経精神薬理学会  

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  • セロトニン1Aアゴニストによるアストロサイトにおけるメタロチオネイン発現誘導とドパミン神経保護

    宮崎 育子, 村上 真樹, 竹島 美香, 鳥越 菜央, 三好 耕, 北村 佳久, 浅沼 幹人

    日本臨床精神神経薬理学会・日本神経精神薬理学会合同年会プログラム・抄録集   23回・43回   251 - 251   2013年10月

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    記述言語:日本語   出版者・発行元:日本臨床精神神経薬理学会・日本神経精神薬理学会  

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  • Transplantation of Melanocytes Obtained from the Skin Ameliorates Apomorphine-Induced Abnormal Behavior in Rodent Hemi-Parkinsonian Models

    Masato Asanuma, Ikuko Miyazaki, Francisco J. Diaz-Corrales, Youichirou Higashi, Masayoshi Namba, Norio Ogawa

    PLoS ONE   8 ( 6 )   e65983   2013年6月

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    記述言語:英語   掲載種別:書評論文,書評,文献紹介等  

    Tyrosinase, which catalyzes both the hydroxylation of tyrosine and consequent oxidation of L-DOPA to form melanin in melanocytes, is also expressed in the brain, and oxidizes L-DOPA and dopamine. Replacement of dopamine synthesis by tyrosinase was reported in tyrosine hydroxylase null mice. To examine the potential benefits of autograft cell transplantation for patients with Parkinson's disease, tyrosinase-producing cells including melanocytes, were transplanted into the striatum of hemi-parkinsonian model rats or mice lesioned with 6-hydroxydopamine. Marked improvement in apomorphine-induced rotation was noted at day 40 after intrastriatal melanoma cell transplantation. Transplantation of tyrosinase cDNA-transfected hepatoma cells, which constitutively produce L-DOPA, resulted in marked amelioration of the asymmetric apomorphine-induced rotation in hemi-parkinsonian mice and the effect was present up to 2 months. Moreover, parkinsonian mice transplanted with melanocytes from the back skin of black newborn mice, but not from albino mice, showed marked improvement in the apomorphine-induced rotation behavior up to 3 months after the transplantation. Dopamine-positive signals were seen around the surviving transplants in these experiments. Taken together with previous studies showing dopamine synthesis and metabolism by tyrosinase, these results highlight therapeutic potential of intrastriatal autograft cell transplantation of melanocytes in patients with Parkinson's disease. © 2013 Asanuma et al.

    DOI: 10.1371/journal.pone.0065983

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  • Protective effect of cepharanthin on cisplatin-induced renal toxicity through metallothionein expression

    Norio Sogawa, Kanji Hirai, Chiharu Sogawa, Kazumi Ohyama, Ikuko Miyazaki, Goichi Tsukamoto, Masato Asanuma, Akira Sasaki, Shigeo Kitayama

    Life Sciences   92 ( 12 )   727 - 732   2013年4月

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    記述言語:英語   掲載種別:書評論文,書評,文献紹介等  

    Aims Cisplatin (CDDP) is a potent anticancer agent, but severe renal toxicity can limit its use. We investigated the protective effect of cepharanthin (CE), a biscoclaurin alkaloid, on the renal toxicity of CDDP. Main methods Mice were given CDDP along with CE. Effects of CE on CDDP toxicity were investigated by assaying markers of renal toxicity together with MT expression, and by histopathological examination of the kidney. MT-null mice were also examined. Key findings CE induced expression of metallothionein (MT). Pre-administration of CE attenuated an increase in blood urea nitrogen (BUN) concentrations after the CDDP injection. A histochemical analysis demonstrated protection against CDDP-induced necrocytosis of kidney tissues by CE. The protective effect of CE did not occur in the MT-null mice. Significance Pretreatment with CE may reduce the renal toxicity of CDDP through expression of MT. © 2013 Elsevier Inc.

    DOI: 10.1016/j.lfs.2013.01.031

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  • 培養アストログリア細胞における細胞保護効果.

    喜多大三, 浅沼幹人, 宮崎育子, 竹島美香

    九州栄養福祉大学研究紀要   ( 10 )   179 - 191   2013年

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  • アストロサイトとParkinson病治療

    神経内科   79 ( 2 )   257 - 261   2013年

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    記述言語:英語   掲載種別:書評論文,書評,文献紹介等  

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  • The mechanisms of electroconvulsive stimuli in BrdU-positive cells of the dentate gyrus in ACTH-treated rats

    Keiko Kuwatsuka, Hiromi Hayashi, Yuka Onoue, Ikuko Miyazaki, Toshihiro Koyama, Masato Asanuma, Yoshihisa Kitamura, Toshiaki Sendo

    Journal of Pharmacological Sciences   122 ( 1 )   34 - 41   2013年

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    記述言語:英語   掲載種別:書評論文,書評,文献紹介等  

    In clinical studies, electroconvulsive stimuli have been associated with improvements in both depression and treatment-resistant depression. In a previous study, treatment with adrenocorticotropic hormone (ACTH) for 14 days decreased adult hippocampal cell proliferation. Furthermore, electroconvulsive stimuli significantly decreased the duration of immobility following repeated administration of ACTH for 14 days in rats. The present study was undertaken to further characterize the mechanism of treatment-resistant antidepressant effects of electroconvulsive stimuli by measuring cell proliferation, brain-derived neurotrophic factor (BDNF) levels, and phosphorylated and total cyclic adenosine monophosphate (cAMP) response element-binding protein (pCREB/CREB) levels in the hippocampus of ACTH-treated rats. Electroconvulsive stimuli increased cell proliferation in both saline-treated and ACTH-treated rats. Mature-BDNF protein levels showed a tendency to decrease in ACTH-treated rats. Electroconvulsive stimuli treatment increased mature-BDNF protein levels in the hippocampus of both saline-treated and ACTH-treated rats. Furthermore, electroconvulsive stimuli increased phospho-Ser133-CREB (pCREB) levels and the ratio of pCREB/CREB in both saline-treated and ACTH-treated rats. These findings suggest that the treatment-resistant antidepressant effects of electroconvulsive stimuli may be attributed, at least in part, to an enhancement of hippocampal cell proliferation. © The Japanese Pharmacological Society.

    DOI: 10.1254/jphs.13015FP

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  • ラットの行動変化から推察する抗がん剤投与による精神機能変化―ドキソルビシンおよびシクロホスファミド投与による影響―

    北村佳久, 服部紗代, 米田沙緒里, 三宅彩香, 小山敏広, 宮崎育子, 浅沼幹人, 千堂年昭

    日本サイコオンコロジー学会総会プログラム・抄録集   26th   132   2013年

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  • Centrosomal aggregates and Golgi fragmentation disrupt vesicular trafficking of DAT

    Francisco J. Diaz-Corrales, Ikuko Miyazaki, Masato Asanuma, Diego Ruano, Rosa M. Rios

    NEUROBIOLOGY OF AGING   33 ( 10 )   2462 - 2477   2012年10月

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    記述言語:英語   掲載種別:書評論文,書評,文献紹介等   出版者・発行元:ELSEVIER SCIENCE INC  

    Lewy bodies containing the centrosomal protein gamma-tubulin and fragmentation of Golgi apparatus (GA) have been described in nigral neurons of Parkinson's disease (PD) patients. However, the relevance of these features in PD pathophysiology remains unknown. We analyzed the impact of proteasome inhibition in the formation of gamma-tubulin-containing aggregates as well as on GA structure. SH-SY5Y cells were treated with the proteasome inhibitor Z-Leu-Leu-Leu-al (MG132) to induce centrosomal-protein aggregates. Then, microtubules (MTs) and Golgi dynamics, as well as the vesicular transport of dopamine transporter (DAT) were evaluated both in vitro and in living cells. MG132 treatment induced gamma-tubulin aggregates which altered microtubule nucleation. MG132-treated cells containing gamma-tubulin aggregates showed fragmentation of GA and perturbation of the trans-Golgi network. Under these conditions, the DAT accumulated at the centrosomal-Golgi region indicating that the vesicular transport of DAT was disrupted. Thus, centrosomal aggregates and fragmentation of GA are 2 closely related processes that could result in the disruption of the vesicular transport of DAT toward the plasma membrane in a model of dopaminergic neuronal degeneration. (C) 2012 Elsevier Inc. All rights reserved.

    DOI: 10.1016/j.neurobiolaging.2011.11.014

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  • Cyclooxygenase-Independent Neuroprotective Effects of Aspirin Against Dopamine Quinone-Induced Neurotoxicity

    Masato Asanuma, Ikuko Miyazaki, Yuri Kikkawa, Naotaka Kimoto, Mika Takeshima, Shinki Murakami, Ko Miyoshi

    NEUROCHEMICAL RESEARCH   37 ( 9 )   1944 - 1951   2012年9月

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    記述言語:英語   掲載種別:書評論文,書評,文献紹介等   出版者・発行元:SPRINGER/PLENUM PUBLISHERS  

    Prostaglandin H synthase exerts not only cyclooxygenase activity but also peroxidase activity. The latter activity of the enzyme is thought to couple with oxidation of dopamine to dopamine quinone. Therefore, it has been proposed that cyclooxygenase inhibitors could suppress dopamine quinone formation. In the present study, we examined effects of various cyclooxygenase inhibitors against excess methyl L-3,4-dihydroxyphenylalanine (L-DOPA)-induced quinoprotein (protein-bound quinone) formation and neurotoxicity using dopaminergic CATH.a cells. The treatment with aspirin inhibited excess methyl L-DOPA-induced quinoprotein formation and cell death. However, acetaminophen did not show protective effects, and indomethacin and meloxicam rather aggravated these methyl L-DOPA-induced changes. Aspirin and indomethacin did not affect the level of glutathione that exerts quenching dopamine quinone in dopaminergic cells. In contrast with inhibiting effects of higher dose in the previous reports, relatively lower dose of aspirin that affected methyl L-DOPA-induced quinoprotein formation and cell death failed to prevent cyclooxygenase-induced dopamine chrome generation in cell-free system. Furthermore, aspirin but not acetaminophen or meloxicam showed direct dopamine quinone-scavenging effects in dopamine-semiquinone generating systems. The present results suggest that cyclooxygenase shows little contribution to dopamine oxidation in dopaminergic cells and that protective effects of aspirin against methyl L-DOPA-induced dopamine quinone neurotoxicity are based on its cyclooxygenase-independent property.

    DOI: 10.1007/s11064-012-0813-2

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  • Dipeptidyl compounds ameliorate the serum-deprivation-induced reduction in cell viability via the neurotrophin-activating effect in SH-SY5Y cells

    Ken-ichi Tanaka, Hiroya Ogo, Hiroaki Kaji, Kaori Miyatake, Erika Tokudome, Kanako Sonoda, Norio Ogawa, Masato Asanuma

    NEUROLOGICAL RESEARCH   34 ( 6 )   619 - 622   2012年7月

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    記述言語:英語   掲載種別:書評論文,書評,文献紹介等   出版者・発行元:MANEY PUBLISHING  

    Objectives and methods: We have searched for low-molecular-weight compounds as potent new non-immunosuppressive immunophilin ligands (NI-IPLs) that are stronger than existent NI-IPLs such as GPI1046 and/or V10367 from the perspective of neuroprotective efficacy. We selected six dipeptidyl compounds as new NI-IPL candidates, and first examined the effects of each of these compounds on the serum-deprivation-induced reduction in the viability of SH-SY5Y cells. In addition, we clarified the effects of these compounds on neurotrophin release into medium in SH-SY5Y cells.
    Results: Pre-treatment with Leu-Ile and Ile-Ile prevented the serum deprivation-induced reduction in cell viability in SH-SY5Y cells. In naive SH-SY5Y cells, treatment with Leu-Ile and Ile-Ile for 24 hours significantly increased both brain-derived neurotrophic factor and glial cell-line-derived neurotrophic factor releases in comparison with relative vehicle treatments. Moreover, none of the dipeptidyl compounds could prevent the concanavalin A-induced enhancement in interleukin-2 and interleukin-4 release in mouse spleen cells.
    Discussion: The immunosuppressive effect is not essential to the neuroprotective properties of dipeptidyl compounds, and Leu-Ile and Ile-Ile have neurotrophin-activating effects, like FK506 and its existing non-immunosuppressive derivatives.

    DOI: 10.1179/1743132812Y.0000000001

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  • EFFLUENT FREE RADICALS ARE ASSOCIATED WITH RESIDUAL RENAL FUNCTION AND PREDICT TECHNIQUE FAILURE IN PERITONEAL DIALYSIS PATIENTS

    Hiroshi Morinaga, Hitoshi Sugiyama, Tatsuyuki Inoue, Keiichi Takiue, Yoko Kikumoto, Masashi Kitagawa, Shigeru Akagi, Kazushi Nakao, Yohei Maeshima, Ikuko Miyazaki, Masato Asanuma, Makoto Hiramatsu, Hirofumi Makino

    PERITONEAL DIALYSIS INTERNATIONAL   32 ( 4 )   453 - 461   2012年7月

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    記述言語:英語   掲載種別:書評論文,書評,文献紹介等   出版者・発行元:MULTIMED INC  

    Objective: Residual renal function (RRF) is associated with low oxidative stress in peritoneal dialysis (PD). In the present study, we investigated the relationship between the impact of oxidative stress on RRF and patient outcomes during PD.
    Methods: Levels of free radicals (FRs) in effluent from the overnight dwell in 45 outpatients were determined by electron spin resonance spectrometry. The FR levels, clinical parameters, and the level of 8-hydroxy-2'-deoxyguanosine were evaluated at study start. The effects of effluent FR level on technique and patient survival were analyzed in a prospective cohort followed for 24 months.
    Results: Levels of effluent FRs showed significant negative correlations with daily urine volume and residual renal Kt/V, and positive correlations with plasma beta(2)-microglobulin and effluent 8-hydroxy-2'-deoxyguanosine. A highly significant difference in technique survival (p &lt; 0.05), but not patient survival, was observed for patients grouped by effluent FR quartile. The effluent FR level was independently associated with technique failure after adjusting for patient age, history of cardiovascular disease, and presence of diabetes mellitus (p &lt; 0.001). The level of effluent FRs was associated with death-censored technique failure in both univariate (p &lt; 0.001) and multivariate (p &lt; 0.01) hazard models. Compared with patients remaining on PD, those withdrawn from the modality had significantly higher levels of effluent FRs (p &lt; 0.005).
    Conclusions: Elevated effluent FRs are associated with RRF and technique failure in stable PD patients. These findings highlight the importance of oxidative stress as an unfavorable prognostic factor in PD and emphasize that steps should be taken to minimize oxidative stress in these patients. Perit Dial Int 2012; 32(4): 453-461

    DOI: 10.3747/pdi.2011.00032

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  • ACTH反復投与ラットにおける海馬細胞新生の減少及びそのメカニズムに関する検討.

    林 宏美, 土居真穂, 尾上由華, 鍬塚圭子, 三宅彩香, 小山敏広, 四宮一昭, 宮崎育子, 浅沼幹人, 北村佳久

    薬学雑誌   132   173 - 178   2012年

  • テアニンの中枢作用に関する文献的考察.

    喜多大三, 浅沼幹人, 宮崎育子, 竹島美香

    九州栄養福祉大学研究紀要   9   45 - 58   2012年

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    記述言語:英語   掲載種別:書評論文,書評,文献紹介等  

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  • Neuroprotective effects of serotonin-1a agonist 8-OH-DPAT in parkinsonian mice

    Ikuko Miyazaki, Shinki Murakami, Mika Takeshima, Masato Asanuma

    JOURNAL OF PHARMACOLOGICAL SCIENCES   118   111P - 111P   2012年

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:JAPANESE PHARMACOLOGICAL SOC  

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  • Protective effects of baicalein against excess L-DOPA-induced dopamine quinone neurotoxicity

    Mika Takeshima, Maiko Murata, Natsuho Urasoe, Shinki Murakami, Ikuko Miyazaki, Masato Asanuma, Taizo Kita

    NEUROLOGICAL RESEARCH   33 ( 10 )   1050 - 1056   2011年12月

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    記述言語:英語   掲載種別:書評論文,書評,文献紹介等   出版者・発行元:MANEY PUBLISHING  

    Objectives: Baicalein, a flavonoid derived from the root of Scutelaria baicalensis Georgi, possesses antioxidative properties including reactive oxygen species scavenging and lipid peroxidation inhibiting activities. The present study was undertaken to investigate the neuroprotective effect of baicalein against dopamine (DA) neurotoxicity induced by exposure to a synthetic DA precursor, L-3,4-dihydroxyphenylalanine (L-DOPA), in cultured dopaminergic CATH. a cells.
    Methods and results: Exposure to L-DOPA for 24 hours reduced the number of viable cells and enhanced protein-bound quinone (quinoprotein) formation in the cell. Both effects were prevented by simultaneous treatment with baicalein. In addition, baicalein prevented the formation of DA semiquinone radicals from DA in an in vitro cell-free system. Long-term baicalein treatment for 96 hours also protected against excess L-DOPA-induced cell death, and also increased glutathione (GSH) levels in CATH. a cells.
    Discussion: Our results indicate that baicalein has neuroprotective properties against excess L-DOPA-induced DA neurotoxicity through the suppression of DA quinone formation. Furthermore, the long-term treatment of baicalein upregulates intracellular GSH contents, which may also exert neuroprotective effects against oxidative stress-induced neuronal damage.

    DOI: 10.1179/1743132811Y.0000000032

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  • α7 Nicotinic acetylcholine receptors in the central amygdaloid nucleus alter naloxone-induced withdrawal following a single exposure to morphine.

    Ishida S, Kawasaki Y, Araki H, Asanuma M, Matsunaga H, Sendo T, Kawasaki H, Gomita Y, Kitamura Y

    Psychopharmacology   214 ( 4 )   923 - 931   2011年4月

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    記述言語:英語   掲載種別:書評論文,書評,文献紹介等  

    DOI: 10.1007/s00213-010-2101-7

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  • ACTH反復投与ラットにおける海馬細胞新生の減少およびそのメカニズムに関する検討

    林宏美, 土居真穂, 尾上由華, 鍬塚圭子, 三宅彩香, 小山敏広, 四宮一昭, 宮崎育子, 浅沼幹人, 北村佳久

    日本薬学会年会要旨集   131st ( 1 )   257   2011年3月

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    記述言語:日本語  

    J-GLOBAL

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  • Astrocyte-Derived Metallothionein Protects Dopaminergic Neurons from Dopamine Quinone Toxicity

    Ikuko Miyazaki, Masato Asanuma, Yuri Kikkawa, Mika Takeshima, Shinki Murakami, Ko Miyoshi, Norio Sogawa, Taizo Kita

    GLIA   59 ( 3 )   435 - 451   2011年3月

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    記述言語:英語   掲載種別:書評論文,書評,文献紹介等   出版者・発行元:WILEY-LISS  

    Our previous studies demonstrated the involvement of quinone formation in dopaminergic neuron dysfunction in the L-DOPA-treated parkinsonian model and in methamphetamine (METH) neurotoxicity. We further reported that the cysteine-rich metal-binding metallothionein (MT) family of proteins protects dopaminergic neurons against dopamine (DA) quinone neurotoxicity by its quinone-quenching property. The aim of this study was to examine MT induction in astrocytes in response to excess DA and the potential neuroprotective effects of astrocyte-derived MTs against DA quinone toxicity. DA exposure significantly upregulated MT-1/-2 in cultured striatal astrocytes, but not in mesencephalic neurons. This DA-induced MT upregulation in astrocytes was blocked by treatment with a DA-transporter (DAT) inhibitor, but not by DA-receptor antagonists. Expression of nuclear factor erythroid 2-related factor (Nrf2) and its binding activity to antioxidant response element of MT-1 gene were significantly increased in the astrocytes after DA exposure. Nuclear translocation of Nrf2 was suppressed by the DAT inhibitor. Quinone formation and reduction of mesencephalic DA neurons after DA exposure were ameliorated by preincubation with conditioned media from DA-treated astrocytes. These protective effects were abrogated by MT-1/-2-specific antibody. Adding exogenous MT-1 to glial conditioned media also showed similar neuroprotective effects. Furthermore, MT-1/-2 expression was markedly elevated specifically in reactive astrocytes in the striatum of L-DOPA-treated hemi-parkinsonian mice or METH-injected mice. These results suggested that excess DA taken up by astrocytes via DAT upregulates MT-1/-2 expression specifically in astrocytes, and that MTs or related molecules secreted specifically by astrocytes protect dopaminergic neurons from damage through quinone quenching and/or scavenging of free radicals. (C)2010 Wiley-Liss, Inc.

    DOI: 10.1002/glia.21112

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  • Chronic Treatment with Imipramine and Lithium Increases Cell Proliferation in the Hippocampus in Adrenocorticotropic Hormone-Treated Rats

    Yoshihisa Kitamura, Maho Doi, Keiko Kuwatsuka, Yuka Onoue, Ikuko Miyazaki, Kazuaki Shinomiya, Toshihiro Koyama, Toshiaki Sendo, Hiromu Kawasaki, Masato Asanuma, Yutaka Gomita

    BIOLOGICAL & PHARMACEUTICAL BULLETIN   34 ( 1 )   77 - 81   2011年1月

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    記述言語:英語   掲載種別:書評論文,書評,文献紹介等   出版者・発行元:PHARMACEUTICAL SOC JAPAN  

    Adult hippocampal neurogenesis is reported to change in animal models of depression and antidepressants. We have used the mitotic marker 5-bromo-2'-deoxyyridine to address the effects of imipramine and lithium on cell proliferation and survival following chronic treatment with adrenocorticotropic hormone (ACTH) in the subgranular zone of the hippocampal dentate gyrus. ACTH treatment for 14d decreased adult hippocampal cell proliferation and survival. Coadministration of imipramine and lithium for 14d blocked the loss of cell proliferation but not cell survival resulting from the chronic treatment with ACTH. The coadministration of imipramine and lithium may have treatment-resistant antidepressive properties, which may be attributed, in part, to a normalization of hippocampal cell proliferation.

    DOI: 10.1248/bpb.34.77

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  • Reply to Ahmad Ghanizadeh, A Novel Hypothesized Clinical Implication of Zonisamide for Autism.

    Asanuma M, Miyazaki I

    Ann Neurol   69   426 - 427   2011年

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    記述言語:英語   掲載種別:書評論文,書評,文献紹介等  

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  • Factors that influence primary cilium length.

    Miyoshi K, Kasahara K, Miyazaki I, Asanuma M

    Acta Medica Okayama   56   279 - 285   2011年

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    記述言語:英語   掲載種別:書評論文,書評,文献紹介等  

    DOI: 10.18926/AMO/47009

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  • High glucose increases metallothionein expression in renal proximal tubular epithelial cells.

    Ogawa D, Asanuma M, Miyazaki, I, Tachibana H, Wada J, Sogawa N, Sugaya T, Kitamura S, Maeshima Y, Shikata K, Makino F

    Exp Diabetes Res   2011   1 - 8   2011年

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    記述言語:英語   掲載種別:書評論文,書評,文献紹介等  

    DOI: 10.1155/2011/534872

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  • L-テアニンのグリア細胞に対する保護作用に関する研究─アストロサイトにおけるL-テアニンによる抗酸化保護作用の賦活─.

    喜多大三, 浅沼幹人, 宮崎育子, 竹島美香

    九州栄養福祉大学研究紀要   8   43 - 53   2011年

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    記述言語:英語   掲載種別:書評論文,書評,文献紹介等  

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  • パーキンソン病とアストロサイト─新たな神経保護療法の標的.

    浅沼幹人, 宮崎育子

    Clinical Neuroscience   29 ( 11 )   1295 - 1297   2011年

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    記述言語:英語   掲載種別:書評論文,書評,文献紹介等  

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  • Effects of imipramine and lithium on the suppression of cell proliferation in the dentate gyrus of the hippocampus in ACTH treated rats

    Hiromi Hayashi, Maho Doi, Yuka Onoue, Keiko Kuwatsuka, Ayaka Miyake, Toshihiro Koyama, Kazuaki Shinomiya, Ikuko Miyazaki, Masato Asanuma, Yoshihisa Kitamura

    JOURNAL OF PHARMACOLOGICAL SCIENCES   115   251P - 251P   2011年

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:JAPANESE PHARMACOLOGICAL SOC  

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  • Dopamine receptors localize to the neuronal primary cilium, a non-synaptic neurotransmission device

    Ko Miyoshi, Kyosuke Kasahara, Shinki Murakami, Ikuko Miyazaki, Masato Asanuma

    NEUROSCIENCE RESEARCH   71   E87 - E87   2011年

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:ELSEVIER IRELAND LTD  

    DOI: 10.1016/j.neures.2011.07.372

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  • Effects of rotenone exposure on primary cultured enteric neuronal or glial cells

    Ikuko Miyazaki, Shinki Murakami, Mika Takeshima, Ko Miyoshi, Masato Asanuma

    NEUROSCIENCE RESEARCH   71   E190 - E190   2011年

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:ELSEVIER IRELAND LTD  

    DOI: 10.1016/j.neures.2011.07.820

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  • Effects of chronic rotenone exposure on enteric neuronal or glial cells in vivo

    Shinki Murakami, Ikuko Miyazaki, Mika Takeshima, Ko Miyoshi, Masato Asanuma

    NEUROSCIENCE RESEARCH   71   E190 - E190   2011年

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:ELSEVIER IRELAND LTD  

    DOI: 10.1016/j.neures.2011.07.821

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  • Effects of bupropion on the forced swim test and release of dopamine in the nucleus accumbens in ACTH-treated rats

    Yoshihisa Kitamura, Takahiko Yagi, Kouhei Kitagawa, Kazuaki Shinomiya, Hiromu Kawasaki, Masato Asanuma, Yutaka Gomita

    NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY   382 ( 2 )   151 - 158   2010年8月

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    記述言語:英語   掲載種別:書評論文,書評,文献紹介等   出版者・発行元:SPRINGER  

    The dopamine reuptake inhibitor bupropion has clinically been proven to improve depression and treatment-resistant depression. We examined its influence on the duration of immobility during the forced swim test in adrenocorticotropic hormone (ACTH)-treated rats and further analyzed the possible role of dopamine receptors in this effect. Additionally, the mechanism by which bupropion acts in this model was explored specifically in relation to the site of action through the use of microinjections into the medial prefrontal cortex and nucleus accumbens. Bupropion significantly decreased the duration of immobility in normal and ACTH-treated rats. This effect was blocked by D2 and D3 receptor antagonists in normal rats. Furthermore, infusions of bupropion into the nucleus accumbens, but not medial prefrontal cortex, decreased the immobility of normal and ACTH-treated rats during the forced swim test. Bupropion treatment plus repeated ACTH treatment significantly increased the extracellular dopamine concentration. These findings suggest the antidepressant-like effect of bupropion to be related to levels of dopamine in the rat nucleus accumbens.

    DOI: 10.1007/s00210-010-0521-x

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  • Effects of Imipramine and Lithium on the Suppression of Cell Proliferation in the Dentate Gyrus of the Hippocampus in Adrenocorticotropic Hormone-treated Rats

    Maho Doi, Ikuko Miyazaki, Tomoko Nagamachi, Kazuaki Shinomiya, Hisashi Matsunaga, Toshiaki Sendo, Hiromu Kawasaki, Masato Asanuma, Yutaka Gomita, Yoshihisa Kitamura

    ACTA MEDICA OKAYAMA   64 ( 4 )   219 - 223   2010年8月

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    記述言語:英語   掲載種別:書評論文,書評,文献紹介等   出版者・発行元:OKAYAMA UNIV MED SCHOOL  

    We examined the influence of chronic adrenocorticotropic hormone (ACTH) treatment on the number of Ki-67-positive cells in the dentate gyrus of the hippocampus in rats. ACTH treatment for 14 days decreased the number of such cells. The administration of imipramine or lithium alone for 14 days had no effect in saline-treated rats. The effect of ACTH was blocked by the administration of imipramine. Furthermore, the coadministration of imipramine and lithium for 14 days significantly increased the number of Ki-67-positive cells in both the saline and ACTH-treated rats. The coadministration of imipramine and lithium normalized the cell proliferation in the dentate gyrus of the hippocampus in rats treated with ACTH.

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  • Induction of Parkinsonism-Related Proteins in the Spinal Motor Neurons of Transgenic Mouse Carrying a Mutant SOD1 Gene

    Nobutoshi Morimoto, Makiko Nagai, Kazunori Miyazaki, Yasuyuki Ohta, Tomoko Kurata, Yasushi Takehisa, Yoshio Ikeda, Tohru Matsuura, Masato Asanuma, Koji Abe

    JOURNAL OF NEUROSCIENCE RESEARCH   88 ( 8 )   1804 - 1811   2010年6月

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    記述言語:英語   掲載種別:書評論文,書評,文献紹介等   出版者・発行元:WILEY-LISS  

    Amyotrophic la