研究者詳細 - 宮﨑　育子

論文 - 宮﨑　育子

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Multifunctional Metallothioneins as a Target for Neuroprotection in Parkinson’s Disease 招待査読

Ikuko Miyazaki, Masato Asanuma

Antioxidants 12 ( 4 ) 894 - 894 2023年4月

担当区分：筆頭著者,　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：MDPI AG

Parkinson’s disease (PD) is characterized by motor symptoms based on a loss of nigrostriatal dopaminergic neurons and by non-motor symptoms which precede motor symptoms. Neurodegeneration accompanied by an accumulation of α-synuclein is thought to propagate from the enteric nervous system to the central nervous system. The pathogenesis in sporadic PD remains unknown. However, many reports indicate various etiological factors, such as oxidative stress, inflammation, α-synuclein toxicity and mitochondrial impairment, drive neurodegeneration. Exposure to heavy metals contributes to these etiopathogenesis and increases the risk of developing PD. Metallothioneins (MTs) are cysteine-rich metal-binding proteins; MTs chelate metals and inhibit metal-induced oxidative stress, inflammation and mitochondrial dysfunction. In addition, MTs possess antioxidative properties by scavenging free radicals and exert anti-inflammatory effects by suppression of microglial activation. Furthermore, MTs recently received attention as a potential target for attenuating metal-induced α-synuclein aggregation. In this article, we summarize MTs expression in the central and enteric nervous system, and review protective functions of MTs against etiopathogenesis in PD. We also discuss neuroprotective strategies for the prevention of central dopaminergic and enteric neurodegeneration by targeting MTs. This review highlights multifunctional MTs as a target for the development of disease-modifying drugs for PD.

DOI： 10.3390/antiox12040894

Neuron-Astrocyte Interactions in Parkinson’s Disease 招待査読

Ikuko Miyazaki, Masato Asanuma

Cells 9 ( 12 ) 2623 - 2623 2020年12月

担当区分：筆頭著者,　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：MDPI AG

Parkinson’s disease (PD) is the second most common neurodegenerative disease. PD patients exhibit motor symptoms such as akinesia/bradykinesia, tremor, rigidity, and postural instability due to a loss of nigrostriatal dopaminergic neurons. Although the pathogenesis in sporadic PD remains unknown, there is a consensus on the involvement of non-neuronal cells in the progression of PD pathology. Astrocytes are the most numerous glial cells in the central nervous system. Normally, astrocytes protect neurons by releasing neurotrophic factors, producing antioxidants, and disposing of neuronal waste products. However, in pathological situations, astrocytes are known to produce inflammatory cytokines. In addition, various studies have reported that astrocyte dysfunction also leads to neurodegeneration in PD. In this article, we summarize the interaction of astrocytes and dopaminergic neurons, review the pathogenic role of astrocytes in PD, and discuss therapeutic strategies for the prevention of dopaminergic neurodegeneration. This review highlights neuron-astrocyte interaction as a target for the development of disease-modifying drugs for PD in the future.

DOI： 10.3390/cells9122623

Mirtazapine exerts astrocyte-mediated dopaminergic neuroprotection 査読

Ryo Kikuoka, Ikuko Miyazaki, Natsuki Kubota, Megumi Maeda, Daiki Kagawa, Masaaki Moriyama, Asuka Sato, Shinki Murakami, Yoshihisa Kitamura, Toshiaki Sendo, Masato Asanuma

Scientific Reports 10 ( 1 ) 20698 - 20698 2020年12月

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 Science and Business Media LLC

<title>Abstract</title>Mirtazapine, a noradrenergic and specific serotonergic antidepressant (NaSSA), is known to activate serotonin (5-HT) 1A receptor. Our recent study demonstrated that stimulation of astrocytic 5-HT1A receptors promoted astrocyte proliferation and upregulated antioxidative property in astrocytes to protect dopaminergic neurons against oxidative stress. Here, we evaluated the neuroprotective effects of mirtazapine against dopaminergic neurodegeneration in models of Parkinson’s disease (PD). Mirtazapine administration attenuated the loss of dopaminergic neurons in the substantia nigra and increased the expression of the antioxidative molecule metallothionein (MT) in the striatal astrocytes of 6-hydroxydopamine (6-OHDA)-injected parkinsonian mice via 5-HT1A receptors. Mirtazapine protected dopaminergic neurons against 6-OHDA-induced neurotoxicity in mesencephalic neuron and striatal astrocyte cocultures, but not in enriched neuronal cultures. Mirtazapine-treated neuron-conditioned medium (Mir-NCM) induced astrocyte proliferation and upregulated MT expression via 5-HT1A receptors on astrocytes. Furthermore, treatment with medium from Mir-NCM-treated astrocytes protected dopaminergic neurons against 6-OHDA neurotoxicity, and these effects were attenuated by treatment with a MT-1/2-specific antibody or 5-HT1A antagonist. Our study suggests that mirtazapine could be an effective disease-modifying drug for PD and highlights that astrocytic 5-HT1A receptors may be a novel target for the treatment of PD.

DOI： 10.1038/s41598-020-77652-4

その他リンク： http://www.nature.com/articles/s41598-020-77652-4

The Rotenone Models Reproducing Central and Peripheral Features of Parkinson’s Disease 招待査読

Ikuko Miyazaki, Masato Asanuma

NeuroSci 1 ( 1 ) 1 - 14 2020年8月

担当区分：筆頭著者,　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：MDPI AG

Parkinson’s disease (PD) is a complex, multi-system, neurodegenerative disorder; PD patients exhibit motor symptoms (such as akinesia/bradykinesia, tremor, rigidity, and postural instability) due to a loss of nigrostriatal dopaminergic neurons, and non-motor symptoms such as hyposmia, autonomic disturbance, depression, and REM sleep behavior disorder (RBD), which precedes motor symptoms. Pathologically, α-synuclein deposition is observed in the central and peripheral nervous system of sporadic PD patients. To clarify the mechanism of neurodegeneration in PD and to develop treatment to slow or stop PD progression, there is a great need for experimental models which reproduce neurological features of PD. Animal models exposed to rotenone, a commonly used pesticide, have received most attention since Greenamyre and his colleagues reported that chronic exposure to rotenone could reproduce the anatomical, neurochemical, behavioral, and neuropathological features of PD. In addition, recent studies demonstrated that rotenone induced neuropathological change not only in the central nervous system but also in the peripheral nervous system in animals. In this article, we review rotenone models especially focused on reproducibility of central and peripheral multiple features of PD. This review also highlights utility of rotenone models for investigation of PD pathogenesis and development of disease-modifying drugs for PD in future.

DOI： 10.3390/neurosci1010001

Chronic Systemic Exposure to Low-Dose Rotenone Induced Central and Peripheral Neuropathology and Motor Deficits in Mice: Reproducible Animal Model of Parkinson’s Disease 招待査読

Ikuko Miyazaki, Nami Isooka, Fuminori Imafuku, Jin Sun, Ryo Kikuoka, Chieko Furukawa, Masato Asanuma

International Journal of Molecular Sciences 21 ( 9 ) 3254 - 3254 2020年5月

担当区分：筆頭著者,　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：MDPI AG

Epidemiological studies demonstrated that pesticide exposure, such as rotenone and paraquat, increases the risk of Parkinson’s disease (PD). Chronic systemic exposure to rotenone, a mitochondrial complex I inhibitor, could reproduce many features of PD. However, the adoption of the models is limiting because of variability in animal sensitivity and the inability of other investigators to consistently reproduce the PD neuropathology. In addition, most of rotenone models were produced in rats. Here, we tried to establish a high-reproducible rotenone model using C57BL/6J mice. The rotenone mouse model was produced by chronic systemic exposure to a low dose of rotenone (2.5 mg/kg/day) for 4 weeks by subcutaneous implantation of rotenone-filled osmotic mini pump. The rotenone-treated mice exhibited motor deficits assessed by open field, rotarod and cylinder test and gastrointestinal dysfunction. Rotenone treatment decreased the number of dopaminergic neuronal cells in the substantia nigra pars compacta (SNpc) and lesioned nerve terminal in the striatum. In addition, we observed significant reduction of cholinergic neurons in the dorsal motor nucleus of the vagus (DMV) and the intestinal myenteric plexus. Moreover, α-synuclein was accumulated in neuronal soma in the SNpc, DMV and intestinal myenteric plexus in rotenone-treated mice. These data suggest that the low-dose rotenone mouse model could reproduce behavioral and central and peripheral neurodegenerative features of PD and be a useful model for investigation of PD pathogenesis.

DOI： 10.3390/ijms21093254

Effects of maternal bisphenol A diglycidyl ether exposure during gestation and lactation on behavior and brain development of the offspring 査読

Ikuko Miyazaki, Ryo Kikuoka, Nami Isooka, Mika Takeshima, Kanau Sonobe, Rei Arai, Hidemaru Funakoshi, Kyle E. Quin, Jonathan Smart, Kazumasa Zensho, Masato Asanuma

Food and Chemical Toxicology 138 111235 - 111235 2020年4月

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

Nami Isooka, Ikuko Miyazaki, Ryo Kikuoka, Kouichi Wada, Erika Nakayama, Kotaro Shin, Daichi Yamamoto, Yoshihisa Kitamura, Masato Asanuma

Neurochemistry International 132 104608 - 104608 2020年1月

Effects of Enteric Environmental Modification by Coffee Components on Neurodegeneration in Rotenone-Treated Mice 招待査読

Ikuko Miyazaki, Nami Isooka, Kouichi Wada, Ryo Kikuoka, Yoshihisa Kitamura, Masato Asanuma

Cells 8 ( 3 ) 221 - 221 2019年3月

担当区分：筆頭著者,　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：MDPI AG

Epidemiological studies have shown that coffee consumption decreases the risk of Parkinson’s disease (PD). Caffeic acid (CA) and chlorogenic acid (CGA) are coffee components that have antioxidative properties. Rotenone, a mitochondrial complex I inhibitor, has been used to develop parkinsonian models, because the toxin induces PD-like pathology. Here, we examined the neuroprotective effects of CA and CGA against the rotenone-induced degeneration of central dopaminergic and peripheral enteric neurons. Male C57BL/6J mice were chronically administered rotenone (2.5 mg/kg/day), subcutaneously for four weeks. The animals were orally administered CA or CGA daily for 1 week before rotenone exposure and during the four weeks of rotenone treatment. Administrations of CA or CGA prevented rotenone-induced neurodegeneration of both nigral dopaminergic and intestinal enteric neurons. CA and CGA upregulated the antioxidative molecules, metallothionein (MT)-1,2, in striatal astrocytes of rotenone-injected mice. Primary cultured mesencephalic or enteric cells were pretreated with CA or CGA for 24 h, and then further co-treated with a low dose of rotenone (1–5 nM) for 48 h. The neuroprotective effects and MT upregulation induced by CA and CGA in vivo were reproduced in cultured cells. Our data indicated that intake of coffee components, CA and CGA, enhanced the antioxidative properties of glial cells and prevents rotenone-induced neurodegeneration in both the brain and myenteric plexus.

DOI： 10.3390/cells8030221

Region-Specific Neuroprotective Features of Astrocytes against Oxidative Stress Induced by 6-Hydroxydopamine 招待査読

Masato Asanuma, Nao Okumura-Torigoe, Ikuko Miyazaki, Shinki Murakami, Yoshihisa Kitamura, Toshiaki Sendo

International Journal of Molecular Sciences 20 ( 3 ) 598 - 598 2019年1月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：MDPI AG

In previous studies, we found regional differences in the induction of antioxidative molecules in astrocytes against oxidative stress, postulating that region-specific features of astrocytes lead region-specific vulnerability of neurons. We examined region-specific astrocytic features against dopaminergic neurotoxin 6-hydroxydopamine (6-OHDA) as an oxidative stress using co-culture of mesencephalic neurons and mesencephalic or striatal astrocytes in the present study. The 6-OHDA-induced reduction of mesencephalic dopamine neurons was inhibited by co-culturing with astrocytes. The co-culture of midbrain neurons with striatal astrocytes was more resistant to 6-OHDA than that with mesencephalic astrocytes. Furthermore, glia conditioned medium from 6-OHDA-treated striatal astrocytes showed a greater protective effect on the 6-OHDA-induced neurotoxicity and oxidative stress than that from mesencephalic astrocytes. The cDNA microarray analysis showed that the number of altered genes in both mesencephalic and striatal astrocytes was fewer than that changed in either astrocyte. The 6-OHDA treatment, apparently up-regulated expressions of Nrf2 and some anti-oxidative or Nrf2-regulating phase II, III detoxifying molecules related to glutathione synthesis and export in the striatal astrocytes but not mesencephalic astrocytes. There is a profound regional difference of gene expression in astrocytes induced by 6-OHDA. These results suggest that protective features of astrocytes against oxidative stress are more prominent in striatal astrocytes, possibly by secreting humoral factors in striatal astrocytes.

DOI： 10.3390/ijms20030598

Therapeutic Strategy of Targeting Astrocytes for Neuroprotection in Parkinson's Disease 招待査読

Ikuko Miyazaki, Masato Asanuma

Current Pharmaceutical Design 23 ( 33 ) 2018年1月

Editorial: Astrocyte-targeted therapeutic strategies for neurological disorders. 招待査読

Ikuko Miyazaki

Current Pharmaceutical Design 23 ( 33 ) 4933 - 4935 2017年

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

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

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

担当区分：筆頭著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：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

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

Ikuko Miyazaki, Masato Asanuma

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

担当区分：筆頭著者,　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：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

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

Ikuko Miyazaki, Shinki Murakami, Takashi Nakano, Nao Torigoe, Ryo Kikuoka, Yoshihisa Kitamura, Toshiaki Sendo, Masato Asanuma

Annals of Pharmacology and Pharmaceutics 1 ( 1 ) 1003 - 1003 2016年

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

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

担当区分：筆頭著者記述言語：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

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

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

担当区分：筆頭著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：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

Neuroprotective Effects of Zonisamide Target Astrocyte 査読

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

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'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

Approaches to Prevent Dopamine Quinone-Induced Neurotoxicity 査読

Ikuko Miyazaki, Masato Asanuma

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

担当区分：筆頭著者,　責任著者記述言語：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'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

Dopaminergic neuron-specific oxidative stress caused by dopamine itself

Ikuko Miyazaki, Masato Asanuma

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

担当区分：筆頭著者,　責任著者記述言語：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

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

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

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

担当区分：筆頭著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：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

Methamphetamine‐induced dopaminergic neurotoxicity is regulated by quinone formation‐related molecules 査読国際誌

Ikuko Miyazaki, Masato Asanuma, Francisco J. Diaz‐Corrales, Masaya Fukuda, Kiyoyuki Kitaichi, Ko Miyoshi, Norio Ogawa

The FASEB Journal 20 ( 3 ) 571 - 573 2006年3月

担当区分：筆頭著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Wiley

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

その他リンク： https://onlinelibrary.wiley.com/doi/full-xml/10.1096/fj.05-4996fje

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

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

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

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

Brain Research 1029 ( 1 ) 120 - 123 2004年12月

担当区分：筆頭著者記述言語：英語掲載種別：研究論文（学術雑誌）

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. © 2004 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.brainres.2004.09.014

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

Ikuko Miyazaki, Masato Asanuma, Youichirou Higashi, Chiharu Aoki Sogawa, Ken-ichi Tanaka, Norio Ogawa

Neuroscience Research 43 ( 4 ) 323 - 333 2002年8月

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

Ikuko Miyazaki, Chiharu Aoki Sogawa, Masato Asanuma, Youichirou Higashi, Ken-ichi Tanaka, Tohru Nakanishi, Norio Ogawa

Neuroscience Letters 293 ( 1 ) 65 - 68 2000年10月

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

Ikuko Miyazaki, Emi Iwata-Ichikawa, Masato Asanuma, Motoyuki Iida, Norio Ogawa

Neurochemical Research 24 ( 7 ) 857 - 860 1999年

Spatiotemporal expression pattern of dyslexia susceptibility 1 candidate 1 (DYX1C1) during rat cerebral cortex development

Kazumasa Zensho, Ikuko Miyazaki, Aika Isse, Ichika Misawa, Kaori Masai, Makio Oka, Hirokazu Tsukahara, Masato Asanuma

Pediatric Research 2025年2月

掲載種別：研究論文（学術雑誌）出版者・発行元：Springer Science and Business Media LLC

Abstract

Background

Developmental dyslexia (DD) is a common learning disorder with significant consequences for affected individuals. Although several candidate genes, including dyslexia susceptibility 1 candidate 1 (DYX1C1), have been implicated in dyslexia, their role in brain development remains unclear. We aimed to elucidate the spatiotemporal expression patterns of DYX1C1 during cerebral cortex development in rats.

Methods

We investigated DYX1C1 expression during cerebral cortex development using rat embryos at various gestational stages (E13.5, 15.5, 17.5 and 20.5) by immunohistochemistry (n = 7 embryos/stage), quantitative real-time PCR (n = 6), and in situ hybridization (n = 11–15).

Results

The DYX1C1-positive cells were predominantly located in the outermost layers of the cortical plate, particularly at E15.5. DYX1C1 mRNA expression peaked at E15.5 and subsequently declined. DYX1C1-positive cells did not co-localize with reelin-positive Cajal-Retzius cells, but co-localized with neuronal markers expressed during development, and had shorter primary cilia than DYX1C1-negative cells.

Conclusions

Our findings highlight the dynamic expression of DYX1C1 in the developing cerebral cortex of rats, implicating its involvement in neurodevelopmental processes. Further investigation of the functional interactions of DYX1C1, particularly its relationship with reelin and its role in cerebrocortical and hippocampal development, may provide insights into the pathophysiology of dyslexia and neurodevelopmental disorders.

Impact

Our study elucidates spatiotemporal expression patterns of endogenous DYX1C1 predominantly in the primitive cortical zone (PCZ), outermost layer of the cortical plate (CP) during cerebral cortex development, particularly peaked at E15.5.

We revealed the spatial relationship between DYX1C1-positive and reelin-expressing Cajal-Retzius (CR) cells, and co-localize with neuronal markers expressed during cerebral cortex development, indicating its contribution to neuronal migration and cortical layer formation.

DYX1C1-positive cells mainly in the PCZ possess shorter primary cilia than DYX1C1-negative cells, suggesting the completion of migration.

DOI： 10.1038/s41390-025-03920-6

その他リンク： https://www.nature.com/articles/s41390-025-03920-6

Editorial: Glial crosstalk in neurological disorders

Ikuko Miyazaki, Masato Asanuma, Francisco Javier Díaz-Corrales

Frontiers in Cell and Developmental Biology 12 2024年11月

Behavioural and neurochemical alterations following acute inflammation induced by intraperitoneal and intratracheal injection with lipopolysaccharide in mice. 査読

Izushi, Y, Tanaka, S, Ueda, T, Ushio, S, Tasaka, Y, Miyazaki, I, Asanuma, M, Kitamura, Y

Naunyn Schmiedebergs Arch Pharmacol 2024年9月

Differentially Expressed Nedd4-binding Protein Ndfip1 Protects Neurons Against Methamphetamine-induced Neurotoxicity. 査読

Masato Asanuma, Ikuko Miyazaki, Jean Kud Cade

Neurotoxicity Research 2024年

Neurogenesis impairment with glial activation in the hippocampus-connected regions of intracerebroventricular streptozotocin-injected mice 査読

Kaori Masai, Yuta Nakayama, Kotaro Shin, Chiaki Sugahara, Ikuko Miyazaki, Takao Yasuhara, Isao Date, Masato Asanuma

Neuroscience Letters 137598 - 137598 2023年12月

Phosphorylated SARM1 is involved in the pathological process of rotenone-induced neurodegeneration. 査読国際誌

Hitoshi Murata, May Tha Zin Phoo, Toshiki Ochi, Nahoko Tomonobu, Ken-Ichi Yamamoto, Rie Kinoshita, Ikuko Miyazaki, Masahiro Nishibori, Masato Asanuma, Masakiyo Sakaguchi

Journal of biochemistry 2023年9月

記述言語：英語掲載種別：研究論文（学術雑誌）

Sterile alpha and Toll/interleukin receptor motif-containing protein 1 (SARM1) is a NAD+ hydrolase that plays a key role in axonal degeneration and neuronal cell death. We reported that c-Jun N-terminal kinase (JNK) activates SARM1 through phosphorylation at Ser-548. The importance of SARM1 phosphorylation in the pathological process of Parkinson's disease (PD) has not been determined. We thus conducted the present study by using rotenone (an inducer of PD-like pathology) and neurons derived from induced pluripotent stem cells (iPSCs) from healthy donors and a patient with familial PD PARK2 (FPD2). The results showed that compared to the healthy neurons, FPD2 neurons were more vulnerable to rotenone-induced stress and had higher levels of SARM1 phosphorylation. Similar cellular events were obtained when we used PARK2-knockdown neurons derived from healthy donor iPSCs. These events in both types of PD-model neurons were suppressed in neurons treated with JNK inhibitors, Ca2+-signal inhibitors, or by a SARM1-knockdown procedure. The degenerative events were enhanced in neurons overexpressing wild-type SARM1 and conversely suppressed in neurons overexpressing the SARM1-S548A mutant. We also detected elevated SARM1 phosphorylation in the midbrain of PD-model mice. The results indicate that phosphorylated SARM1 plays an important role in the pathological process of rotenone-induced neurodegeneration.

DOI： 10.1093/jb/mvad068

Central and enteric neuroprotective effects by Eucommia ulmoides extracts on neurodegeneration in rotenone-induced parkinsonian mouse. 査読

Fuminori Imafuku, Ikuko Miyazaki, Jin Sun, Sunao Kamimai, Takashi Shimizu, Toshiaki Toyota, Yusei Okamoto, Nami Isooka, Ryo Kikuoka, Yoshihisa Kitamura, Masato Asanuma

76 ( 4 ) 373 - 383 2022年1月

Neuroprotective Effects of Anti-high Mobility Group Box-1 Monoclonal Antibody Against Methamphetamine-Induced Dopaminergic Neurotoxicity 査読

Kaori Masai, Keita Kuroda, Nami Isooka, Ryo Kikuoka, Shinki Murakami, Sunao Kamimai, Dengli Wang, Keyue Liu, Ikuko Miyazaki, Masahiro Nishibori, Masato Asanuma

Neurotoxicity Research 39 ( 5 ) 1511 - 1523 2021年10月

Influence of 5-HT2A receptor function on anxiety-like behavior induced by a combination treatment with doxorubicin and cyclophosphamide in rats 査読国際誌

Hironori Tabuchi, Yoshihisa Kitamura, Soichiro Ushio, Shiho Kan, Yudai Wada, Yusuke Sumiyoshi, Yasuhisa Izushi, Ikuko Miyazaki, Masato Asanuma, Toshiaki Sendo

Psychopharmacology 238 ( 12 ) 3607 - 3614 2021年9月

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 Science and Business Media LLC

Anxiety-like behavior induced by a combination of doxorubicin and cyclophosphamide may be mediated by serotonin (5-HT)2A receptor hyperactivity. The anxiolytic effects of fluoxetine may be inhibited by this combination. The present study examined the mechanisms underlying anxiety-like behavior induced by the combination doxorubicin and cyclophosphamide in rats. Anxiety-like behavior was induced during a light-dark test by the doxorubicin and cyclophosphamide treatment (once a week for 2 weeks). 5-HT2A receptor and 5-HT2A receptor-mediated extracellular signal-related kinase (ERK)1/2 levels were measured using Western blotting. 5-HT reuptake activity in fluoxetine-treated rats was also examined using microdialysis. ( ±)-1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane, a 5-HT2A receptor agonist, induced anxiety-like behavior. The fluoxetine treatment increased extracellular 5-HT concentrations in the hippocampus of vehicle- and doxorubicin and cyclophosphamide-treated rats. 5-HT transporter levels in the hippocampus were not affected by chemotherapy. The doxorubicin and cyclophosphamide treatment did not alter 5-HT2A receptor levels in the frontal cortex. However, chemotherapy increased 5-HT2A receptor-mediated ERK1/2 phosphorylation levels significantly more than the vehicle treatment. The present results suggest that anxiety-like behavior induced by the combination of doxorubicin and cyclophosphamide is mediated by 5-HT2A receptor hyperactivity without an increase in 5-HT2A receptor levels in rats.

DOI： 10.1007/s00213-021-05979-5

その他リンク： https://link.springer.com/article/10.1007/s00213-021-05979-5/fulltext.html

Glutathione and Related Molecules in Parkinsonism 招待査読

Masato Asanuma, Ikuko Miyazaki

International Journal of Molecular Sciences 22 ( 16 ) 8689 - 8689 2021年8月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：MDPI AG

Glutathione (GSH) is the most abundant intrinsic antioxidant in the central nervous system, and its substrate cysteine readily becomes the oxidized dimeric cystine. Since neurons lack a cystine transport system, neuronal GSH synthesis depends on cystine uptake via the cystine/glutamate exchange transporter (xCT), GSH synthesis, and release in/from surrounding astrocytes. Transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), a detoxifying master transcription factor, is expressed mainly in astrocytes and activates the gene expression of various phase II drug-metabolizing enzymes or antioxidants including GSH-related molecules and metallothionein by binding to the antioxidant response element (ARE) of these genes. Accumulating evidence has shown the involvement of dysfunction of antioxidative molecules including GSH and its related molecules in the pathogenesis of Parkinson’s disease (PD) or parkinsonian models. Furthermore, we found several agents targeting GSH synthesis in the astrocytes that protect nigrostriatal dopaminergic neuronal loss in PD models. In this article, the neuroprotective effects of supplementation and enhancement of GSH and its related molecules in PD pathology are reviewed, along with introducing new experimental findings, especially targeting of the xCT-GSH synthetic system and Nrf2–ARE pathway in astrocytes.

DOI： 10.3390/ijms22168689

N-Acetylcysteine Attenuates the Anxiety-Like Behavior and Spatial Cognition Impairment Induced by Doxorubicin and Cyclophosphamide Combination Treatment in Rats 査読

Yoshihisa Kitamura, Soichiro Ushio, Yusuke Sumiyoshi, Yudai Wada, Ikuko Miyazaki, Masato Asanuma, Toshiaki Sendo

Pharmacology 106 ( 5-6 ) 286 - 293 2021年

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：S. Karger AG

<b><i>Background:</i></b> Cancer patients can suffer from psychological and cognitive disorders after chemotherapy, which influence quality of life. <b><i>Objective:</i></b> Oxidative stress may contribute to the psychological and cognitive disorders induced in rats by chemotherapy. In the present study, we examined the effects of N-acetylcysteine, an anti-oxidant, on anxiety-like behavior and cognitive impairment in rats treated with a combination of doxorubicin and cyclophosphamide. <b><i>Methods:</i></b> Rats were intraperitoneally injected with doxorubicin and cyclophosphamide once a week for 2 weeks. The light-dark test and the novel location recognition test were used to assess anxiety-like behavior and spatial cognition, respectively. The rats’ hippocampal levels of glutathione (GSH) and glutathione disulfide (GSSG) were measured using a GSSG/GSH quantification kit. <b><i>Results:</i></b> Combined treatment with doxorubicin and cyclophosphamide produced anxiety-like behavior and cognitive impairment in rats. N-acetylcysteine reversed the anxiety-like behavior and inhibition of novel location recognition induced by the combination treatment. Furthermore, the combination of doxorubicin and cyclophosphamide significantly reduced the rats’ hippocampal GSH/GSSG ratios. N-acetylcysteine reversed the reduction in the GSH/GSSG ratio seen in the doxorubicin and cyclophosphamide-treated rats. <b><i>Conclusion:</i></b> These results suggest that N-acetylcysteine inhibits doxorubicin and cyclophosphamide-induced anxiety-like behavior and cognitive impairment by reducing oxidative stress in the hippocampus.

DOI： 10.1159/000512117

Glial cells as a target of neuroprotection in the central and peripheral nervous system in Parkinson’s disease. 招待査読

Nami Isooka, Ikuko Miyazaki, Masato Asanuma

Acta Med Okayama 75 ( 5 ) 549 - 556 2021年

Therapeutic strategy for parkinson’s disease: Targeting zinc-binding protein in astrocytes

Ikuko Miyazaki, Masato Asanuma

Folia Pharmacologica Japonica 156 ( 2 ) 76 - 80 2021年

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Japanese Pharmacological Society

Parkinson’s disease (PD) is a progressive neurodegenerative disease with motor symptoms, such as tremor, akinesia/bradykinesia, rigidity and postural instability due to a loss of nigrostriatal dopaminergic neurons
PD patients also exhibit non-motor symptoms, such as hyposmia, orthostatic hypotension and constipation, which precede motor symptoms. Pathologically, Lewy bodies and neurites, which contains α-synuclein, are observed in the central and peripheral nervous system. To date, it is hypothesized that PD pathology appears first in the olfactory bulb and the enteric nervous system, and propagates progressively through the substantia nigra to finally reach the cerebral cortex. Major medications at present are nosotropic treatments to improve motor dysfunction in PD. Therefore, development of disease-modifying drug is required to slow or prevent PD progression. Astrocytes are known to play an important role in the maintenance of the neuronal environment and exert neuroprotective effects by production of antioxidants and neurotrophic factors and clearing toxic molecules. In the previous study, we demonstrated that astrocytes produced antioxidative molecules metallothionein (MT)-1/2 in response to oxidative stress and protected dopaminergic neurons against oxidative stress. MTs are cysteine-rich proteins possessing antioxidative properties. MTs bind to metals such as zinc (Zn) and copper (Cu) and function in metal homeostasis and detoxification
MTs regulate Zn-mediated transcriptional activation of various genes. Recently, it is reported that MTs prevent Cu-induced aggregation of α-synuclein. In this article, we review a new therapeutic strategy of neuroprotection in PD by targeting MTs in astrocytes.

DOI： 10.1254/fpj.20082

Anti-oxidants in astrocytes as target of neuroprotection for parkinson’s disease

Masato Asanuma, Ikuko Miyazaki

Folia Pharmacologica Japonica 156 ( 1 ) 14 - 20 2021年

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Japanese Pharmacological Society

Recently, it has been reported that dysfunction of astrocytes is involved vulnerability of neuronal cells in several neurological disorders. Glutathione (GSH) is the most abundant intrinsic antioxidant in the central nervous system, and its substrate cysteine is readily becomes the oxidized dimeric cystine. Since neurons lack a cystine transport system, neuronal GSH synthesis depends on cystine uptake via the cystine/glutamate exchange transporter (xCT), GSH synthesis and release in/from surrounding astrocytes. The expression and release of the zinc-binding protein metallothionein (MT) in astrocytes, which is a strong antioxidant, is induced and exerts neuroprotective in the case of dopaminergic neuronal damage. In addition, the transcription factor Nrf2 induces expression of MT-1 and GSH related molecules. We previously revealed that several antiepileptic drugs, serotonin 5-HT1A receptor agonists, plant-derived chemicals (phytochemicals) increased xCT expression, Nrf2 activation, GSH or MT expression and release in/from astrocytes, and exerted a neuroprotective effect against dopaminergic neurodegeneration in Parkinson’s disease model. Our serial studies on neuroprotection via antioxidant defense mechanism of astrocytes have found three target molecular systems of astrocytes for neuroprotection: (1) xCT-GSH synthetic system, (2) Nrf2 system and (3) 5-HT1A receptor-Nrf2-MT system, 5-HT1A-S100β system. In this article, possible neuroprotective strategy for Parkinson’s disease has been reviewed targeting antioxidative molecules in astrocytes.

DOI： 10.1254/fpj.20071

The neurotoxicity of psychoactive phenethylamines “2C series” in cultured monoaminergic neuronal cell lines 査読

Masato Asanuma, Ikuko Miyazaki, Masahiko Funada

Forensic Toxicology 38 ( 2 ) 394 - 408 2020年7月

Cerebellar Blood Flow and Gene Expression in Crossed Cerebellar Diaschisis after Transient Middle Cerebral Artery Occlusion in Rats 査読

Naoya Kidani, Tomohito Hishikawa, Masafumi Hiramatsu, Shingo Nishihiro, Kyohei Kin, Yu Takahashi, Satoshi Murai, Kenji Sugiu, Takao Yasuhara, Ikuko Miyazaki, Masato Asanuma, Isao Date

International Journal of Molecular Sciences 21 ( 11 ) 4137 - 4137 2020年6月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：MDPI AG

Crossed cerebellar diaschisis (CCD) is a state of hypoperfusion and hypometabolism in the contralesional cerebellar hemisphere caused by a supratentorial lesion, but its pathophysiology is not fully understood. We evaluated chronological changes in cerebellar blood flow (CbBF) and gene expressions in the cerebellum using a rat model of transient middle cerebral artery occlusion (MCAO). CbBF was analyzed at two and seven days after MCAO using single photon emission computed tomography (SPECT). DNA microarray analysis and western blotting of the cerebellar cortex were performed and apoptotic cells in the cerebellar cortex were stained. CbBF in the contralesional hemisphere was significantly decreased and this lateral imbalance recovered over one week. Gene set enrichment analysis revealed that a gene set for “oxidative phosphorylation” was significantly upregulated while fourteen other gene sets including “apoptosis”, “hypoxia” and “reactive oxygen species” showed a tendency toward upregulation in the contralesional cerebellum. MCAO upregulated the expressions of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) in the contralesional cerebellar cortex. The number of apoptotic cells increased in the molecular layer of the contralesional cerebellum. Focal cerebral ischemia in our rat MCAO model caused CCD along with enhanced expression of genes related to oxidative stress and apoptosis.

DOI： 10.3390/ijms21114137

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

Kengo Nakahara, Kana Fujikawa, Hideki Hiraoka, Ikuko Miyazaki, Masato Asanuma, Akihiro Ito, Nobumasa Takasugi, Takashi Uehara

Biological and Pharmaceutical Bulletin 42 ( 6 ) 1044 - 1047 2019年6月

Involvement of 5-HT_2A 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

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-Schmiedeberg's Archives of Pharmacology 390 ( 4 ) 369 - 378 2017年4月

3-O-Methyldopa inhibits astrocyte-mediated dopaminergic neuroprotective effects of l-DOPA 査読

Masato Asanuma, Ikuko Miyazaki

BMC Neuroscience 17 ( 1 ) 2016年12月

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 査読

Tsuboi C, Kawasaki Y, Yoshitome K, Yagi K, Miura T, Esumi S, Miyazaki I, Asanuma M, Kitamura Y, Sendo T

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

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

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

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 ( 1 ) 220 - 231 2016年1月

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

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

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

Journal of Clinical Biochemistry and Nutrition 59 ( 2 ) 93 - 99 2016年

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：日本酸化ストレス学会 JCBN事務局

<p><span style="font-variant: small-caps;">l</span>-Theanine (γ-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 <span style="font-variant: small-caps;">l</span>-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 <span style="font-variant: small-caps;">l</span>-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 <span style="font-variant: small-caps;">l</span>-theanine in neuron-astrocyte co-cultures but not in neuron-rich cultures. Exposure to <span style="font-variant: small-caps;">l</span>-theanine increased the levels of glutathione in both astrocytes and glial conditioned medium. The glial conditioned medium from <span style="font-variant: small-caps;">l</span>-theanine-pretreated striatal astrocytes attenuated dopamine-induced neurotoxicity and quinoprotein formation in mesencephalic neurons. In addition, replacement of <span style="font-variant: small-caps;">l</span>-glutamate with <span style="font-variant: small-caps;">l</span>-theanine in an in vitro cell-free glutathione-synthesis system produced glutathione-like thiol compounds. Furthermore, <span style="font-variant: small-caps;">l</span>-theanine administration (4 mg/kg, p.o.) for 14 days significantly increased glutathione levels in the striatum of mice. The results suggest that <span style="font-variant: small-caps;">l</span>-theanine provides neuroprotection against oxidative stress-induced neuronal damage by humoral molecules released from astrocytes, probably including glutathione.</p>

DOI： 10.3164/jcbn.16-15

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

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

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 査読

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

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

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

Shinki Murakami, Ikuko Miyazaki, Ko Miyoshi, Masato Asanuma

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

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

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

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

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

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

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

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

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

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

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.

DOI： 10.1007/s12640-014-9480-1

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

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

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.

DOI： 10.1111/epi.12750

Striatal Astrocytes Act as a Reservoir for L-DOPA 査読

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

PLOS ONE 9 ( 9 ) e106362 2014年9月

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.

DOI： 10.1371/journal.pone.0106362

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

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

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

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

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

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

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.

DOI： 10.1371/journal.pone.0097918

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

Taizo Kita, Masato Asanuma, Ikuko Miyazaki, Mika Takeshima

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

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.

DOI： 10.1254/jphs.13R19CP

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

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

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

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.

DOI： 10.1248/bpb.b13-00749

Metallothionein deficiency exacerbates diabetic nephropathy in streptozotocin-induced diabetic mice 査読

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

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 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

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

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

PLoS ONE 8 ( 6 ) e65983 2013年6月

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.

DOI： 10.1371/journal.pone.0065983

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

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

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.

DOI： 10.1016/j.lfs.2013.01.031

アストロサイトとParkinson病治療

浅沼幹人, 宮崎育子

神経内科 79 ( 2 ) 262 - 268 2013年

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

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

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

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

Centrosomal aggregates and Golgi fragmentation disrupt vesicular trafficking of DAT 査読

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

Neurobiology of Aging 33 ( 10 ) 2462 - 2477 2012年10月

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

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

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

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

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

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

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 < 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 < 0.001). The level of effluent FRs was associated with death-censored technique failure in both univariate (p < 0.001) and multivariate (p < 0.01) hazard models. Compared with patients remaining on PD, those withdrawn from the modality had significantly higher levels of effluent FRs (p < 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

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 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

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

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

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

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

Factors That Influence Primary Cilium Length 査読

Ko Miyoshi, Kyosuke Kasahara, Ikuko Miyazaki, Masato Asanuma

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

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

A Novel Hypothesized Clinical Implication of Zonisamide for Autism Reply

Masato Asanuma, Ikuko Miyazaki

ANNALS OF NEUROLOGY 69 ( 2 ) 426 - 427 2011年2月

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

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

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

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 1295 - 1297 2011年

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 ( 8 ) 43 - 53 2011年

High Glucose Increases Metallothionein Expression in Renal Proximal Tubular Epithelial Cells 査読国際誌

Daisuke Ogawa, Masato Asanuma, Ikuko Miyazaki, Hiromi Tachibana, Jun Wada, Norio Sogawa, Takeshi Sugaya, Shinji Kitamura, Yohei Maeshima, Kenichi Shikata, Hirofumi Makino

Experimental Diabetes Research 2011 1 - 8 2011年

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

Metallothionein (MT) is an intracellular metal-binding, cysteine-rich protein, and is a potent antioxidant that protects cells and tissues from oxidative stress. Although the major isoforms MT-1 and -2 (MT-1/-2) are highly inducible in many tissues, the distribution and role of MT-1/-2 in diabetic nephropathy are poorly understood. In this study, diabetes was induced in adult male rats by streptozotocin, and renal tissues were stained with antibodies for MT-1/-2. MT-1/-2 expression was also evaluated in mProx24 cells, a mouse renal proximal tubular epithelial cell line, stimulated with high glucose medium and pretreated with the antioxidant vitamin E. MT-1/-2 expression was gradually and dramatically increased, mainly in the proximal tubular epithelial cells and to a lesser extent in the podocytes in diabetic rats, but was hardly observed in control rats. MT-1/-2 expression was also increased by high glucose stimulation in mProx24 cells. Because the induction of MT was suppressed by pretreatment with vitamin E, the expression of MT-1/-2 is induced, at least in part, by high glucose-induced oxidative stress. These observations suggest that MT-1/-2 is induced in renal proximal tubular epithelial cells as an antioxidant to protect the kidney from oxidative stress, and may offer a novel therapeutic target against diabetic nephropathy.

DOI： 10.1155/2011/534872

その他リンク： http://downloads.hindawi.com/journals/jdr/2011/534872.xml

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

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

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.

Antioxidative and neuroprotective effects of metallothioneins on dopaminergic neurons

Ikuko Miyazaki, Masato Asanuma

Handbook of Free Radicals: Formation, Types and Effects 557 - 568 2010年

記述言語：英語掲載種別：論文集(書籍)内論文出版者・発行元：Nova Science Publishers, Inc.

Metallothioneins (MTs) are a family of low molecular weight, cysteine-rich, ubiquitous, and inducible intracellular proteins that bind to heavy metals such as zinc, copper, and cadmium, participating in metal homeostasis and detoxification. The mammalian MT family comprises four isoforms: MT-1, MT-2, MT-3, and MT-4. The two major isoforms, MT-1 and-2, are expressed in most organs including the brain. MT-1 and-2 help to regulate metal homeostasis in the brain, as well as neural protective functions in various pathological and inflammatory conditions. MT-3, called growth inhibitory factor, is mainly expressed in the central nervous system and decreased in the brain of Alzheimer's disease. Attention has been focused on MTs as radical scavengers because of their abundant thiol groups, which participate exclusively in the formation of metal-thiolate clusters. The reactive oxygen or nitrogen species (ROS/RNS), generated in the oxidation of an excess amount of dopamine (DA), is thought to play an important role in dopaminergic neurotoxicity. In contrast to the general oxidative stress, the pathogenecity of quinone formation has been recently received attention as dopaminergic neuron-specific oxidative stress. When the DA neurons are damaged, an excess amount of cytosolic DA exists outside of the synaptic vesicle is spontaneously oxidized and produces superoxide and DA/DOPA quinones. DA quinone conjugates with cysteine-residues on functional proteins to form quinoproteins. Therefore, intrinsic thiol molecule MTs could be a therapeutic tool against dopaminergic neurotoxicity to prevent DA quinone from binding to the sulfhydryl groups of cysteine on functional proteins by their conjugation with DA quinone. Indeed, our recent study showed that MT exerts protective effects against the long-term L-DOPA treatment-induced DA quinone neurotoxicity in parkinsonian mice by its quenching property of DA quinone. In this article, we primarily review recent studies from our and other groups on the antioxidative and neuroprotective roles of MTs against oxidative stress including DA quinone neurotoxicity in dopaminergic neurons. © 2010 by Nova Science Publishers, Inc. All rights reserved.

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

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

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

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

Ko Miyoshi, Kyosuke Kasahara, Ikuko Miyazaki, Masato Asanuma

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

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

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

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

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

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

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―

浦添夏帆, 村田麻衣子, 青柳東彦, 安東勢津子, 宮崎育子, 浅沼幹人, 喜多大三

九州栄養福祉大学研究紀要 6 ( 6 ) 75 - 86 2009年

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

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

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

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

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

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

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'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

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 査読

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

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<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<0.05). Moreover, the production of dihydroxyphenylglycol was reduced in the anti-HMGB1-treated group (p<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

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

Masato Asanuma, Ikuko Miyazaki

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

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

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

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

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

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

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

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

Biological roles for neuronal primary cilia 査読

Ko Miyoshi, Ikuko Miyazaki, Masato Asanuma

PSYCHIATRY AND CLINICAL NEUROSCIENCES 62 ( 1 ) S6 - S6 2008年2月

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

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

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

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

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 ( 5 ) 69 - 81 2008年

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 ( 5 ) 55 - 67 2008年

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 ( 3 ) 235 - 239 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

Quinone formation as a common factor for dopamine neuron damages by excessive dopamine outside of vesicles

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

Journal of Okayama Medical Association 119 ( 3 ) 235 - 239 2008年

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

Masato Asanuma, Ikuko Miyazaki

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

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

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

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

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 ( 4 ) 89 - 97 2007年

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

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 >= 2.0 and <= 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 <= 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

Characterization of pericentrin isoforms in vivo 査読

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

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

Nonsteroidal anti-inflammatory drugs in Parkinson’s disease: possible involvement of quinone formation 査読

Masato Asanuma, Ikuko Miyazaki

Expert Review of Neurotherapeutics 6 ( 9 ) 1313 - 1325 2006年9月

Embryonic expression of pericentrin suggests universal roles in ciliogenesis 査読

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

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.

DOI： 10.1007/s00427-006-0065-8

Centrosome overduplication induced by rotenone treatment affects the cellular distribution of p53 tumor suppressor protein in the neuroblastoma B65 cell line 査読

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

PSYCHIATRY AND CLINICAL NEUROSCIENCES 60 S18 - S26 2006年4月

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

Recently, the formation of inclusion bodies in several neurodegenerative diseases, including Parkinson's disease, has been associated with the aggregation of unfolded proteins recruited in the centrosome. We have reported previously that rotenone, an insecticide that is used to produce experimental models of Parkinsonism, induced the aggregation of the alpha-synuclein protein in the centrosome, and it notably affected the structure and function of this organelle in primary cultures of mesencephalic neurons and astrocytes. However, it is still obscure the mechanisms through which the disorganization and centrosomal dysfunction could induce cell death. In this study the rat neuroblastoma B65 cell line was chronically exposed to rotenone, and then the distribution of the centrosomal protein gamma-tubulin was studied by immunocytochemistry and Western blot analyses. Finally, the configuration of mitotic spindles and distribution of the p53 protein was observed in the control and rotenone-treated groups. Rotenone treatment increased the number of cells having centrosome overduplication and multipolar mitotic spindles. In contrast, rotenone induced redistribution of the p53 protein, which was colocalized with the gamma-tubulin protein in the perinuclear region of cells having overduplicated centrosomes. In addition, the p53 positive signal was markedly intense in cells containing aberrant chromosome segregation and micronuclei. Our results suggest that centrosome overduplication may play an important role in the redistribution of the p53 protein in rotenone-treated cells, and this could represent an alternative mechanism of rotenone to induce apoptosis in neuronal cells.

DOI： 10.1111/j.1440-1819.2006.01526.x

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

Norio Ogawa, Masato Asanuma, Ikuko Miyazaki, FJ Diaz-Corrales, Ko Miyoshi

JOURNAL OF NEUROLOGY 252 23 - 31 2005年10月

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

Prednisolone Inhibits Proliferation of Cultured Pulmonary Artery Smooth Muscle Cells of Patients With Idiopathic Pulmonary Arterial Hypertension 査読国際誌

Aiko Ogawa, Kazufumi Nakamura, Hiromi Matsubara, Hideki Fujio, Tetsuya Ikeda, Kaoru Kobayashi, Ikuko Miyazaki, Masato Asanuma, Katsumasa Miyaji, Daiji Miura, Kengo Fukushima Kusano, Hiroshi Date, Tohru Ohe

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

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Ovid Technologies (Wolters Kluwer Health)

<bold>
<italic>Background—</italic>
</bold>
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.

<bold>
<italic>Methods and Results—</italic>
</bold>
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
³
H-thymidine incorporation. PSL (2×10
⁻⁴
and 2×10
⁻³
mol/L) significantly inhibited PDGF-stimulated proliferation (
<italic>P</italic>
<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 (2×10
⁻⁴
mol/L) also inhibited PDGF-induced SMC migration.

<bold>
<italic>Conclusions—</italic>
</bold>
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.

DOI： 10.1161/circulationaha.105.536169

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

Masato Asanuma, Ikuko Miyazaki, Francisco J. Diaz-Corrales, Masako Shimizu, Ken-ichi Tanaka, Norio Ogawa

Neurological Research 27 ( 5 ) 533 - 539 2005年7月

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

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

Neuroscience 133 ( 1 ) 117 - 135 2005年1月

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 ( 1 ) 30 - 34 2005年

記述言語：日本語出版者・発行元：公益社団法人日本薬理学会

従来，ある事象に関与すると考えられる分子の同定は，既知の関与分子と連関のあると報告された分子の発現の増減を一つ一つ確認していく，あるいは既知の分子と結合するタンパクをFar-Western法，two-hybrid法などで見つけていくという手法が用いられてきた．しかし，これではある事象に関与する既知の分子機構の枠を越えた新たな分子機構を発見したり，新たな観点に基づく分子仮説を提唱できるような発見をすることは難しかった．これに対して，10-20年前から，ある事象で発現が増減しているmRNAをスクリーニングする手法として，differential display法とそれに続くライブラリースクリーニング，RACE法などが広く用いられ，キット化された．さらに，近年1,000-10,000ものcDNA断片をブロットしたナイロン・グラス・プラスチックcDNAアレイが市販あるいはオーダーメードされるようになり，様々な生物学的・病理学的事象で発現が変化している遺伝子の網羅的検索が可能になった．近年のポストゲノムの潮流と遺伝子とタンパクの発現の乖離から，二次元電気泳動などによる発現タンパクのスクリーニング，さらに抗体がブロットされた抗体アレイを用いてのタンパク発現の網羅的検索も可能になってきている．しかし，これらの網羅的検索法はそれぞれ長所および短所，限界を有しており，目的に応じて使い分ける必要がある．本稿では，主に覚醒剤の急性毒性発現にかかわる遺伝子・分子の分子生物学的網羅的検索法の自検例を交えて，それらの長所・短所について概説する．<br>

DOI： 10.1254/fpj.126.30

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

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

Acta Medica Okayama 58 ( 5 ) 221 - 233 2004年10月

記述言語：英語出版者・発行元：Okayama University Medical School

<p>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.</p>

DOI： 10.18926/AMO/32105

Specific Gene Expression and Possible Involvement of Inflammation in Methamphetamine-Induced Neurotoxicity 査読

Masato Asanuma, Ikuko Miyazaki, Youichirou Higashi, Takeshi Tsuji, Norio Ogawa

Annals of the New York Academy of Sciences 1025 ( 1 ) 69 - 75 2004年10月

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

Youichirou Higashi, Masato Asanuma, Ikuko Miyazaki, Norio Ogawa

Neurological Research 26 ( 6 ) 671 - 676 2004年9月

Parkin attenuates manganese‐induced dopaminergic cell death 査読

Youichirou Higashi, Masato Asanuma, Ikuko Miyazaki, Nobutaka Hattori, Yoshikuni Mizuno, Norio Ogawa

Journal of Neurochemistry 89 ( 6 ) 1490 - 1497 2004年6月

DISC1 localizes to the centrosome by binding to kendrin 査読

Ko Miyoshi, Masato Asanuma, Ikuko Miyazaki, Francisco J. Diaz-Corrales, Taiichi Katayama, Masaya Tohyama, Norio Ogawa

Biochemical and Biophysical Research Communications 317 ( 4 ) 1195 - 1199 2004年5月

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

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

Neuroscience Letters 354 ( 1 ) 59 - 63 2004年1月

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

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

ドパミン受容体とトランスポーター．

小川紀雄, 宮崎育子

脳の科学 292,53-59 2004年

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

Masato Asanuma, Ikuko Miyazaki, Norio Ogawa

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

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

PP4-061 抗体アレイを用いた下部尿路閉塞モデルラット膀胱平滑筋層におけるタンパク発現のprofiling(一般演題(ポスター))

藤田治, 横山光彦, 浅沼幹人, 宮崎育子, 小川紀雄, 公文裕巳

日本泌尿器科学会雑誌 95 ( 2 ) 545 - 545 2004年

Methamphetamine-induced neurotoxicity in mouse brain is attenuated by ketaprofen a non-steroidal anti-inflammatory drug 査読

ASANUMA M

Neurosci Lett 352 ( 1 ) 13 - 16 2003年11月

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

M.Emdadul Haque, Masato Asanuma, Youichirou Higashi, Ikuko Miyazaki, Ken-ichi Tanaka, Norio Ogawa

Neuroscience Research 47 ( 1 ) 31 - 37 2003年9月

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

M Emdadul Haque, Masato Asanuma, Youichirou Higashi, Ikuko Miyazaki, Ken-ichi Tanaka, Norio Ogawa

Biochimica et Biophysica Acta (BBA) - General Subjects 1619 ( 1 ) 39 - 52 2003年1月

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

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

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

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

Masato Asanuma, Ikuko Miyazaki, Norio Ogawa

NEUROTOXICITY RESEARCH 5 ( 3 ) 165 - 176 2003年

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

The p53-activated Gene, PAG608, Requires a Zinc Finger Domain for Nuclear Localization and Oxidative Stress-induced Apoptosis 査読

Youichirou Higashi, Masato Asanuma, Ikuko Miyazaki, M. Emdadul Haque, Naoko Fujita, Ken-ichi Tanaka, Norio Ogawa

Journal of Biological Chemistry 277 ( 44 ) 42224 - 42232 2002年11月

Aggravation of 6-hydroxydopamine-induced dopaminergic lesions in metallothionein-I and -II knock-out mouse brain 査読

Masato Asanuma, Ikuko Miyazaki, Youichirou Higashi, Ken-ichi Tanaka, Md Emdadul Haque, Naoko Fujita, Norio Ogawa

Neuroscience Letters 327 ( 1 ) 61 - 65 2002年7月

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

Michiyo Yoshioka, Ken-ichi Tanaka, Ikuko Miyazaki, Naoko Fujita, Youichirou Higashi, Masato Asanuma, Norio Ogawa

Neuroscience Research 43 ( 3 ) 259 - 267 2002年7月

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

Masato Asanuma, Ikuko Miyazaki, Youichirou Higashi, Jean Lud Cadet, Norio Ogawa

Neuroscience Letters 325 ( 3 ) 191 - 194 2002年6月

GPI1046 prevents dopaminergic dysfunction by activating glutathione system in the mouse striatum 査読

Ken-ichi Tanaka, Michiyo Yoshioka, Ikuko Miyazaki, Naoko Fujita, Norio Ogawa

Neuroscience Letters 321 ( 1-2 ) 45 - 48 2002年3月

Inhibition of Tyrosinase Reduces Cell Viability in Catecholaminergic Neuronal Cells 査読

Youichirou Higashi, Masato Asanuma, Ikuko Miyazaki, Norio Ogawa

Journal of Neurochemistry 75 ( 4 ) 1771 - 1774 2002年1月

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

Chronic cerebral hypoperfusion induces striatal alterations due to the transient increase of NO production and the depression of glutathione content 査読

Ken-ichi Tanaka, Naoko Wada-Tanaka, Ikuko Miyazaki, Masahiko Nomura, Norio Ogawa

Neurochemical Research 27 ( 4 ) 331 - 336 2002年

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

Masato Asanuma, Sakiko Nishibayashi-Asanuma, Ikuko Miyazaki, Masahiro Kohno, Norio Ogawa

Journal of Neurochemistry 76 ( 6 ) 1895 - 1904 2001年12月

Progressive cortical atrophy after forebrain ischemia in diabetic rats 査読

Fumio Kondo, Masato Asanuma, Ikuko Miyazaki, Yoichi Kondo, Ken-ichi Tanaka, Hirohumi Makino, Norio Ogawa

Neuroscience Research 39 ( 3 ) 339 - 346 2001年3月

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

Aoki Sogawa Chiharu, Asanuma Masato, Sogawa Norio, Miyazaki Ikuko, Nakanishi Tohru, Furuta Hiroaki, Ogawa Noriko

Acta Medica Okayama 55 ( 1 ) 1 - 9 2001年2月

記述言語：英語出版者・発行元：Okayama University Medical School

<p>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.</p>

DOI： 10.18926/AMO/32031

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

Ken-ichi Tanaka, Ikuko Miyazaki, Naoko Fujita, Md Emdadul Haque, Masato Asanuma, Norio Ogawa

Neurochemical Research 26 ( 1 ) 31 - 36 2001年

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

Chiharu Aoki Sogawa, Ikuko Miyazaki, Norio Sogawa, Masato Asanuma, Norio Ogawa, Hiroaki Furuta

Brain Research 853 ( 2 ) 310 - 316 2000年1月

Dopamine D2 receptor-mediated antioxidant and neuroprotective effects of ropinirole, a dopamine agonist 査読

Motoyuki Iida, Ikuko Miyazaki, Ken-Ichi Tanaka, Hideaki Kabuto, Emi Iwata-Ichikawa, Norio Ogawa

Brain Research 838 ( 1-2 ) 51 - 59 1999年8月

記述言語：英語掲載種別：研究論文（学術雑誌）

Recent information suggests that free radicals are closely involved in the pathogenesis and/or progression of Parkinson's disease (PD). High-dose levodopa therapy has been suggested to increase oxidative stress, thereby accelerating the progression of PD. Based on this viewpoint, free radical scavenging, antioxidant and neuroprotective agents which may prevent the progression of PD have recently attracted considerable attention. For example, ergot derivative dopamine (DA) agonists have been reported to scavenge free radicals in vitro and show a neuroprotective effect in vivo. Non-ergot DA agonists have also recently been used in the treatment of PD despite the lack of substantial evidence for any free radical scavenging activity or antioxidant activity. The present study was conducted to assess the in vitro free radical scavenging and antioxidant activities of ropinirole, a non-ergot DA agonist, as well as its glutathione (GSH), catalase and superoxide dismutase (SOD) activating effects and neuroprotective effect in vivo. Ropinirole scavenges free radicals and suppresses lipid peroxidation in vitro, but these activities are very weak, suggesting that the antioxidant effect of ropinirole observed in vitro may be a minor component of its neuroprotective effect in vivo. Administration of ropinirole for 7 days increased GSH, catalase and SOD activities in the striatum and protected striatal dopaminergic neurons against 6- hydroxydopamine (6-OHDA) in mice. Pre-treatment with sulpiride prevented ropinirole from enhancing striatal GSH, catalase and SOD activities and abolished the protection of dopaminergic neurons against 6-OHDA. Our findings indicate that activation of GSH, catalase and SOD mediated via DA D2 receptors may be the principal mechanism of neuroprotection by ropinirole.

DOI： 10.1016/S0006-8993(99)01688-1

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

Yoichi Kondo, Masato Asanuma, Emi Iwata, Fumio Kondo, Ikuko Miyazaki, Norio Ogawa

Neurochemical Research 24 ( 1 ) 9 - 13 1999年

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

Emi Iwata-Ichikawa, Yoichi Kondo, Ikuko Miyazaki, Masato Asanuma, Norio Ogawa

Journal of Neurochemistry 72 ( 6 ) 2334 - 2344 1999年

記述言語：英語掲載種別：研究論文（学術雑誌）

We examined the effects of oxidative stress on rat cultured mesencephalic neurons and glial cells. Glial cells were more resistant to 6- 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 γ-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 gila conditioned medium. Neurons maintained in gila conditioned medium up-regulated the level of TRE- binding activity, γ-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

マウス脳内における鉄結合蛋白ラクトフェリンの分布

近藤洋一, 岩田恵美, 宮崎育子, 相見良成, 遠山育夫, 木村宏, 小川紀雄

神経化学 37 ( 3 ) 488 - 488 1998年9月

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

Emi Iwata, Ikuko Miyazaki, Masato Asanuma, Azusa Iida, Norio Ogawa

Neuroscience Letters 251 ( 1 ) 49 - 52 1998年7月

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

Kyoko Iida, Emi Iwata, Masato Asanuma, Sakiko N Asanuma, Marvin Gómez-Vargas, Ikuko Miyazaki, Tohru Nakanishi, Norio Ogawa

Neuroscience Research 30 ( 2 ) 185 - 193 1998年2月

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

Yoichi Kondo, Masato Asanuma, Hideaki Kabuto, Emi Iwata, Fumio Kondo, Ikuko Miyazaki, Norio Ogawa

J. Brain Sci. 23 250 - 260 1997年

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