Faculty Profiles - ASANUMA Masato

Papers - ASANUMA Masato

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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 2025.2

Publishing type：Research paper (scientific journal) Publisher：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

Other Link： https://www.nature.com/articles/s41390-025-03920-6

Editorial: Glial crosstalk in neurological disorders Reviewed

Ikuko Miyazaki, Masato Asanuma, Francisco Javier Díaz-Corrales

Frontiers in Cell and Developmental Biology 12 1515052 2024.11

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

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

Neuroscience Letters 820 137598 - 137598 2024.1

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

Yasuhisa Izushi, Shouki Tanaka, Teppei Ueda, Soichiro Ushio, Yuichi Tasaka, Ikuko Miyazaki, Masato Asanuma, Yoshihisa Kitamura

Naunyn-Schmiedeberg's Archives of Pharmacology 2024

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

Masato Asanuma, Ikuko Miyazaki, Jean Lud Cadet

Neurotoxicity Research 2024

Phosphorylated SARM1 is involved in the pathological process of rotenone-induced neurodegeneration Reviewed

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

The Journal of Biochemistry 174 ( 6 ) 533 - 548 2023.9

Language：English Publishing type：Research paper (scientific journal) Publisher：Oxford University Press (OUP)

Abstract

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

Other Link： https://academic.oup.com/jb/article-pdf/174/6/533/54447957/mvad068.pdf

Multifunctional Metallothioneins as a Target for Neuroprotection in Parkinson’s Disease Reviewed

Ikuko Miyazaki, Masato Asanuma

Antioxidants 12 ( 4 ) 894 - 894 2023.4

Authorship：Last author Language：English Publishing type：Research paper (scientific journal) Publisher：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

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

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

Acta Medica Okayama 76 ( 4 ) 373 - 383 2022.8

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal)

Parkinson's disease (PD) is a progressive neurodegenerative disease of both the central and peripheral / enteric nervous systems. Oxidative stress and neuroinflammation are associated with the pathogenesis of PD, suggesting that anti-oxidative and anti-inflammatory compounds could be neuroprotective agents for PD. Eucommia ulmoides (EU) is a traditional herbal medicine which exerts neuroprotective effects by anti-inflammatory and anti-oxidative properties. Our previous study showed that treatment with chlorogenic acid, a component of EU, protected against neurodegeneration in the central and enteric nervous systems in a PD model. In this study, we examined the effects of EU extract (EUE) administration on dopaminergic neurodegeneration, glial response and α-synuclein expression in the substantia nigra pars compacta (SNpc), and intestinal enteric neurodegeneration in low-dose rotenone-induced PD model mice. Daily oral administration of EUE ameliorated dopaminergic neurodegeneration and α-synuclein accumulation in the SNpc. EUE treatment inhibited rotenone-induced decreases in the number of total astrocytes and in those expressing the antioxidant molecule metallothionein. EUE also prevented rotenone-induced microglial activation. Furthermore, EUE treatment exerted protective effects against intestinal neuronal loss in the PD model. These results suggest that EU exerts neuroprotective effects in the central and enteric nervous systems of rotenone-induced parkinsonism mice, in part by glial modification.

DOI： 10.18926/AMO/63889

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

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 2021.10

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：Springer Science and Business Media LLC

DOI： 10.1007/s12640-021-00402-5

Other Link： https://link.springer.com/article/10.1007/s12640-021-00402-5/fulltext.html

Glial cells as possible targets of neuroprotection through neurotrophic and antioxidative molecules in the central and enteric nervous systems in Parkinson’s disease. Reviewed

Nami Isooka, Ikuko Miyazaki, Masato Asanuma

Acta Medica Okayama 75 ( 5 ) 549 - 556 2021.10

Influence of 5-HT2A receptor function on anxiety-like behavior induced by a combination treatment with doxorubicin and cyclophosphamide in rats. Reviewed International journal

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 2021.9

Language：English Publishing type：Research paper (scientific journal)

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

Glutathione and Related Molecules in Parkinsonism Invited Reviewed

Masato Asanuma, Ikuko Miyazaki

International Journal of Molecular Sciences 22 ( 16 ) 8689 - 8689 2021.8

Authorship：Lead author,　Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：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

Lactoferrin-like Immunoreactivity in Distinct Neuronal Populations in the Mouse Central Nervous System. Reviewed

Shigeyoshi Shimaoka, Hitomi Hamaoka, Junji Inoue, Masato Asanuma, Ikuo Tooyama, Yoichi Kondo

Acta Medica Okayama 75 ( 2 ) 153 - 167 2021.4

Language：English Publishing type：Research paper (scientific journal)

Lactoferrin (Lf) is an iron-binding glycoprotein mainly found in exocrine secretions and the secondary granules of neutrophils. In the central nervous system (CNS), expression of the Lf protein has been reported in the lesions of some neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, as well as in the aged brain. Lf is primarily considered an iron chelator, protecting cells from potentially toxic iron or iron-requiring microorganisms. Other biological functions of Lf include immunomodulation and transcriptional regulation. However, the roles of Lf in the CNS have yet to be fully clarified. In this study, we raised an antiserum against mouse Lf and investigated the immunohistochemical localization of Lf-like immunoreactivity (Lf-LI) throughout the CNS of adult mice. Lf-LI was found in some neuronal populations throughout the CNS. Intense labeling was found in neurons in the olfactory systems, hypothalamic nuclei, entorhinal cortex, and a variety of brainstem nuclei. This study provides detailed information on the Lf-LI distribution in the CNS, and the findings should promote further understanding of both the physiological and pathological significance of Lf in the CNS.

DOI： 10.18926/AMO/61894

アストロサイトの亜鉛関連分子を標的としたパーキンソン病治療戦略

宮崎育子, 浅沼幹人

日本薬理学雑誌 156 ( 2 ) 76 - 80 2021.2

パーキンソン病での神経保護標的としてのアストロサイトの抗酸化分子

浅沼幹人, 宮崎育子

日本薬理学雑誌 156 ( 1 ) 14 - 20 2021.1

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

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

Pharmacology 106 ( 5-6 ) 286 - 293 2021

Language：English Publishing type：Research paper (scientific journal) Publisher：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

Neuron-Astrocyte Interactions in Parkinson’s Disease Invited Reviewed

Ikuko Miyazaki, Masato Asanuma

Cells 9 ( 12 ) 2623 - 2623 2020.12

Authorship：Last author Language：English Publishing type：Research paper (scientific journal) Publisher：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 Reviewed

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 2020.12

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：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

Other Link： http://www.nature.com/articles/s41598-020-77652-4

The Rotenone Models Reproducing Central and Peripheral Features of Parkinson’s Disease Reviewed

Ikuko Miyazaki, Masato Asanuma

NeuroSci 1 ( 1 ) 1 - 14 2020.8

Authorship：Last author Language：English Publishing type：Research paper (scientific journal) Publisher：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

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

Masato Asanuma, Ikuko Miyazaki, Masahiko Funada

Forensic Toxicology 38 ( 2 ) 394 - 408 2020.7

Authorship：Lead author,　Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：Springer Science and Business Media LLC

DOI： 10.1007/s11419-020-00527-w

Other Link： http://link.springer.com/article/10.1007/s11419-020-00527-w/fulltext.html

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

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 2020.6

Language：English Publishing type：Research paper (scientific journal) Publisher：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

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

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

International Journal of Molecular Sciences 21 ( 9 ) 3254 - 3254 2020.5

Authorship：Last author Language：English Publishing type：Research paper (scientific journal) Publisher：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 Reviewed

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 2020.4

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

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

Neurochemistry International 132 104608 - 104608 2020.1

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

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

Biological and Pharmaceutical Bulletin 42 ( 6 ) 1044 - 1047 2019.6

Effects of Enteric Environmental Modification by Coffee Components on Neurodegeneration in Rotenone-Treated Mice Reviewed

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

Cells 8 ( 3 ) 221 - 221 2019.3

Authorship：Last author Language：English Publishing type：Research paper (scientific journal) Publisher：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 Reviewed

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

International Journal of Molecular Sciences 20 ( 3 ) 598 - 598 2019.1

Authorship：Lead author,　Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：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

Involvement of 5-HT2A receptor hyperfunction in the anxiety-like behavior induced by doxorubicin and cyclophosphamide combination treatment in rats Reviewed

Yuka Nakamura, Yoshihisa Kitamura, Yusuke Sumiyoshi, Nanami Naito, Shiho Kan, Soichiro Ushio, Ikuko Miyazaki, Masato Asanuma, Toshiaki Sendo

Journal of Pharmacological Sciences 138 ( 3 ) 192 - 197 2018.11

Language：English Publishing type：Research paper (scientific journal) Publisher：Elsevier BV

We examined whether combination treatment with doxorubicin and cyclophosphamide, a traditional chemotherapy for breast cancer, induced anxiety-like behavior in rats. Furthermore, we evaluated the role of the serotonin (5-HT)2A receptor subtype in the anxiety-like behavior induced by such chemotherapy. Rats were intraperitoneally injected with doxorubicin and cyclophosphamide once a week for 2 weeks. This caused the rats to display anxiety-like behavior during the light-dark test. In addition, we examined the rats' 5-HT2A receptor-mediated behavioral responses. Combination treatment with doxorubicin and cyclophosphamide significantly increased (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane, (a 5-HT2A receptor agonist)-induced wet-dog shake activity. This anxiety-like behavior was significantly inhibited by mirtazapine, a 5-HT2A receptor antagonist/5-HT1A receptor agonist, and tandospirone, a partial 5-HT1A receptor agonist, but not by fluoxetine, a selective serotonin reuptake inhibitor. The anxiety-like behavior induced by doxorubicin and cyclophosphamide combination treatment is mediated by hyperfunctioning of the 5-HT2A receptor. Thus, 5-HT2A receptor antagonists or 5-HT1A receptor agonists might be useful for treating chemotherapy-induced anxiety disorders.

DOI： 10.1016/j.jphs.2018.10.001

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

Ken-Ichi Tanaka, Takao Yagi, Takeshi Nanba, Masato Asanuma

Acta Medica Okayama 72 ( 5 ) 479 - 485 2018.10

Authorship：Last author Language：English Publishing type：Research paper (scientific journal)

© 2018, by Okayama University Medical School. We tried to clarify the applicability of a single prolonged stress (SPS) protocol as post-traumatic stress disorder (PTSD) model in mice. To investigate PTSD pathophysiology, we conducted hypothalamo-pituitary-adrenal (HPA) negative feedback testing at 1, 4, 8 and 12 weeks after the SPS by administrating a dexamethasone (DEX) suppression test. The SPS induced over-suppression of the HPA system by DEX treatment at 8 and 12 weeks. To investigate PTSD-like behavioral characteristics, we subjected mice to testing in a light/dark box (to assess anxiety), a Y-maze (working memory), a cliff avoidance (visual cognition), and an open field (locomotor activity) at 1, 4, 8 and 12 weeks after the SPS. In the light/dark box test, the SPS-applied mice spent significantly less time in the light box at 8 or 12 weeks. In the cliff avoidance test, the SPS-applied mice spent significantly less time in the open area at 1 week. However, in both the Y-maze test and the open field test, SPS-applied mice tended toward slight decreases in a time-dependent manner until 12 weeks. Therefore, SPS-applied mice may thus be useful for assessing characteristics relevant to PTSD that coincide with changes in the HPA axis.

DOI： 10.18926/AMO/56245

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

Shinki Murakami, Ikuko Miyazaki, Masato Asanuma

Nutritional Neuroscience 21 ( 3 ) 176 - 184 2018.3

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

Ken-ichi Tanaka, Kanako Sonoda, Masato Asanuma

Advances in Parkinson's Disease 6 93 - 100 2017.8

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

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 2017.4

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

Ikuko Miyazaki, Masato Asanuma

Current Pharmaceutical Design 23 ( 33 ) 4936 - 4947 2017

Language：English Publishing type：Research paper (scientific journal) Publisher：Bentham Science Publishers B.V.

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

DOI： 10.2174/1381612823666170710163731

Identification of transcription factors activated by methylmercury in mouse brain Reviewed

Min-Soek Kim, Tsutomu Takahashi, Jin-Yong Lee, Nobuhiko Miura, Masato Asanuma, Gi-Wook Hwang, Akira Naganuma

Fundamental Toxicological Sciences 4 ( 1 ) 37 - 39 2017

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

Masato Asanuma, Ikuko Miyazaki

BMC Neuroscience 17 ( 1 ) 52 2016.12

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

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

Journal of Clinical Biochemistry and Nutrition 59 ( 2 ) 93 - 99 2016.9

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 Reviewed

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

Environmental Science and Pollution Research 23 ( 10 ) 10262 - 10269 2016.5

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

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

Experimental Neurology 275 220 - 231 2016.1

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

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

Journal of Neurochemistry 136 ( 1 ) 194 - 204 2016.1

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

Ikuko Miyazaki, Masato Asanuma

Current Medicinal Chemistry 23 ( 7 ) 686 - 700 2016

Authorship：Last author Language：English Publishing type：Research paper (scientific journal) Publisher：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. Reviewed

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

Annals of Pharmacology and Pharmaceutics 1 ( 1 ) 1003 2016

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

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

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 Reviewed

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 2015.10

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

Shinki Murakami, Ikuko Miyazaki, Ko Miyoshi, Masato Asanuma

Neurochemical Research 40 ( 6 ) 1165 - 1178 2015.6

Possible involvement of iron-induced oxidative insults in neurodegeneration Reviewed

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

Neuroscience Letters 588 29 - 35 2015.2

Evaluation of drug-dependence liabilities and cytotoxicities of harmine : Harmful effects of hallucinogenic alkaloids found in plants

61 ( 28 ) 61 - 72 2015

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

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

Acta Medica Okayama 68 ( 6 ) 317 - 322 2014.12

Authorship：Last author Language：English Publishing type：Research paper (scientific journal) Publisher：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

Methylphenidate improves learning impairments and hyperthermia‐induced seizures caused by an S cn1a mutation Reviewed

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 2014.10

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

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

Neurotoxicity Research 26 ( 3 ) 285 - 298 2014.10

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：Springer Science and Business Media LLC

DOI： 10.1007/s12640-014-9480-1

Other Link： http://link.springer.com/article/10.1007/s12640-014-9480-1/fulltext.html

Striatal Astrocytes Act as a Reservoir for L-DOPA Reviewed

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

PLoS ONE 9 ( 9 ) e106362 - e106362 2014.9

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

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

Pharmacology Biochemistry and Behavior 122 240 - 245 2014.7

Language：English Publishing type：Research paper (scientific journal) Publisher：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 Reviewed International journal

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 - e97918 2014.5

Authorship：Last author Language：English Publishing type：Research paper (scientific journal) Publisher：Public Library of Science (PLoS)

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 Reviewed

Taizo Kita, Masato Asanuma, Ikuko Miyazaki, Mika Takeshima

Journal of Pharmacological Sciences 124 ( 3 ) 313 - 319 2014.3

Language：English Publishing type：Research paper (scientific journal) Publisher：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 Reviewed

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

Biological & Pharmaceutical Bulletin 37 ( 2 ) 327 - 330 2014.2

Language：English Publishing type：Research paper (scientific journal) Publisher：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 Reviewed

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 2014.1

Language：English Publishing type：Research paper (scientific journal) Publisher：American Physiological Society

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

アストロサイトによる神経機能修飾とパーキンソン病での神経保護 Invited

浅沼幹人

岡山医学会雑誌 126 ( 3 ) 203 - 208 2014

Cytoprotective effects of theanine contributed to the umami taste of green tea on cultured astroglial cells

10 ( 10 ) 179 - 191 2013.12

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

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

Neurobiology of Disease 59 244 - 256 2013.11

Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal)

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

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

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

PLoS ONE 8 ( 6 ) e65983 - e65983 2013.6

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

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

Life Sciences 92 ( 12 ) 727 - 732 2013.4

Language：English Publishing type：Research paper (scientific journal)

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 Invited

浅沼幹人, 宮崎育子

神経内科 79 ( 2 ) 257 - 261 2013

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

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

Language：English Publishing type：Research paper (scientific journal)

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

Bibliographic review on the central actions of theanine

9 ( 9 ) 45 - 58 2012.12

Centrosomal aggregates and Golgi fragmentation disrupt vesicular trafficking of DAT Reviewed

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

Neurobiology og Aging 33 ( 10 ) 2462 - 2477 2012.10

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCIENCE INC

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

DOI： 10.1016/j.neurobiolaging.2011.11.014

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

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

Neurochemical Research 37 ( 9 ) 1944 - 1951 2012.9

Authorship：Lead author,　Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：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. Reviewed

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 2012.7

Language：English Publishing type：Research paper (scientific journal) Publisher：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

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

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

Neurological Research 34 ( 6 ) 619 - 622 2012.7

Authorship：Last author Language：English Publishing type：Research paper (scientific journal) Publisher：MANEY PUBLISHING

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

DOI： 10.1179/1743132812Y.0000000001

Investigation on the Mechanisms for the Suppression of Cell Proliferation in the Dentate Gyrus of the Hippocampus in ACTH Treated Rats

Hayashi Hiromi, Doi Maho, Onoue Yuka, Kuwatsuka Keiko, Miyake Ayaka, Koyama Toshihiro, Shinomiya Kazuaki, Miyazaki Ikuko, Aasanuma Masato, Kitamura Yoshihisa

YAKUGAKU ZASSHI 132 ( 2 ) 173 - 178 2012

Language：Japanese Publishing type：Research paper (conference, symposium, etc.) Publisher：The Pharmaceutical Society of Japan

We previously reported that adrenocorticotropic hormone (ACTH)-treated rats serve as a valuable animal model for tricyclic antidepressant-resistant depressive conditions. The present study was undertaken to investigate the changes in neurogenesis in the hippocampus of ACTH-treated rats. Chronic treatment of ACTH decreased the number of bromodeoxyuridine-labeled cells in the dentate gyrus, and the coadministration of imipramine and lithium, and electroconvulsive stimuli recovered these reductions. Furthermore, chronic ACTH treatment also decreased the expression of brain-derived neurotrophic factor, and the coadministration of imipramine and lithium, and electroconvulsive stimuli recovered these reductions. These results suggest that antidepressant-resistant depression is caused by the suppression of neurogenesis, and the coadministration of imipramine and lithium, and electroconvulsive stimuli exert an antidepressant-like effect by recovering proliferative signals and neurogenesis.<br>

DOI： 10.1248/yakushi.132.173

Other Link： https://jlc.jst.go.jp/DN/JALC/00387666301?from=CiNii

A study on L-theanine-mediated cytoprotection in glial cells : L-theanine up-regulates antioxidant defenses in astrocytes

8 ( 8 ) 43 - 53 2011.12

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

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

Neurological Research 33 ( 10 ) 1050 - 1056 2011.12

Language：English Publishing type：Research paper (scientific journal) Publisher：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 Reviewed

Ko Miyoshi, Kyosuke Kasahara, Ikuko Miyazaki, Masato Asanuma

Acta Medica Okayama 65 ( 5 ) 279 - 285 2011.10

Authorship：Last author Language：English Publishing type：Research paper (scientific journal) Publisher：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

alpha 7 Nicotinic acetylcholine receptors in the central amygdaloid nucleus alter naloxone-induced withdrawal following a single exposure to morphine Reviewed

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

Psychopharmacology 214 ( 4 ) 923 - 931 2011.4

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER

Negative motivational withdrawal from acute opiate dependence was induced by an opioid antagonist, and the withdrawal signs prevented by pretreatment with nicotine.
The present study was undertaken to examine the mechanism of nicotine-induced attenuation of withdrawal precipitated by naloxone in rats administered a single dose of morphine.
Conditioned place aversion (CPA) was precipitated by naloxone in rats exposed once to morphine. Nicotinic acetylcholine receptor (nAChR) agonists were microinjected into the central amygdaloid nucleus (CeA) before naloxone was administered. Additionally, c-Fos expression in the amygdala was measured in rats exposed to alpha 7 nAChR ligands.
The microinjection of nicotine (0.3 and 1.0 mu g/mu l) into the CeA dose-dependently inhibited naloxone-induced CPA. This inhibition of CPA was reversed by methyllycaconitine (MLA), an alpha 7 nAChR antagonist. CPA was also significantly attenuated by the microinjection of tropisetron (3.0 mu g/mu l), an alpha 7 nAChR agonist and 5-hydroxytriptamine 3 (5-HT3) receptor antagonist, but not by ondansetron (1.0 and 3.0 mu g/mu l), a 5-HT3 receptor antagonist. The microinjection of PNU-282987 (3.0 mu g/mu l), a selective alpha 7 nAChR agonist, into the CeA also inhibited CPA. Furthermore, nicotine increased c-Fos expression in the CeA, but not the medial or basolateral amygdaloid nucleus. The increase of c-Fos in the CeA was significantly inhibited by MLA.
Nicotine-induced attenuation of CPA precipitated by naloxone is mediated by the alpha 7 nAChR subtype, and the CeA is one of the regions of the brain involved in the effect of nicotine on acutely opiate-dependent subjects.

DOI： 10.1007/s00213-010-2101-7

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

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

Glia 59 ( 3 ) 435 - 451 2011.3

Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：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

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

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 2011.1

Language：English Publishing type：Research paper (scientific journal) Publisher：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

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

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 534872 - 534872 2011

Language：English Publishing type：Research paper (scientific journal) Publisher：HINDAWI PUBLISHING CORPORATION

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

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. Invited

浅沼幹人, 宮崎育子

Clinical Neuroscience 29 ( 11 ) 1295 - 1297 2011

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

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 2010.8

Language：English Publishing type：Research paper (scientific journal) Publisher：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.

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

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

Naunyn-Schmiedebergs Archives of Pharmacology 382 ( 2 ) 151 - 158 2010.8

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER

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

DOI： 10.1007/s00210-010-0521-x

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

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

Journal of Neuroscience Research 88 ( 8 ) 1804 - 1811 2010.6

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-LISS

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

DOI： 10.1002/jnr.22341

Neuroprotective Effects of Zonisamide Target Astrocyte Reviewed

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 2010.2

Authorship：Lead author,　Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：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

A study on bioactivity and function of chemical compounds in food and foodstuff: search for angiotensin 1-converting enzyme inhibitory substances in some edible mushrooms using fluorescent substrate

Bulletin of Kyushu Nutrition Welfare University 6 ( 6 ) 9 - 20 2009.12

A study on bioactivity and function of chemical compounds in food and foodstuff: effect of phytic acid on cultured dopamine neuronal cells

Bulletin of Kyushu Nutrition Welfare University 6 ( 6 ) 75 - 86 2009.12

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

Ko Miyoshi, Kyosuke Kasahara, Ikuko Miyazaki, Masato Asanuma

Biochemical and Biophysical Research Communications 388 ( 4 ) 757 - 762 2009.10

Authorship：Last author Language：English Publishing type：Research paper (scientific journal) Publisher：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

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

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

Neuroscience Letters 462 ( 3 ) 235 - 238 2009.10

Authorship：Last author Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER IRELAND LTD

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

DOI： 10.1016/j.neulet.2009.07.024

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

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

FASEB Journal 23 ( 10 ) 3289 - 3297 2009.10

Authorship：Last author Language：English Publishing type：Research paper (scientific journal) Publisher：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

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

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

Naunyn-Schmiedebergs Archives of Pharmacology 380 ( 1 ) 59 - 66 2009.7

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER

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

DOI： 10.1007/s00210-009-0405-0

Approaches to Prevent Dopamine Quinone-Induced Neurotoxicity Reviewed

Ikuko Miyazaki, Masato Asanuma

Neurochemical Research 34 ( 4 ) 698 - 706 2009.4

Authorship：Last author Language：English Publisher：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

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

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

Neurochemical Research 34 ( 4 ) 764 - 774 2009.4

Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：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

Dopamine-Induced Behavioral Changes and Oxidative Stress in Methamphetamine-Induced Neurotoxicity Reviewed

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

International Review of Neurobiology 88 43 - 64 2009

Effects of L-theanine on cultured dopaminergic neuronal and glial cells

Bulletin of Kyushu Nutrition Welfare University 5 ( 5 ) 69 - 81 2008.12

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

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

Neurotoxicity Research 14 ( 4 ) 295 - 305 2008.12

Language：English Publishing type：Research paper (scientific journal) Publisher：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

A study on the effect of chemicals migrated from food and its ingredient in cultured monoamine neuronal cells: effect of docosahexaenoic acid on dopamine-induced neurotoxicity

Bulletin of Kyushu Nutrition Welfare University 5 ( 5 ) 55 - 67 2008.12

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

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

Toxicology Letters 180 ( 3 ) 231 - 231 2008.8

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

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 2008.7

Language：English Publishing type：Research paper (scientific journal) Publisher：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

Dopaminergic neuron-specific oxidative stress caused by dopamine itself Reviewed

Ikuko Miyazaki, Masato Asanuma

Acta Medica Okayama 62 ( 3 ) 141 - 150 2008.6

Authorship：Last author Language：English Publishing type：Research paper (scientific journal) Publisher：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

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

Masato Asanuma, Ikuko Miyazaki

Current Pharmacutical Design 14 ( 14 ) 1428 - 1434 2008.5

Authorship：Lead author,　Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：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 Reviewed

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

Neuroscience Research 60 ( 4 ) 355 - 363 2008.4

Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal)

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. © 2007 Elsevier Ireland Ltd and the Japan Neuroscience Society.

DOI： 10.1016/j.neures.2007.12.006

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

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

American Journal of Nephrology 28 ( 4 ) 661 - 668 2008.4

Language：English Publishing type：Research paper (scientific journal) Publisher：KARGER

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

DOI： 10.1159/000121357

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

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 2008.3

Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：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

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

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

Chemico-Biological Interactions 172 ( 1 ) 11 - 21 2008.3

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER IRELAND LTD

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

DOI： 10.1016/j.cbi.2007.11.010

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

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

Biochemical Pharmacology 75 ( 3 ) 752 - 760 2008.2

Language：English Publishing type：Research paper (scientific journal) Publisher：PERGAMON-ELSEVIER SCIENCE LTD

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

DOI： 10.1016/j.bcp.2007.09.019

Quinone formation as a common neurotoxic factor in dopaminergic neurotoxicity induced by an excess amount of cytosolic dopamine Invited Reviewed

Miyazaki Ikuko, Asanuma Masato, DIAZ-CORRALES Francisco J., Miyoshi Ko, Ogawa Norio

Okayama Igakkai Zasshi (Journal of Okayama Medical Association) 119 ( 1 ) 235 - 239 2008.1

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

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

Neuroscience Research 60 ( 1 ) 106 - 113 2008.1

Authorship：Lead author,　Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：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

[New perspectives on the mechanism of methamphetamine-induced neurotoxicity] Reviewed

28 ( 2 ) 49 - 61 2008

A study on dopamine-induced neurotoxicity on chemicals migrated from food container and cans: effect of bisphenol A on cultured dopamine neuronal cells

Bulletin of Kyushu Nutrition Welfare University 4 ( 4 ) 89 - 97 2007.12

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

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

FEBS Letters 581 ( 25 ) 5003 - 5008 2007.10

Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：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

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

Masato Asanuma, Ikuko Miyazaki

Experimental Neurology 206 ( 2 ) 172 - 178 2007.8

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

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

Toxicology Letters 170 ( 1 ) 75 - 82 2007.4

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER IRELAND LTD

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

DOI： 10.1016/j.toxlet.2007.02.007

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

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

Neuroscience Letters 414 ( 3 ) 263 - 267 2007.3

Authorship：Lead author,　Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：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

Characterization of pericentrin isoforms in vivo Reviewed

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

Biochemical and Biophysical Research Communications 351 ( 3 ) 745 - 749 2006.12

Language：English Publishing type：Research paper (scientific journal) Publisher：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

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

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

Acta Medica Okayama 60 ( 6 ) 299 - 309 2006.12

Language：English Publishing type：Research paper (scientific journal) Publisher：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

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

Ken-ichi Tanaka, Norio Ogawa, Masato Asanuma

Neuroscience Letters 410 ( 2 ) 85 - 89 2006.12

Authorship：Last author Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER IRELAND LTD

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

DOI： 10.1016/j.neulet.2006.08.021

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

Masato Asanuma, Ikuko Miyazaki

Expert Review of Neurotherapeutics 6 ( 9 ) 1313 - 1325 2006.9

Authorship：Lead author,　Corresponding author Language：English Publisher：EXPERT REVIEWS

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

DOI： 10.1586/14737175.6.9.1313

Embryonic expression of pericentrin suggests universal roles in ciliogenesis Reviewed

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

Development Genes and Evolution 216 ( 9 ) 537 - 542 2006.9

Language：English Publishing type：Research paper (scientific journal) Publisher：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

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

Shizuo Narimatsu, Rei Yonemoto, Keita Saito, Kazuo Takaya, Takuya Kumamoto, Tsutomu Ishikawa, Masato Asanuma, Masahiko Funada, Kimio Kiryu, Shinsaku Naito, Yuzo Yoshida, Shigeo Yamamoto, Nobumitsu Hanioka

Biochemical Pharmacology 71 ( 9 ) 1377 - 1385 2006.4

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

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

Psychiatry and Clinical Neurosciences 60 S18 - S26 2006.4

Methamphetamine‐induced dopaminergic neurotoxicity is regulated by quinone formation‐related molecules Reviewed

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

The FASEB Journal 20 ( 3 ) 571 - 573 2006.3

腹膜透析におけるラジカル分子特異的測定と腹膜硬化症早期診断マーカーの確立.

杉山斉, 菊本陽子, 浅沼幹人, 平松信, 槇野博史

腎臓 29 ( 2 ) 112 - 117 2006

ドパミン受容体アゴニストによるドパミンニューロン死の制御. Invited

浅沼幹人

Clinical Neuroscience 23 ( 12 ) 1342 - 1343 2005.12

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

浅沼幹人, 小川紀雄

医学のあゆみ 215 ( 10 ) 785 - 792 2005.12

L-DOPA treatment from the viewpoint of neuroprotection Reviewed

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

Journal of Neurology 252 ( S4 ) iv23 - iv31 2005.10

Prednisolone Inhibits Proliferation of Cultured Pulmonary Artery Smooth Muscle Cells of Patients With Idiopathic Pulmonary Arterial Hypertension Reviewed International journal

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 2005.9

Language：English Publishing type：Research paper (scientific journal) Publisher：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

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

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

Clinical Neuropharmacology 28 ( 4 ) 155 - 160 2005.7

Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal)

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

:-drug dependence and toxicity Invited

Asanuma Masato, Miyazaki Ikuko

Folia Pharmacologica Japonica 126 ( 1 ) 30 - 34 2005.7

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

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

Neurological Research 27 ( 5 ) 533 - 539 2005.7

Common anti-apoptotic roles of parkin and α-synuclein in human dopaminergic cells Reviewed

Yutaka Machida, Tomoki Chiba, Atsushi Takayanagi, Yoshikazu Tanaka, Masato Asanuma, Norio Ogawa, Akihiko Koyama, Takeshi Iwatsubo, Shosuke Ito, Poul Hening Jansen, Nobuyoshi Shimizu, Keiji Tanaka, Yoshikuni Mizuno, Nobutaka Hattori

Biochemical and Biophysical Research Communications 332 ( 1 ) 233 - 240 2005.6

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

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

Neuroscience 133 ( 1 ) 117 - 135 2005.1

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

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

Brain Research 1029 ( 1 ) 120 - 123 2004.12

Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal)

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

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

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

Acta Medica Okayama 58 ( 5 ) 221 - 233 2004.10

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

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

Annals of the New York Academy of Sciences 1025 ( 1 ) 69 - 75 2004.10

パーキンソン病における細胞死の機序． Invited

小川紀雄, 浅沼幹人, 三好耕

日本臨床 62 ( 9 ) 1629 - 1634 2004.9

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

Youichirou Higashi, Masato Asanuma, Ikuko Miyazaki, Norio Ogawa

Neurological Research 26 ( 6 ) 671 - 676 2004.9

Metallothioneins and neurodegenerative diseases Reviewed

Isao Hozumi, Masato Asanuma, Mitsunori Yamada, Yoko Uchida

Journal of Health Science 50 ( 4 ) 323 - 331 2004.8

Language：English Publishing type：Research paper (scientific journal) Publisher：PHARMACEUTICAL SOC JAPAN

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

DOI： 10.1248/jhs.50.323

Molecular Basis of Anti-Apoptotic Effect of Immunophilin Ligands on Hydrogen Peroxide–Induced Apoptosis in Human Glioma Cells Reviewed

Ken-ichi Tanaka, Masato Asanuma, Norio Ogawa

Neurochemical Research 29 ( 8 ) 1529 - 1536 2004.8

Parkin attenuates manganese‐induced dopaminergic cell death Reviewed

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

Journal of Neurochemistry 89 ( 6 ) 1490 - 1497 2004.6

DISC1 localizes to the centrosome by binding to kendrin Reviewed

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 2004.5

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

浅沼幹人

内科 93 ( 4 ) 611 - 615 2004.4

Neuroprotective Effects of Nonsteroidal Anti-inflammatory Drugs on Neurodegenerative Diseases Reviewed

Masato Asanuma, Ikuko Miyazaki, Norio Ogawa

Current Pharmaceutical Design 10 ( 6 ) 695 - 700 2004.2

Parkinson病薬物治療の将来 ―進行抑制薬実現の可能性． Invited

小川紀雄, 浅沼幹人, 田中健一

医学のあゆみ 208 ( 6 ) 583 - 588 2004.2

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〜． Invited

浅沼幹人, 宮崎育子, 小川紀雄

医薬ジャーナル 40 ( 1 ) 111 - 116 2004.1

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

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

Neuroscience Letters 354 ( 1 ) 59 - 63 2004.1

遺伝子改変によるパーキンソン病モデル． Invited

浅沼幹人, 宮崎育子

脳の科学 292 ( 2004年増刊号 ) 165 - 170 2004

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

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

心電図 24 ( 1 ) 15 - 21 2004

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：(一社)日本不整脈心電学会

欧米における大規模臨床試験の結果は,β遮断薬が慢性心不全の生命予後改善のみならず,突然死も有意に抑制することを明らかにした.しかし,患者背景の異なる我が国における,β遮断薬の有効性は必ずしも明確ではない.そこで,著者等の自験例を基に,致死性不整脈患者或いは慢性心不全患者に対するカルベジロールを中心としたβ遮断薬の予後に対する影響及び突然死予防効果,その機序について検討した

DOI： 10.5105/jse.24.15

Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2004&ichushi_jid=J00681&link_issn=&doc_id=20040205230006&doc_link_id=%2Fdn4eleca%2F2004%2F002401%2F007%2F0032-0039%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fdn4eleca%2F2004%2F002401%2F007%2F0032-0039%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Direct Evidence for Increased Hydroxyl Radicals in Angiotensin II-induced Cardiac Hypertrophy through Angiotensin II Type 1a Receptor Reviewed International journal

Mikio Kakishita, Kazufumi Nakamura, Masato Asanuma, Hiroshi Morita, Hironori Saito, Kengo Kusano, Yoichi Nakamura, Tetsuro Emori, Hiromi Matsubara, Takeshi Sugaya, Norio Ogawa, Tohru Ohe

Journal of Cardiovascular Pharmacology 42 ( Suppl 1 ) S67 - S70 2003.12

Language：English Publishing type：Research paper (scientific journal) Publisher：Ovid Technologies (Wolters Kluwer Health)

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

DOI： 10.1097/00005344-200312001-00015

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

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

Neuroscience Letters 352 ( 1 ) 13 - 16 2003.11

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 23 ( 10 ) 2736 - 2741 2003.10

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

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

Neuroscience Research 47 ( 1 ) 31 - 37 2003.9

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

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

Biochimica et Biophysica Acta - General Subjects 1619 ( 1 ) 39 - 52 2003.1

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

Masato Asanuma, Ikuko Miyazaki, Norio Ogawa

Neurotoxicity Research 5 ( 3 ) 165 - 176 2003.1

非ステロイド性消炎鎮痛薬の神経保護作用の新展開. Reviewed

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 ( 3 ) 111 - 119 2003

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 3 ( 1 ) 69 - 70 2003

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

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

Journal of Biological Chemistry 277 ( 44 ) 42224 - 42232 2002.11

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

浅沼幹人

ファルマシア 38 ( 11 ) 1105 - 1106 2002.11

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

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

Neuroscience Research 43 ( 4 ) 323 - 333 2002.8

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

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

Neuroscience Letters 327 ( 1 ) 61 - 65 2002.7

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

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

Neuroscience Research 43 ( 3 ) 259 - 267 2002.7

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

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

Neuroscience Letters 325 ( 3 ) 191 - 194 2002.6

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 22 ( 1 ) 212 - 215 2002.1

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

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

Journal of Neurochemistry 76 ( 6 ) 1895 - 1904 2001.3

Delta opioid peptide [D-Ala2, D-Leu5]enkephalin causes a near complete blockade of the neuronal damage induced by a single high dose of methamphetamine: Examining the role of p53 Reviewed

Teruo Hayashi, Hiroshi Hirata, Masato Asanuma, Bruce Ladenheim, Li-I Tsao, Jean Lud Cadet, Tsung-Ping Su

Synapse 39 ( 4 ) 305 - 312 2001.3

Progressive cortical atrophy after forebrain ischemia in diabetic rats Reviewed

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

Neuroscience Research 39 ( 3 ) 339 - 346 2001.3

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

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

Acta Medica Okayama 55 ( 1 ) 1 - 9 2001.2

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

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

Neurochemical Research 26 ( 1 ) 31 - 36 2001

酸化ストレスと神経細胞死. Invited

小川紀雄, 浅沼幹人

Clinical Neuroscience 19 ( 6 ) 665 - 667 2001

フリーラジカルと脳障害. Invited

浅沼幹人, 小川紀雄

Clinical Neuroscience 19 ( 5 ) 555 - 559 2001

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

Ken-ichi Tanaka, Naoko Fujita, Masato Asanuma, Norio Ogawa

Acta Medica Okayama 54 ( 6 ) 275 - 280 2000.12

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

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

Neuroscience Letters 293 ( 1 ) 65 - 68 2000.10

Inhibition of Tyrosinase Reduces Cell Viability in Catecholaminergic Neuronal Cells Reviewed

Youichirou Higashi, Masato Asanuma, Ikuko Miyazaki, Norio Ogawa

Journal of Neurochemistry 75 ( 4 ) 1771 - 1774 2000.10

Direct interactions of methamphetamine with the nucleus Reviewed

Masato Asanuma, Teruo Hayashi, Sonia V Ordonèz, Norio Ogawa, Jean Lud Cadet

Molecular Brain Research 80 ( 2 ) 237 - 243 2000.9

Bromocriptine markedly suppress levodopa-induced abnormal increase of dopamine turnover in the parkinsonian striatum Reviewed

Norio Ogawa, Ken-ichi Tanaka, Masato Asanuma

Neurochemical Research 25 ( 6 ) 755 - 758 2000.6

フリーラジカルと神経細胞死. Invited

浅沼幹人, 小川紀雄

Clinical Neuroscience 18 ( 4 ) 415 - 417 2000.4

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

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

Brain Research 853 ( 2 ) 310 - 316 2000.1

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

Yoichi Kondo, Fumio Kondo, Masato Asanuma, Ken-ichi Tanaka, Norio Ogawa

Neurochemical Research 25 ( 2 ) 205 - 209 2000

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

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

Neurochemical Research 24 ( 7 ) 857 - 860 1999.7

Glial Cells Protect Neurons Against Oxidative Stress via Transcriptional Up-Regulation of the Glutathione Synthesis Reviewed

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

Journal of Neurochemistry 72 ( 6 ) 2334 - 2344 1999.6

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

Marvin Gómez-Vargas, Masato Asanuma, Sakiko Nishibayashi-Asanuma, Emi Iwata, Norio Ogawa

Neurochemical Research 24 ( 5 ) 629 - 635 1999.5

パーキンソン病と活性酸素・窒素種. Invited

浅沼幹人, 小川紀雄

神経研究の進歩 43 ( 2 ) 264 - 274 1999.4

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

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

Neurochemical Research 24 ( 1 ) 9 - 13 1999

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

Norio Ogawa, Kiminao Mizukawa, Hitoo Nishino, Masato Asanuma, Mitsutoshi Yamamoto

Journal of Brain Science 25 ( 3-4 ) 133 - 138 1999

Neural transplantation normalizes dopaminergic dysfunction in an animal model of parkinson's disease Reviewed

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

Journal of Brain Science 25 ( 3-4 ) 133 - 138 1999

Language：English Publishing type：Research paper (scientific journal)

Levodopa (L-DOPA) is the most commonly used pharmacotherapy in patients with Parkinson's disease (PD), but is also associated with adverse effects during chronic use and a decreased ability to control PD as the disease progresses. Neural transplantation of dopamine-synthesizing cells is being explored as a possible alternative to L-DOPA for the treatment of PD. In a rodent model of PD, we demonstrated that neural transplantation of dopamine-releasing cells (from fetal midbrain areas) led to normalisation of striatal D1 and D2 dopamine receptors to their non-PD levels at 3 months post-transplantation, which was accompanied by near normalization of rotational behavior. Immunohistochemical evaluation showed that grafted fetal dopaminergic cells survive, synthesize and release dopamine for at least 3 months post-transplantation. Grafting of neuronal cells into the brain therefore represents a promising approach to restoring disturbed motor function characteristic of PD.

ホスホジエステラーゼ Invited

浅沼幹人

生体の科学 49 ( 5 ) 499 - 501 1998.10

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

Ken-ichi Tanaka, Naoko Wada, Koji Hori, Masato Asanuma, Masahiko Nomura, Norio Ogawa

Journal of Neuroscience Methods 84 ( 1-2 ) 63 - 68 1998.10

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

Hiroshi Hirata, Masato Asanuma, Jean Lud Cadet

Synapse 30 ( 2 ) 150 - 155 1998.10

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

Masato Asanuma, Jean Lud Cadet

Molecular Brain Research 60 ( 2 ) 305 - 309 1998.10

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

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

Neuroscience Letters 251 ( 1 ) 49 - 52 1998.7

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

Hiroshi Hirata, Masato Asanuma, Jean Lud Cadet

Molecular Brain Research 58 ( 1-2 ) 209 - 216 1998.7

Parkinson病とNO. Invited

小川紀雄, 浅沼幹人

Clinical Neuroscience 16 ( 7 ) 806 - 808 1998.7

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

Marvin Gómez-Vargas, Sakiko Nishibayashi-Asanuma, Masato Asanuma, Yoichi Kondo, Emi Iwata, Norio Ogawa

Brain Research 790 ( 1-2 ) 202 - 208 1998.4

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

Masato Asanuma, Hiroshi Hirata, Jean Lud Cadet

Neuroscience 85 ( 3 ) 907 - 917 1998.4

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

Motoko Kawai, Shingoro Matsuura, Masato Asanuma, Norio Ogawa

Neurochemical Research 23 ( 4 ) 455 - 461 1998.4

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

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

Neuroscience Research 30 ( 2 ) 185 - 193 1998.2

Effects of Lecithinized SOD on Sequential Change in SOD Activity after Cerebral Contusion in Rats Reviewed

Masatoshi Yunoki, Masamitsu Kawauchi, Naoya Ukita, Yasuhiro Noguchi, Shinsaku Nishio, Yasuhiro Ono, Shoji Asari, Takashi Ohmoto, Masato Asanuma, Norio Ogawa

Acta Neurochir Suppl 71 142 - 145 1998

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

Hisashi Tanii, Norio Taniguchi, Ichiro Tsujio, Masato Asanuma, Emi Iwata, Takashi Kudo, Norio Ogawa, Masatoshi Takeda

Psychiatry and Clinical Neurosciences 51 ( 6 ) 415 - 420 1997.12

Effects of Lecithinized Superoxide Dismutase on Traumatic Brain Injury in Rats Reviewed

Masatoshi Yunoki, Masamitsu Kawauchi, Naoya Ukita, Yasuhiro Noguchi, Shinsaku Nishio, Yasuhiro Ono, Shoji Asari, Takashi Ohmoto, Masato Asanuma, Norio Ogawa

Journal of Neurotrauma 14 ( 10 ) 739 - 746 1997.10

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

Emi Iwata, Masato Asanuma, Sakiko Nishibayashi, Yoichi Kondo, Norio Ogawa

Molecular Brain Research 50 ( 1-2 ) 213 - 220 1997.10

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

Yoichi Kondo, Masato Asanuma, Sakiko Nishibayashi, Emi Iwata, Norio Ogawa

Brain Research 772 ( 1-2 ) 37 - 44 1997.10

Genetic association between susceptibility to Parkinson's disease and α1-antichymotrypsin polymorphism Reviewed

Mitsutoshi Yamamoto, Ikuko Kondo, Norio Ogawa, Masato Asanuma, Yoshiaki Yamashita, Yoshikuni Mizuno

Brain Research 759 ( 1 ) 153 - 155 1997.6

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

Ken-ichi Tanakaa, Norio Ogawa, Masato Asanuma, Yoichi Kondo

Regulatory Peptides 70 ( 2-3 ) 173 - 178 1997.6

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

Hiroshi Asahara, Koushi Fujisawa, Tetsuji Kobata, Tomoko Hasunuma, Toshiro Maeda, Masato Asanuma, Norio Ogawa, Hajime Inoue, Takayuki Sumida, Kusuki Nishioka

Arthritis & Rheumatism 40 ( 5 ) 912 - 918 1997.5

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

Masato Asanuma, Sakiko N Asanuma, Marvin Gómez-Vargas, Mitsutoshi Yamamoto, Norio Ogawa

Neuroscience Letters 225 ( 2 ) 109 - 112 1997.4

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

浅沼幹人

Prog. Med. 17 ( 2 ) 423 - 430 1997.2

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

Sakiko Nishibayashi, Yoichi Kondo, Masato Asanuma, Emi Iwata, Marvin Gomez-Vargas, Norio Ogawa

Journal of Brain Science 23 ( 1 ) 33 - 40 1997

Language：English Publishing type：Research paper (scientific journal) Publisher：JAPAN BRAIN SCI SOC

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

神経細胞死と活性酸素・フリーラジカル.. Invited

小川紀雄, 近藤洋一, 岩田恵美, 浅沼幹人, 飯田基之

フリーラジカルの臨床 11 101 - 106 1997

Chronic administration of Oren-gedoku-to (TJ15) inhibits ischemic-induced changes in brain indoleamine metabolism and muscarinic receptor binding in the Mongolian gerbil Reviewed

Hideaki Kabuto, Masato Asanuma, Sakiko Nishibayashi, Motoyuki Iida, Norio Ogawa

Neurochemical Research 22 ( 1 ) 33 - 36 1997

Effects of Lecithinized SOD on Contusion Injury in Rats Reviewed

Masatoshi Yunoki, Yasuhiro Noguchi, Shinsaku Nishio, Yasuhiro Ono, Masamitsu Kawauchi, Shoji Asai, Takashi Ohmoto, Masato Asanuma, Norio Ogawa

Acta Neurochir Suppl 70 182 - 184 1997

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

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

Journal of Brain Science 23 ( 4 ) 250 - 260 1997

Scavenging Effects of Dopamine Agonists on Nitric Oxide Radicals Reviewed

Sakiko Nishibayashi, Masato Asanuma, Masahiro Kohno, Marvin Gómez-Vargas, Norio Ogawa

Journal of Neurochemistry 67 ( 5 ) 2208 - 2211 1996.11

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

Masato Asanuma, Sakiko Nishibayashi, Emi Iwata, Yoichi Kondo, Tohru Nakanishi, Marvin Gómez Vargas, Norio Ogawa

Molecular Brain Research 41 ( 1-2 ) 210 - 215 1996.9

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

Ken-ichi Tanaka, Norio Ogawa, Masato Asanuma, Yoichi Kondo, Masahiko Nomura

Brain Research 729 ( 1 ) 55 - 65 1996.8

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCIENCE BV

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

DOI： 10.1016/S0006-8993(96)00400-3

Effects of Bromocriptine on Dopamine Turnover with or without Levodopa Reviewed

Norio Ogawa, Masato Asanuma, Ken-ichi Tanaka, Koji Matsuura, Kyoko Iida, Mitsutoshi Yamamoto

Journal of International Medical Research 24 ( 3 ) 271 - 277 1996.5

Publishing type：Research paper (scientific journal) Publisher：SAGE Publications

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

DOI： 10.1177/030006059602400306

L-DOPA合剤の変更による老齢パーキンソン病患者の問題症状の改善 Invited

浅沼幹人

老化と疾患 9 ( 4 ) 521 - 525 1996.4

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

Tohru Nakanishi, Kazuhiro Ishii, Nobuyuki Fukushima, Masato Asanuma, Emi Iwata, Norio Ogawa

Biochemistry and Molecular Biology International 38 ( 4 ) 763 - 772 1996.4

Language：English Publishing type：Research paper (scientific journal) Publisher：ACADEMIC PRESS AUST

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

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

Yoichi Kondo, Norio Ogawa, Masato Asanuma, Koji Matsuura, Sakiko Nishibayashi, Emi Iwata

Neuroscience Research 24 ( 4 ) 409 - 414 1996.3

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

Norio Ogawa, Masato Asanuma, Ken-ichi Tanaka, Hiroshi Hirata, Yoichi Kondo, Masaki Goto, Masamitsu Kawauchi, Toshio Ogura

Brain Research 712 ( 1 ) 60 - 68 1996.3

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

Masato Asanuma, Yoichi Kondo, Sakiko Nishibayashi, Emi Iwata, Tohru Nakanishi, Norio Ogawa

Neuroscience Letters 201 ( 2 ) 127 - 130 1995.12

脳の老化と生化学 Invited

浅沼幹人, 小川紀雄

臨床と研究 72 ( 11 ) 2654 - 2658 1995.11

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

Hiroshi Asahara, Masato Asanuma, Norio Ogawa, Sakiko Nishibayashi, Hajime Inoue

Biochemistry and Molecular Biology International 37 ( 5 ) 827 - 832 1995.11

Language：English Publishing type：Research paper (scientific journal) Publisher：ACADEMIC PRESS AUST

Our objective was to clarify the DNA-binding activity of transcription factor NF-kappa B as related to cytokine induction in the synovium of patients with rheumatoid arthritis (RA) and osteoarthritis (OA). Synovial membranes were obtained during arthroplasty of the knee from 7 patients with RA and 4 patients with OA. Nuclear extracts obtained from the synovial membranes were examined by electrophoretic mobility shift assay to determine the DNA-binding activity of NF-kappa B. Markedly high DNA-binding activity of NF-kappa B was detected in the synovial membranes of RA patients, while virtually no activity was observed in those of OA patients. These results suggest that the high induction of NF-kappa B in the nuclear extracts may be relatively specific to synovial membranes in RA. NF-kappa B may regulate the production of cytokines at the site of synovial inflammation.

Effects of single cyclosporin A pretreatment on pentylenetetrazol-induced convulsion and on TRE-binding activity in the rat brain Reviewed

Masato Asanuma, Sakiko Nishibayashi, Yoichi Kondo, Emi Iwata, Masaaki Tsuda, Norio Ogawa

Molecular Brain Research 33 ( 1 ) 29 - 36 1995.10

M1 Receptors in Blood Pressure–Controlled Ischemic Spontaneously Hypertensive Rats Reviewed

Hiroshi Hirata, Masato Asanuma, Ken-ichi Tanaka, Yoichi Kondo, Norio Ogawa

Stroke 26 ( 7 ) 1268 - 1272 1995.7

Publishing type：Research paper (scientific journal) Publisher：Ovid Technologies (Wolters Kluwer Health)

<italic>Background and Purpose</italic>
Hypertension is a primary aggravating factor in cerebral infarction. An acute rise in blood pressure (BP) at the time of a stroke may be harmful to the brain in a hypertensive subject because both cerebral vascular structure and function are altered by hypertension. Muscarinic M
₁
receptors are concerned with memory and learning. We aimed to evaluate the effect of controlling BP in hypertensive subjects at the time of stroke with a biochemical index of brain damage.

<italic>Methods</italic>
We gave a single dose of either the antihypertensive α-blocker phentolamine (2 mg/kg IP) or the calcium antagonist nicardipine (2 mg/kg IP) at the start of bilateral carotid artery occlusion to spontaneously hypertensive rats undergoing 3 hours of transient ischemia; we measured the time course of mean BP (MBP) and changes in the M
₁
receptor and its mRNA in three brain regions 2 weeks after the transient ischemia.

<italic>Results</italic>
Administration of phentolamine or nicardipine not only significantly suppressed the ischemia-induced rise of MBP, it actually decreased MBP during ischemia. In an ischemic control group, M
₁
receptor binding decreased in the frontal cortex and M
₁
receptor mRNA increased in the hippocampus 2 weeks after the ischemia. In contrast, both phentolamine- and nicardipine-treated ischemic rats showed no changes in either index compared with sham-operated controls.

<italic>Conclusions</italic>
Controlling BP during an ischemic insult attenuates ischemia-induced damage of M
₁
receptors in the brain of spontaneously hypertensive rats. These results suggest that a rapid intensive increase of BP at the time of a stroke may exacerbate brain damage in hypertensive individuals.

DOI： 10.1161/01.str.26.7.1268

神経変性過程における免疫制御薬シクロスポリンAの効果 Invited

小川紀雄, 浅沼幹人

Dementia 9 ( 2 ) 153 - 161 1995.4

Cholecystokinin alterations and effects of levodopa administration in the MPTP-treated mouse brain Reviewed

Emi Iwata, Masato Asanuma, Yoichi Kondo, Sakiko Nishibayashi, Koji Matsuura, Norio Ogawa

Research Communications in Molecular Pathology and Pharmacology 88 ( 1 ) 31 - 38 1995.4

Language：English Publishing type：Research paper (scientific journal) Publisher：P J D PUBLICATIONS LTD

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

Protective effects of pergolide on dopamine levels in the 6-hydroxydopamine-lesioned mouse brain Reviewed

Masato Asanuma, Norio Ogawa, Sakiko Nishibayashi, Motoko Kawai, Yoichi Kondo, Emi Iwata

Archives Internationales de Pharmacodynamie et de Therapie 329 ( 2 ) 221 - 230 1995.3

Authorship：Lead author,　Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：ARCH INT PHARMACODYNAMIE

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

Cyclosporin A prevents ischemia-induced reduction of muscarinic acetylcholine receptors with suppression of microglial activation in gerbil hippocampus Reviewed

Yoichi Kondo, Norio Ogawa, Masato Asanuma, Sakiko Nishibayashi, Emi Iwata, Akitane Mori

Neuroscience Research 22 ( 1 ) 123 - 127 1995.3

Regional Differences in Late-Onset Iron Deposition, Ferritin, Transferrin, Astrocyte Proliferation, and Microglial Activation after Transient Forebrain Ischemia in Rat Brain Reviewed

Yoichi Kondo, Norio Ogawa, Masato Asanuma, Zensuke Ota, Akitane Mori

Journal of Cerebral Blood Flow & Metabolism 15 ( 2 ) 216 - 226 1995.3

Publishing type：Research paper (scientific journal) Publisher：SAGE Publications

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

DOI： 10.1038/jcbfm.1995.27

Angiotensin II Induces in vivo c-fosExpression from Rat Renal Cortex and Medulla Reviewed

Teruaki Omiya, Takayoshi Yamauchi, Toshio Ogura, Masato Asanuma, Zensuke Ota

Renal Physiology and Biochemistry 18 ( 2 ) 81 - 88 1995.3

Neuropeptide levels in discrete brain regions in the iminodipropionitrile-induced persistent dyskinesia rat model Reviewed

Yoshiro Kawada, Norio Ogawa, Masato Asanuma, Akitane Mori

Regulatory Peptides 55 ( 1 ) 103 - 110 1995.1

Effects of repeated injection of cyclosporin A on pentylenetetrazol-induced convulsion and cyclophilin mRNA levels in rat brain Reviewed

Masato Asanuma, Norio Ogawa, Sakiko Nishibayashi, Yoichi Kondo, Akitane Mori

Neurochemical Research 20 ( 1 ) 101 - 105 1995.1

老齢ラット脳内における転写制御因子AP-1のFos-Jun/Jun dimer比の変化 Reviewed

浅沼幹人, 近藤洋一, 西林佐紀子, 岩田恵美, 松浦弘治, 小川紀雄, 森昭胤

Neurosciences 21 125 - 128 1995

Chronic effects of transient forebrain ischemia on monoamines in the spontaneously hypertensive rat brain Reviewed

Sakiko Nishibayashi, Masato Asanuma, Yoichi Kondo, Emi Iwata, Koji Matsuura, Toshio Ogura, Norio Ogawa

Biogenic Amines 11 ( 2 ) 187 - 194 1995

Language：English Publishing type：Research paper (scientific journal) Publisher：VSP BV

Using the 3-hr common carotid occlusion model in spontaneously hypertensive rats (SHRs), we investigated the changes in monoamines and their metabolites up to the chronic phase, 6 mouths after the transient forebrain ischemia, in various brain regions. In the striatum, the levels of dopamine (DA) at the 3rd week and serotonin (5-HT) at the 2nd week were 1.6-fold and 2.4-fold higher than the levels in the respective sham-operated controls coinciding with increases in their metabolites, homovanillic acid and 5-hydroxyindoleacetic acid. However, these marked increases in both transmitters were transient aid their levels recovered to the sham-operated levels. This transient increase in DA release in the striatum may be caused by ischemia-induced disruption of nerve endings, and may aggravate tissue damage in the striatum at the chronic phase after ischemia. Transient or lasting changes in noradrenaline, DA, 5-HT and their metabolites were also observed in other brain regions, the thalamus+midbrain and the hippocampus of SHRs after transient ischemia. These ischemia-induced alterations in monoamines at the chronic phase may be partly involved in the late-onset sequelae seen in the cerebrovascular disorders.

中枢神経における転写制御因子結合活性に対する酸化的ストレスの影響 Reviewed

岩田恵美, 浅沼幹人, 西林佐紀子, 近藤洋一, 松浦弘治, 小川紀雄, 森昭胤

Neurosciences 21 77 - 80 1995

ラット脳血流慢性低潅流時におけるアセチルコリン系の変化 Reviewed

西林佐紀子, 浅沼幹人, 近藤洋一, 岩田恵美, 松浦弘治, 飯田享子, 小川紀雄, 森昭胤

Neurosciences 21 109 - 112 1995

Cholecystokinin alterations and effects of levodopa administration in the MPTP-treated mouse brain

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

Research Communications in Molecular Pathology and Pharmacology 88 ( 1 ) 31 - 38 1995

Language：English Publishing type：Research paper (scientific journal)

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

Regional changes in α-tubulin and β-actin mRNA accumlations after transient ischemia in spontaneously hypertensive rat brains Reviewed

Yoichi Kondo, Norio Ogawa, Masato Asanuma, Hiroshi Hirata, Sakiko Nishibayashi, Akitane Mori

Research Communications in Molecular Pathology and Pharmacology 86 ( 2 ) 139 - 153 1994.11

Language：English Publishing type：Research paper (scientific journal) Publisher：P J D PUBLICATIONS LTD

Regional changes in the mRNA accumulations for cytoskeletal proteins alpha-tubulin and beta-actin were examined by in situ hybridization and Northern blot analysis in spontaneously hypertensive rat brains at chronic stages after 3 hours of transient ischemia. alpha-Tubulin mRNA accumulations showed no significant change at 2 weeks after transient ischemia except for a significant decrease in the frontal cortex (9.7%, p < 0.01) coinciding with ischemia induced histological changes. beta-Actin mRNA level was significantly increased in the parietal cortex (8.5%), septum (10.0%), amygdala (11.0%), CA4 area (5.8%) and the dentate gyrus (7.5%) of the hippocampus at 2 weeks after recirculation compared with a sham-operated control group (p<0.01). The ischemic areas of hippocampal and frontocortical lesions receive afferent neurons from those regions where beta-actin mRNA was increased, suggesting that ischemia-induced increases in beta-actin mRNA may reflect actin synthesis in these neurons to compensate for lost synaptic connections. Two cytoskeletal mRNA concentrations reacted differently to cerebral ischemia, and did not parallel histological signs of ischemia either temporally or spatially.

Chronic administration of acetylcholinesterase inhibitor in the senescent Rat brain Reviewed

Ken-ichi Tanaka, Norio Ogawa, Masato Asanuma, Yoichi Kondo, Akitane Mori

Neurobiology of Aging 15 ( 6 ) 721 - 725 1994.11

Tubulin and actin mRNAs in the young-adult and the aged rat brain: effects of repeated administration with bifemelane hydrochloride Reviewed

Sakiko Nishibayashi, Norio Ogawa, Masato Asanuma, Yoichi Kondo, Akitane Mori

Archives of Gerontology and Geriatrics 19 ( 3 ) 265 - 272 1994.11

Bromocriptine protects mice against 6-hydroxydopamine and scavenges hydroxyl free radicals in vitro Reviewed

Norio Ogawa, Ken-ichi Tanaka, Masato Asanuma, Motoko Kawai, Toshiki Masumizu, Masahiro Kohno, Akitane Mori

Brain Research 657 ( 1-2 ) 207 - 213 1994.9

Reduced choline acetyltransferase activity and muscarinic M1 receptor levels in aged Fisher 344 rat brains did not parallel their respective mRNA levels Reviewed

Norio Ogawa, Masato Asanuma, Yoichi Kondo, Sakiko Nishibayashi, Akitane Mori

Brain Research 658 ( 1-2 ) 87 - 92 1994.9

Effects of Repeated Immunosuppressant Treatment on Rat Pentylenetetrazol-Induced Convulsion Reviewed

Masato Asanuma, Yoichi Kondo, Norio Ogawa, Akitane Mori

Japanese Journal of Psychiatry and Neurology 48 ( 2 ) 281 - 284 1994.6

Amantadine(Symmetrel)の使い方と問題点 Invited

浅沼幹人, 小川紀雄

内科 73 ( 5 ) 868 - 870 1994.5

Changes in lipid peroxidation, Cu/Zn-superoxide dismutase and its mRNA following an intracerebroventricular injection of 6-hydroxydopamine in mice Reviewed

Norio Ogawa, Masato Asanuma, Yoichi Kondo, Hiroshi Hirata, Sakiko Nishibayashi, Akitane Mori

Brain Research 646 ( 2 ) 337 - 340 1994.5

Iminodipropionitrile投与によって発症させたジスキネジアモデルラットの脳内神経ペプチドの変化 Reviewed

河田義郎, 小川紀雄, 浅沼幹人, 森昭胤

Neurosciences 20 41 - 44 1994.4

Differential effects of chronic l-DOPA treatment on lipid peroxidation in the mouse brain with or without pretreatment with 6-hydroxydopamine Reviewed

Norio Ogawa, Masato Asanuma, Yoichi Kondo, Yoshiro Kawada, Mitsutoshi Yamamoto, Akitane Mori

Neuroscience Letters 171 ( 1-2 ) 55 - 58 1994.4

虚血と神経毒による晩発性脳障害 Invited

小川紀雄, 浅沼幹人, 水川公直

老年期痴呆研究会誌 6 16 - 19 1994.2

Acetylcholinesterase inhibitor ENA-713 protects against ischemia-induced decrease in pre- and postsynaptic cholinergic indices in the gerbil brain following transient ischemia Reviewed

Ken-ichi Tanaka, Norio Ogawa, Kiminao Mizukawa, Masato Asanuma, Yoichi Kondo, Sakiko Nishibayashi, Akitane Mori

Neurochemical Research 19 ( 2 ) 117 - 122 1994.2

Pitfalls in Assessment of c-fos mRNA Expression in the Brain: Effects of Animal Handling Reviewed

Masato Asanuma, Norio Ogawa

Reviews in the Neurosciences 5 ( 2 ) 1994.1

Effect of vagatomy on hyperactivity and increased dopamine turnover induced by intraperitoneal administration of thyrotropin-releasing hormone Reviewed

Norio Ogawa, Masato Asanuma, Yoichi Kondo, Hiroshi Hirata, Naoharu Nakayama, Akitane Mori

Brain Research 633 ( 1-2 ) 167 - 170 1994.1

脳障害過程での免疫系の関与-免疫抑制薬cyclosporine Aを用いた実験的研究- Reviewed

小川紀雄, 浅沼幹人, 近藤洋一

日本神経精神薬理学会雑誌 14 377 - 381 1994

Regional changes in α-tubulin and β-actin mRNA accumulations after transient ischemia in spontaneously hypertensive rat brains

Y. Kondo, N. Ogawa, M. Asanuma, H. Hirata, S. Nishibayashi, A. Mori

Research Communications in Molecular Pathology and Pharmacology 86 ( 2 ) 139 - 153 1994

Language：English Publishing type：Research paper (scientific journal)

Regional changes in the mRNA accumulations for cytoskeletal proteins α- tubulin and β-actin were examined by in situ hybridization and Northern blot analysis in spontaneously hypertensive rat brains at chronic stages after 3 hours of transient ischemia. α-Tubulin mRNA accumulations showed no significant change at 2 weeks after transient ischemia except for a significant decrease in the frontal cortex (9.7%, p &lt
0.01) coinciding with ischemia induced histological changes. β-Actin mRNA level was significantly increased in the parietal cortex (8.5%), septum (10.0%), amygdala (11.0%), CA4 area (5.8%) and the dentate gyrus (7.5%) of the hippocampus at 2 weeks after recirculation compared with a sham-operated control group (p &lt
0.01). The ischemic areas of hippocampal and frontocortical lesions receive afferent neurons from those regions where β-actin mRNA was increased, suggesting that ischemia-induced increases in β-actin mRNA may reflect actin synthesis in these neurons to compensate for lost synaptic connections. Two cytoskeletal mRNA concentrations reacted differently to cerebral ischemia, and did not parallel histological signs of ischemia either temporally or spatially.

Alterations in the binding of the phosphodiesterase inhibitor, rolipram, after transient ischemia in the gerbil brain Reviewed

Masato Asanuma, Norio Ogawa, Hiroshi Hirata, Yoichi Kondo, Sakiko Nishibayashi, Mitsutoshi Yamamoto, Akitane Mori

Research Communications in Molecular Pathology and Pharmacology 82 ( 3 ) 279 - 285 1993.12

Authorship：Lead author,　Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：P J D PUBLICATIONS LTD

To determine ischemia-induced changes in phosphodiesterase (PDE), changes in the membranous binding sites of rolipram, a cAMP-selective PDE inhibitor, were examined in the gerbil brain following transient 5 min forebrain ischemia. Coinciding with the delayed neuronal death (DND) in the hippocampal CA1 region, affinities for cerebral rolipram bindings decreased on Day 4, when intrinsic cAMP, substrate for PDE, might increase. The number of rolipram binding sites was significantly reduced in the hippocampus on Day 14, despite the lack of change on Day 4. This reduction in rolipram binding was in agreement with the previously reported late onset reduction of muscarinic receptors, progressing more slowly than DND. Slowly progressive mechanisms may be involved in the ischemia-induced reduction of the hippocampal rolipram binding sites which may be PDEs

ドキサゾシン投与において脳血流増加を認めた脳梗塞合併高血圧症の一例 Reviewed

山本光利, 浅沼幹人, 小川紀雄

臨床と研究 70 ( 9 ) 2975 - 2978 1993.9

Abnormalities in muscarinic cholinergic receptors and their G-protein coupling systems in the cerebral frontal cortex in Alzheimer's disease Reviewed

Norio Ogawa, Kiminao Mizukawa, Masato Asanuma, Ichiro Kanazawa

Archives of Gerontology and Geriatrics 17 ( 2 ) 77 - 89 1993.9

Rapid response of striatal muscarinic M1-receptor mRNA to muscarinic cholinergic agents in rat brain Reviewed

Hsi-hsien Chou, Norio Ogawa, Masato Asanuma, Hiroshi Hirata, Yoichi Kondo, Akitane Mori

Molecular Brain Research 19 ( 3 ) 211 - 214 1993.8

脊髄小脳変性症/生化学的な進歩 Invited

浅沼幹人, 小川紀雄

Clinical Neuroscience 11 ( 6 ) 626 - 629 1993.6

Regional changes in neuropeptide levels after 5,7-dihydroxytryptamine-induced serotonin depletion in the rat brain Reviewed

Yoichi Kondo, Norio Ogawa, Masato Asanuma, Hiroshi Hirata, Ken-ichi Tanaka, Yoshiro Kawada, Akitane Mori

Journal of Neural Transmission 92 ( 2-3 ) 151 - 157 1993.6

Effects of the acetylcholinesterase inhibitor ENA-713 on ischemia-induced changes in acetylcholine and aromatic amine levels in the gerbil brain Reviewed

Ken-ichi Tanaka, Norio Ogawa, Masato Asanuma, Hiroshi Hirata, Yoichi Kondo, Naoharu Nakayama, Akitane Mori

Archives Internationales de Pharmacodynamie et de Therapie 323 ( 1-2 ) 85 - 96 1993.5

Language：English Publishing type：Research paper (scientific journal) Publisher：ARCH INT PHARMACODYNAMIE

The effects of a new acetylcholinesterase inhibitor, ENA-713, on ischemia-induced changes in acetylcholine, monoamines, and their metabolites, were studied in the gerbil. ENA-713 (0.2 mg/kg) or saline was administered intraperitoneally to gerbils 30 min before induction of cerebral ischemia by bilateral carotid occlusion. Pretreatment with ENA-713 mitigated the ischemia-induced abnormalities of the cholinergic, dopaminergic and serotoninergic systems in the gerbil brain, although it had virtually no effect on acetylcholine, monoamines, or their metabolites in any region of the normal gerbil brain. These findings suggest that ENA-713 has beneficial effects against ischemia-induced cerebral disorders. Thus, ENA-713 seems to be promising as a preventive or therapeutic agent for cerebrovascular dementia due to cerebral ischemia and might be useful for the treatment of Alzheimer-type dementia which is associated with multiple neurotransmitter abnormalities in the brain.

一過性脳虚血後の晩発性ムスカリン性受容体減少に対する免疫抑制剤Cyclosporin Aの阻止効果 Reviewed

小川紀雄, 浅沼幹人, 近藤洋一, 水川公直, 森昭胤

Neurosciences 19 ( 1 ) 81 - 84 1993.4

The preventive effect of cyclosporin A, an immunosuppressant, on the late onset reduction of muscarinic acetylcholine receptors in gerbil hippocampus after transient forebrain ischemia Reviewed

Norio Ogawa, Ken-ichi Tanaka, Yoichi Kondo, Masato Asanuma, Kiminao Mizukawa, Akitane Mori

Neuroscience Letters 152 ( 1-2 ) 173 - 176 1993.4

ニユーロトランスミッターのレセプター結合実験法 Invited

浅沼幹人, 小川紀雄

実験医学 11 ( 3 ) 216 - 223 1993.3

脳に対するカルシウム拮抗薬の功罪-カルシウム拮抗薬のドーパミン受容体に対する作用- Invited

浅沼幹人

Clinical Calcium 3 ( 3 ) 97 - 102 1993.3

Amytriptyline投与により無動・姿勢保持障害・歩行障害等の症状改善と同時に前頭葉脳血流低下の著明な改善を認めた進行性核上麻痺の一例 Reviewed

浅沼幹人, 平田洋, 近藤洋一, 小川紀雄

臨床神経学 33 ( 3 ) 317 - 321 1993.3

Effects of repeated administration of rolipram, a cAMP-specific phosphodiesterase inhibitor, on acetylcholinergic indices in the aged rat brain Reviewed

Masato Asanuma, Norio Ogawa, Yoichi Kondo, Hiroshi Hirata, Akitane Mori

Archives of Gerontology and Geriatrics 16 ( 2 ) 191 - 198 1993.3

Cholinergic deficits in aged rat brain are corrected with nicergoline Reviewed

Norio Ogawa, Masato Asanuma, Hiroshi Hirata, Yoichi Kondo, Yoshiro Kawada, Akitane Mori

Archives of Gerontology and Geriatrics 16 ( 2 ) 103 - 110 1993.3

大腸ファイバー検査直後よりwearing off現象の著明な改善のみられたParkinson病 Reviewed

近藤洋一, 平田洋, 浅沼幹人, 小川紀雄, 太田善介

神経内科 38 ( 3 ) 291 - 292 1993.3

脳血管障害後遺症に対する塩酸ビフェメラン長期投与の効果 Reviewed

浅沼幹人, 平田洋, 近藤洋一, 小川紀雄

臨床と研究 70 ( 2 ) 572 - 576 1993.2

Effect of chronic ceruletide treatment on dopaminergic neurotransmitters, receptors and their mRNAs in the striatum of rats with dyskinesia induced by iminodipropionitrile Reviewed

Hiroshi Hirata, Norio Ogawa, Masato Asanuma, Zensuke Ota, Akitane Mori

Brain Research 604 ( 1-2 ) 197 - 204 1993.2

Ischemia-induced changes in α-tubulin and β-actin mRNA in the gerbil brain and effects of bifemelane hydrochloride Reviewed

Masato Asanuma, Norio Ogawa, Hiroshi Hirata, Hsi-hsien Chou, Yoichi Kondo, Akitane Mori

Brain Research 600 ( 2 ) 243 - 248 1993.1

脳血管障害総論/脳神経化学の進歩 Invited

小川紀雄, 浅沼幹人, 近藤洋一

日本臨床 51(1993年増刊上巻) 61 - 68 1993

Effective Treatment by Bifemerane Hydrochloride for Emotional Incontinence and Regional Blood Flow in Patient with Cerebral Infarction Reviewed

M. Yamamoto, M. Asanuma, N. Ogawa

Nippon Ronen Igakkai Zasshi. Japanese Journal of Geriatrics 30 ( 1 ) 70 - 73 1993

Language：Japanese Publishing type：Research paper (scientific journal)

The authors report that bifemerane hydrochloride treatment improved emotional incontinence in patient with cerebral infarction. Before and after bifemerane hydrochloride treatment, 99mTc-HM PAO single photon emission CT (SPECT) was performed. After treatment, regional cerebral blood flows (CBF) in frontal lobe area increased selectively. These findings suggest that emotional incontinence and decreased CBF of the frontal lobe area were closely associated in this case. © 1993, The Japan Geriatrics Society. All rights reserved.

DOI： 10.3143/geriatrics.30.70

Degeneration of dopaminergic neurons and free radicals: Possible participation of levodopa Reviewed

Norio Ogawa, Rei Edamatsu, Kiminao Mizukawa, Masato Asanuma, Masahiro Kohno, Akitane Mori

Advances in Neurology 60 242 - 250 1993

A case of progressive supranuclear palsy showing marked improvements of frontal hypoperfusion, as well as parkinsonism with amitriptyline

M. Asanuma, H. Hirata, Y. Kondo, N. Ogawa

Clinical Neurology 33 ( 3 ) 317 - 321 1993

Comparison of the effects of bifemelane hydrochloride, idebenone and indeloxazine hydrochloride on ischemia-induced changes in brain monoamines and their metabolites in gerbils Reviewed

Kumiko Haba, Norio Ogawa, Masato Asanuma, Hiroshi Hirata, Akitane Mori

Journal of Neural Transmission 88 ( 3 ) 187 - 198 1992.10

Opposite effects of rough and gentle handling with repeated saline administration on c-fos mRNA expression in the rat brain Reviewed

Masato Asanuma, Norio Ogawa, Hiroshi Hirata, Hsi-hsien Chou, Ken-ichi Tanaka, Akitane Mori

Journal of Neural Transmission 90 ( 3 ) 163 - 169 1992.10

Authorship：Lead author,　Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：Springer Science and Business Media LLC

DOI： 10.1007/bf01250958

Other Link： http://link.springer.com/article/10.1007/BF01250958/fulltext.html

Muscarinic cholinergic receptor-mediated modulation on striatal c-fos mRNA expression induced by levodopa in rat brain Reviewed

Hsi-hsien Chou, Norio Ogawa, Masato Asanuma, Hirata Hirata, Akitane Mori

Journal of Neural Transmission 90 ( 3 ) 171 - 181 1992.10

Post-ischemic administration of bifemelane hydrochloride prohibits ischemia-induced depletion of the muscarinic M1-receptor and its mRNA in the gerbil hippocampus Reviewed

Norio Ogawa, Masato Asanuma, Kiminao Mizukawa, Hirata Hirata, Hsi-hsien Chou, Akitane Mori

Brain Research 591 ( 1 ) 171 - 175 1992.9

Effects of chronic codergocrine mesylate administration on the brain somatostatinergic system in aged rats Reviewed

Ken-ichi Tanaka, Norio Ogawa, Masato Asanuma, Hiroshi Hirata, Yoichi Kondo, Hsi-hsien Chou, Akitane Mori

Archives of Gerontology and Geriatrics 15 ( 2 ) 133 - 139 1992.9

長期パーキンソン病患者に対するタンパク質摂取制限療法の効果,副作用および適応に関する検討 Reviewed

平田洋, 浅沼幹人, 近藤洋一, 小川紀雄

臨床神経学 32 ( 9 ) 973 - 978 1992.9

薬物療法-L-DOPAを中心に Invited

浅沼幹人, 小川紀雄

MEDICO 23 ( 7 ) 9997 - 10001 1992.7

Effects of chronic catecholamine depletions on muscarinic M1-receptor and its mRNA in rat brain Reviewed

Masato Asanuma, Norio Ogawa, Kumiko Haba, Hiroshi Hirata, Akitane Mori

Journal of the Neurological Sciences 110 ( 1-2 ) 205 - 214 1992.7

Effects of dihydroergotoxine on central cholinergic neuronal systems and discrimination learning test in aged rats Reviewed

Norio Ogawa, Masahiko Nomura, Kumiko Haba, Masato Asanuma, Ken-ichi Tanaka, Koji Hori, Akitane Mori

Brain Research 586 ( 2 ) 229 - 234 1992.7

Effects of chronic bifemelane hydrochloride administration on receptors for N-methyl-d-aspartate in the aged-rat brain Reviewed

Norio Ogawa, Kiminao Mizukawa, Kumiko Haba, Masato Asanuma, Akitane Mori

Neurochemical Research 17 ( 7 ) 687 - 691 1992.7

脳梗塞後遺症における脳循環改善薬の有効症状スペクトラムの比較

小川紀雄, 浅沼幹人, 平田洋, 近藤洋一

Prog. Med. 12 ( 6 ) 1337 - 1344 1992.6

Age-Related Changes in Cerebrospinal Fluid γ-Aminobutyric Acid Concentration Reviewed

Haruhiko Takayama, Norio Ogawa, Mitsutoshi Yamamoto, Masato Asanuma, Hiroshi Hirata, Zensuke Ota

Clinical Chemistry and Laboratory Medicine 30 ( 5 ) 1992.5

Late onset and long-lasting suppressive effects of ceruletide, an analogue of cholecystokinin, on c-fos mRNA expression in the rat striatum Reviewed

Masato Asanuma, Norio Ogawa, Hiroshi Hirata, Kumiko Haba, Hsi-hsien Chou, Akitane Mori

Neuroscience Letters 138 ( 2 ) 233 - 236 1992.4

Effects of propentophylline on ischemia induced loss of muscarinic cholinergic receptor binding in the gerbil hippocampus Reviewed

Hiroshi Hirata, Norio Ogawa, Kumiko Haba, Masato Asanuma, Hsi-hsien Chou, Akitane Mori

Research Communications in Chemical Pathology and Pharmacology 75 ( 3 ) 365 - 368 1992.3

Language：English Publishing type：Research paper (scientific journal) Publisher：P J D PUBLICATIONS LTD

Super-delayed loss of muscarinic-1 (M1) receptors and the protective effect of propentofylline on these changes were examined in the gerbil hippocampus after transient ischemia with radioactive pirenzepine. M1 receptors were markedly decreased in the gerbil hippocampus 14 days after transient ischemia. Single administration of propentofylline (20mg/kg, ip) just after transient ischemia almost completely prevented the ischemia-induced decrease in the number of M1 receptors, and had no effect in sham-operated controls. These findings suggest that one of the therapeutic efficacies of propentofylline is the result of the normalization of the dysfunction of the acetylcholine neuronal system in cerebrovascular disease.

多発性脳梗塞におけるnicergolineの臨床効果と¹²³I-IMP SPECT上の脳血流改善

小川紀雄, 浅沼幹人, 平田洋, 太田善介

臨床と研究 69 ( 3 ) 949 - 957 1992.3

Changes of neuropeptides and their receptors in experimental stroke gerbil brains Reviewed

Kumiko Haba, Norio Ogawa, Masato Asanuma, Hiroshi Hirata, Yukiko H. Sora, Akitane Mori

Journal of the Neurological Sciences 108 ( 1 ) 88 - 92 1992.3

Development of a Simple Spasticity Quantification Method: Effects of Tizanidine on Spasticity in Patients with Sequelae of Cerebrovascular Disease Reviewed

Norio Ogawa, Masato Asanuma, Hiroshi Hiraata, Zensuke Ota, Yasuhide Yamawaki, Mitsutoshi Yamamoto

Journal of International Medical Research 20 ( 1 ) 78 - 86 1992.2

Publishing type：Research paper (scientific journal) Publisher：SAGE Publications

A simple method that can be performed at the bedside using a spring balance was developed in order to quantify spasticity. The effects of tizanidine on spasticity were evaluated in 30 patients with sequelae of cerebrovascular disease using this method. Treatment with tizanidine was effective in 60% of the patients; there were high correlations between spasticity before and after tizanidine administration and the severity of symptoms and also between the degree of improvement in spasticity and in that of the symptoms. Atonic seizures, due to overdose of tizanidine, were observed in only one patient. The simple spasticity quantification method developed was useful for monitoring tizanidine administration in order to prevent drug overdose. The method appears to be very useful for evaluating the degree of spasticity at the bedside and in measuring the effects of antispastic drugs.

DOI： 10.1177/030006059202000109

Effects of chronic administration of lisuride hydrogen maleate on aromatic amine and metabolite levels in the gerbil brain following bilateral common carotid ligation Reviewed

Hiroshi Hirata, Norio Ogawa, Kumiko Haba, Masato Asanuma, Hsi-hsien Chou, Akitane Mori

Archives Internationales de Pharmacodynamie et de Therapie 315 ( 1-2 ) 5 - 15 1992.1

Language：English Publishing type：Research paper (scientific journal) Publisher：ARCH INT PHARMACODYNAMIE

Cerebral monoaminergic neurotransmitters and their metabolites show various concentration changes in gerbils following bilateral carotid ligation. The present study evaluated the effect of chronic administrations of lisuride hydrogen maleate (lisuride) on these changes. Lisuride (0.01 mg/kg or 0.05 mg/kg) or vehicle was intraperitoneally administered to gerbils for 14 consecutive days before the induction of a 30 min ischemia by bilateral carotid ligation. Animals were sacrified immediately and the levels of dopamine, DOPAC, homovanillic acid, noradrenaline, serotonin and 5-hydroxyindoleacetic acid determined by HPLC in the striatum, cortex, hippocampus and diencephalon/midbrain. Lisuride itself had no effect on any compound determined in any region. In the carotid-ligated gerbil brain, however, lisuride corrected the reduction of dopamine in the striatum, normalized or reduced increases in the (DOPAC + homovanillic acid)/dopamine ratio in the striatum, hippocampus and diencephalon/midbrain, and increased the levels of serotonin in all four regions. The present study, together with previous reports, indicate that lisuride may interfere with ischemia-induced cerebrovascular disturbances and, in such a way, improve some pathological sequelae of cerebrovascular disease.

Chronic administration of lisuride hydrogen maleate increases muscarinic acetylcholine receptor binding in aged rat brain Reviewed

Haruhiko Takayama, Masato Asanuma, Kiminao Mizukawa, Hiroshi Hirata, Hirohiko Sato, Zensuke Ota, Norio Ogawa

Japanese Journal of Geriatrics 29 ( 1 ) 24 - 28 1992.1

Language：Japanese Publishing type：Research paper (scientific journal)

Changes in the distribution and densities of muscarinic acetylcholine receptors (mACh-R) in young adult and aged rat brain, and the effects of chronic administration of lisuride hydrogen maleate (lisuride) on these changes were studied by in vitro quantitative autoradiography of [3H] quinuclidinyl benzilate binding. mACh-R was relatively higher in the striatum, hippocampus and cerebral cortex in the young adult rats. In contrast, mACh-R binding was markedly reduced in the striatum, accumbens nucleus, amygdaloid nucleus and frontal cerebral cortex of aged rats compared to young adult rats. However, chronic administration of lisuride significantly increased mACh-R binding in the parietal cerebral cortex of aged rats compared to young adult rats. However, chronic administration of lisuride significantly increased mACh-R binding in the parietal cerebral cortex as well as in the above-mentioned regions in aged rats. This lisuride-induced increase in mACh-R of aged rat brain is considered to have important implications concerning the mechanism of therapeutic efficacy of lisuride.

DOI： 10.3143/geriatrics.29.24

超高齢者の脳血管障害後遺症に対する脳代謝改善薬の有効症状のプロフィールの相違

浅沼幹人, 平田洋, 高山晴彦, 更井哲夫, 小川紀雄

臨床と研究 69 ( 1 ) 265 - 275 1992.1

Effects of bifemelane hydrochloride on loss of N-methyl-D-aspartate receptor and muscarinic cholinergic receptor binding in the gerbil hippocampus after transient ischemia Reviewed

Masato Asanuma, Norio Ogawa, Kumiko Haba, Hiroshi Hirata, Hsi-hsien Chou, Akitane Mori

Archives Internationales de Pharmacodynamie et de Therapie 315 ( 1-2 ) 16 - 21 1992.1

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal) Publisher：ARCH INT PHARMACODYNAMIE

The effects of bifemelane hydrochloride on changes of N-methyl-D-aspartate receptors and muscarinic cholinergic receptors were examined in the gerbil hippocampus after transient ischemia with radioactive-specific ligands. There were marked reductions in both these receptors in the gerbil hippocampus 14 days after transient ischemia, without changes in the respective affinities. Post-ischemia bifemelane treatment almost completely prevented the ischemia-induced decreases in the numbers of these receptors, and had no effect in sham-operated controls. The results of the present study suggest that this drug prevents postsynaptic dysfunction induced by transient ischemia, and may be useful in the therapy of both the chronic and the acute stage of cerebrovascular disease.

Distinction between declarative memory and procedural memory using 8-arm radial maze task : Biphasic effects of thyrotropin reloading hormone on scopolamine-induced amnesia. Reviewed

Norio Ogawa, Masato Asanuma, Hiroshi Hirata, Hsi-hsien Chou, Yoichi Kondo, Setsuko Ogawa, Akitane Mori

Research Communications in Psysiology, Psychiatry and Behavior 17 ( 1-2 ) 1 - 15 1992

Influence of protein-restricted diet on motor response fluctuations in Parkinson's disease

H. Hirata, M. Asanuma, Y. Kondo, N. Ogawa

Clinical Neurology 32 ( 9 ) 973 - 978 1992

Language：Japanese Publishing type：Research paper (scientific journal)

The clinical management of Parkinson's disease has been revolutionized by the introduction of levodopa therapy. It has significantly reduced disability and has extended life expectancies of patients with Parkinson's disease. However, motor response fluctuations frequently appear in patients after long-term treatment with levodopa. In this study, we investigated the effect of protein-restricted diet on fluctuations in eight patients with Parkinson's disease who had been receiving long-term levodopa treatment (mean 12.5 yrears). Two weeks of protein-restricted daytime diet (7.5 g total at breakfast and lunch) was followed by 12.5 g total at breakfast and lunch. At night, high-protein diet (40-50 g at dinner) was offered to the patients in order to maintain total daily protein intake at Japanese standard level. The medication schedule of levodopa and other antiparkinsonian drugs was not changed within 2 weeks after the study was began. Fluctuations were reduced in 7 of the 8 patients. But in only one patient (case 6), dyskinesia and general condition got worse and stopped this therapy. Body weight, serum protein and albumin levels did not change significantly for at least three months after the study was begun in every 6 patients who were examined. Homovanillic acid level of cerebrospinal fluid reduced in every 4 patients who were examined. We concluded that protein-restricted diet during the daytime offers a fascinating technique for the control of motor response fluctuations in patients with Parkinson's undergoing long-term levodopa treatment. But this therapy must be indicated carefully. Mechanism of this therapy may has something to do with improvement of dopamine metabolism in the brain.

Distribution of the beta-2 adrenergic receptor messenger RNA in the rat brain by in situ hybridization histochemistry: Effects of chronic reserpine treatment Reviewed

Masato Asanuma, Norio Ogawa, Kiminao Mizukawa, Kumiko Haba, Hiroshi Hirata, Akitane Mori

Neurochemical Research 16 ( 12 ) 1253 - 1256 1991.12

Authorship：Lead author,　Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：Springer Science and Business Media LLC

DOI： 10.1007/bf00966654

Other Link： http://link.springer.com/article/10.1007/BF00966654/fulltext.html

Calcium antagonist flunarizine hydrochloride affects striatal D2 dopamine receptors in the young adult and aged rat brain Reviewed

Masato Asanuma, Norio Ogawa, Kumiko Haba, Hiroshi Hirata, Akitane Mori

Archives of Gerontology and Geriatrics 13 ( 3 ) 271 - 278 1991.11

ソマトスタチン減少剤 Invited

浅沼幹人, 小川紀雄

生体の科学 42 ( 5 ) 505 - 506 1991.10

Effects of beta-adrenergic blocking agents on specific binding of [3H]D-Ala2-Met5-enkephalinamide and [3H]naloxone. Reviewed

Haruhiko Takayama, Norio Ogawa, Masato Asanuma, Hiroshi Hirata, Toshio Ogura, Zensuke Ota

Acta Medica Okayama 45 ( 5 ) 295 - 299 1991.10

Dopamine deficiency in the Weaver mutant mouse: An animal model of olivopontocerebeller atrophy Reviewed

Hsi-hsien Chou, Norio Ogawa, Masato Asanuma, Hiroshi Hirata, Akitane Mori

Research Communications in Chemical Pathology and Pharmacology 74 ( 1 ) 117 - 120 1991.10

Language：English Publishing type：Research paper (scientific journal) Publisher：P J D PUBLICATIONS LTD

The dopamine system in weaver mutant mice, a model of cerebellar atrophy, was studied. Dopamine levels of 6-week-old weaver mice were 37%, 44%, 34%, and 41% of levels in age-matched controls in the cerebral cortex, hippocampus, septal region and striatum, respectively. Noradrenaline levels did not differ from controls. This study shows that weaver mice have specific deficiencies in the dopamine system.

Long-lasting effect of ceruletide on dyskinesia and monoaminergic neuronal pathways in rats treated with iminodipropionitrile Reviewed

Norio Ogawa, Kumiko Haba, Masato Asanuma, Akitane Mori

Brain Research 556 ( 2 ) 271 - 279 1991.8

神経伝達物質とパーキンソン病 Invited

浅沼幹人, 小川紀雄

臨床成人病 21 ( 7 ) 1191 - 1199 1991.7

Chronic Lisuride Hydrogen Maleate Administration Enhances Muscarinic Receptor Binding in Senescent Rat Brain Reviewed

Hiroshi Hirata, Norio Ogawa, Kiminao Mizukawa, Kumiko Haba, Masato Asanuma, Akitane Mori, Zensuke Ota

Journal of International Medical Research 19 ( 4 ) 318 - 325 1991.7

Language：English Publishing type：Research paper (scientific journal) Publisher：SAGE Publications

Changes in the regional density of muscarinic-1 (M₁) receptors and the effect of lisuride hydrogen maleate on these changes were studied in senescent rat brain by in vitro autoradiography. In young adult controls, M₁ receptor binding was most dense in the striatum and hippocampus, followed by the cerebral cortex and amygdala. Binding to M₁ receptors was markedly lower in these areas of the senescent brain compared with the young adult brain. These decreases were reversed by intraperitoneal administration of 50 μg/kg·day lisuride for 14 days. The present results indicate that the therapeutic efficacy of lisuride depends on normalization of not only monoamine systems but also acetylcholine systems.

DOI： 10.1177/030006059101900404

脳血管障害後遺症における意欲低下・問題行動に対する塩酸インデロキサジンの改善効果

浅沼幹人, 平田洋, 高山晴彦, 更井哲夫, 小川紀雄

Prog. Med. 11 ( 6 ) 1527 - 1530 1991.6

イブジラストの脳梗塞症例における脳血流改善作用-SPECTを用いて-

高山晴彦, 浅沼幹人, 佐藤博彦, 平田洋, 太田善介, 小川紀雄

臨床と研究 68 ( 6 ) 1857 - 1862 1991.6

Loss of N-methyl-d-aspartate (NMDA) receptor binding in rat hippocampal areas at the chronic stage after transient forebrain ischemia: Histological and NMDA receptor binding studies Reviewed

Norio Ogawa, Kumiko Haba, Kiminao Mizukawa, Masato Asanuma, Hiroshi Hirata, Akitane Mori

Neurochemical Research 16 ( 5 ) 519 - 524 1991.5

Chronic bifemelane hydrochloride administration enhances muscarinic cholinergic recepotr binding in the senescent rat brain Reviewed

Norio Ogawa, Kiminao Mizukawa, Kumiko Haba, Masato Asanuma, Akitane Mori

Journal of Medicine 22 ( 1 ) 17 - 27 1991.1

Language：English Publishing type：Research paper (scientific journal) Publisher：P J D PUBLICATIONS LTD

In senescent rats, the binding ability of muscarinic cholinergic receptors (MCR) was markedly decreased in the cerebral cortex, hippocampus, thalamus, and the striatum compared with young adult rats. This decrease was markedly improved by chronic administration of bifemelane hydrochloride (bifemelane). In view of the findings that bifemelane markedly inhibits the decrease in acetylcholine (ACh) associated with cerebral ischemia, and that it improves amnesia induced by scopalamine, it may be inferred that bifemelane between in situ malignant melanoma and other melanin-containing in situ malignancies has been presented. All types of malignant melanoma which originate within the epidermis or epithelium have an in situ phase and show horizontal growth, and small early forms defy classification. The classification of the most common types of malignant melanoma has been revised. Although the level of invasion and tumor thickness are useful prognostic and therapeutic parameters, their determination is crude and subject to several shortcomings.

レセルピン慢性投与のアセチルコリン系神経機構に及ぼす影響 Reviewed

浅沼幹人, 羽場久美子, 小川紀雄, 森昭胤

Neurosciences 17 ( 1 ) 87 - 90 1991.1

パーキンソン病 Invited

浅沼幹人, 小川紀雄

Brain Medical 3 ( 4 ) 351 - 358 1991

Super-Delayed Changes of Muscarinic Acetylcholine Receptor in the Gerbil Hippocampus Following Transient Ischemia Reviewed

Norio Ogawa, Kumiko Haba, Masato Asanuma, Kiminao Mizukawa, Akitane Mori

Advances in Experimental Medicine and Biology 287 343 - 347 1991

Chronic administration of bifemelane hydrochoride increases somatostatin receptor binding in aged rat brain

H. Sato, K. Mizukawa, N. Ogawa, M. Asanuma, H. Takayama, Z. Ota

Japanese Journal of Geriatrics 28 ( 1 ) 18 - 23 1991

神経ペプチドとレセプター

小川紀雄, 浅沼幹人, 羽場久美子

内分泌学の進歩 8 55 - 74 1991

Regional responses of rat brain opioid receptors upon castration and testosterone replacement Reviewed

Haruhiko Takayama, Norio Ogawa, Masato Asanuma, Zensuke Ota

Research Communications in Chemical Pathology and Pharmacology 70 ( 3 ) 355 - 358 1990.12

Language：English Publishing type：Research paper (scientific journal) Publisher：P J D PUBLICATIONS LTD

Regional responses of rat brain opioid receptors (Op-Rs) upon castration and testosterone replacement were studied using [H-3]naloxone (NAL) binding for u-type and [H-3]D-Ala2-methionine-enkephalin (ENK) binding for delta-type Op-R. Castration itself produced an increase in specific NAL and ENK binding in the olfactory bulb and thalamus+midbrain. In the hypothalamus, specific ENK binding was increased without any change in NAL binding. After the testosterone replacement in castrated rats, specific NAL binding was decreased and returned to the control level in the thalamus+midbrain, but remained high in the olfactory bulb. Specific ENK binding was decreased and returned to the control level in the olfactory bulb, hypothalamus and thalamus+midbrain. These results indicated that there are regional differences between u- and delta-type Op-R responses to castration and testosterone replacement. Op-R subtypes were regulated differentially by endogenous hormonal changes, such as testosterone.

老齢ラットにおけるNMDAレセプターの減少とBifemelane Hydrochloride投与による回復

小川紀雄, 水川公直, 羽場久美子, 浅沼幹人

Geriat. Med.（老年医学） 28 ( 12 ) 1845 - 1849 1990.12

Alterations of somatostatin and its modulation by levodopa in MPTP-treated mouse brain Reviewed

Masato Asanuma, Norio Ogawa, Yukiko H. Sora, Khitisak Pongdhana, Kumiko Haba, Akitane Mori

Journal of the Neurological Sciences 100 ( 1-2 ) 155 - 160 1990.12

Effects of chronic administration of mergocryptine on changes in neurotransmitter levels in the ischemic gerbil brain. Reviewed

Norio Ogawa, Kumiko Haba, Masato Asanuma, Mitsuhiro Kawata, Akitane Mori

Archives Internationales de Pharmacodynamie et de Therapie 308 ( 1-2 ) 21 - 31 1990.11

Language：English Publishing type：Research paper (scientific journal) Publisher：ARCH INT PHARMACODYNAMIE

Changes in various neurotransmitter systems of the gerbil brain during ischemia and the effects of administration of mergocryptine, a new ergot derivative, were studied. Gerbils intraperitoneally administered 0.5 mg/kg of mergocryptine or the vehicle once a day for 14 days were used. The administration of mergocryptine to control animals had no effect on the contents of neurotransmitters or their metabolites in various regions of the brain, but it corrected abnormalities in the neurotransmitter systems caused by ischemia. These results suggest the usefulness of mergocryptine against the deleterious effects of brain ischemia.

塩酸フルナリジンの線条体D2ドーパミンレセプターに対する作用 Reviewed

小川紀雄, 浅沼幹人, 高山晴彦, 佐藤博彦, 貫名至

臨床神経学 30 ( 11 ) 1221 - 1226 1990.11

Comparison of formaldehyde-preperfused frozen and freshly frozen tissue preparation for the in situ hybridization for alpha-tubulin messenger RNA in the rat brain Reviewed

Masato Asanuma, Norio Ogawa, Kiminao Mizukawa, Kumiko Haba, Akitane Mori

Research Communications in Chemical Pathology and Pharmacology 70 ( 2 ) 183 - 192 1990.11

ニューロトランスミッターとドプス-パーキンソン病治療薬としての基礎と臨床- Invited

小川紀雄, 浅沼幹人

薬の知識 41 ( 3 ) 3 - 8 1990.3

老齢ラット脳におけるアセチルコリン系神経機構障害とnicergolineによる補正

小川紀雄, 水川公直, 羽場久美子, 浅沼幹人

Geriat. Med.（老年医学） 27 ( 8 ) 1198 - 1204 1989.8

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