研究者詳細 - 宮﨑　育子

論文 - 宮﨑　育子

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

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

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

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

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

DOI： 10.1096/fj.05-4996fje

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

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

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

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

記述言語：英語掲載種別：研究論文（学術雑誌）

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

DOI： 10.1097/01.wnf.0000175523.33334.24

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

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

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

担当区分：筆頭著者記述言語：英語掲載種別：研究論文（学術雑誌）

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

DOI： 10.1016/j.brainres.2004.09.014

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

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

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

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

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

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

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

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

Neurochemical Research 24 ( 7 ) 857 - 860 1999年

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

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

Pediatric Research 2025年2月

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

Abstract

Background

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

Methods

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

Results

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

Conclusions

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

Impact

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

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

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

DOI： 10.1038/s41390-025-03920-6

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

Editorial: Glial crosstalk in neurological disorders

Ikuko Miyazaki, Masato Asanuma, Francisco Javier Díaz-Corrales

Frontiers in Cell and Developmental Biology 12 2024年11月

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

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

Naunyn Schmiedebergs Arch Pharmacol 2024年9月

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

Masato Asanuma, Ikuko Miyazaki, Jean Kud Cade

Neurotoxicity Research 2024年

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

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

Neuroscience Letters 137598 - 137598 2023年12月

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

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

Journal of biochemistry 2023年9月

記述言語：英語掲載種別：研究論文（学術雑誌）

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

DOI： 10.1093/jb/mvad068

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

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

76 ( 4 ) 373 - 383 2022年1月

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

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

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

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

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

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

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

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

DOI： 10.1007/s00213-021-05979-5

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

Glutathione and Related Molecules in Parkinsonism 招待査読

Masato Asanuma, Ikuko Miyazaki

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

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：MDPI AG

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

DOI： 10.3390/ijms22168689

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

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

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

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

Background: Cancer patients can suffer from psychological and cognitive disorders after chemotherapy, which influence quality of life. Objective: 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. Methods: 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. Results: 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. Conclusion: 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

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

Nami Isooka, Ikuko Miyazaki, Masato Asanuma

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

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

Ikuko Miyazaki, Masato Asanuma

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

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

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

DOI： 10.1254/fpj.20082

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

Masato Asanuma, Ikuko Miyazaki

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

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

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

DOI： 10.1254/fpj.20071

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論文 - 宮﨑　育子