研究者詳細 - 宮﨑　育子

論文 - 宮﨑　育子

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

Ikuko Miyazaki, Masato Asanuma

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

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

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

DOI： 10.3390/antiox12040894

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

Ikuko Miyazaki, Masato Asanuma

Cells 9 ( 12 ) 2623 - 2623 2020年12月

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

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

DOI： 10.3390/cells9122623

Mirtazapine exerts astrocyte-mediated dopaminergic neuroprotection 査読

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

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

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

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

DOI： 10.1038/s41598-020-77652-4

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

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

Ikuko Miyazaki, Masato Asanuma

NeuroSci 1 ( 1 ) 1 - 14 2020年8月

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

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

DOI： 10.3390/neurosci1010001

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

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

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

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

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

DOI： 10.3390/ijms21093254

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

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

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

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

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

Neurochemistry International 132 104608 - 104608 2020年1月

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

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

Cells 8 ( 3 ) 221 - 221 2019年3月

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

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

DOI： 10.3390/cells8030221

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

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

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

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：MDPI AG

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

DOI： 10.3390/ijms20030598

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

Ikuko Miyazaki, Masato Asanuma

Current Pharmaceutical Design 23 ( 33 ) 2018年1月

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

Ikuko Miyazaki

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

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

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

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

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

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

DOI： 10.1111/jnc.13405

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

Ikuko Miyazaki, Masato Asanuma

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

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

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

DOI： 10.2174/0929867323666160122115057

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

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

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

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

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

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

担当区分：筆頭著者記述言語：英語掲載種別：研究論文（学術雑誌）

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

DOI： 10.1016/j.nbd.2013.08.003

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

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

GLIA 59 ( 3 ) 435 - 451 2011年3月

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

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

DOI： 10.1002/glia.21112

Neuroprotective Effects of Zonisamide Target Astrocyte 査読

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

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

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

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

DOI： 10.1002/ana.21885

Approaches to Prevent Dopamine Quinone-Induced Neurotoxicity 査読

Ikuko Miyazaki, Masato Asanuma

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

担当区分：筆頭著者,　責任著者記述言語：英語出版者・発行元：SPRINGER/PLENUM PUBLISHERS

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

DOI： 10.1007/s11064-008-9843-1

Dopaminergic neuron-specific oxidative stress caused by dopamine itself

Ikuko Miyazaki, Masato Asanuma

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

担当区分：筆頭著者,　責任著者記述言語：英語出版者・発行元：OKAYAMA UNIV MED SCHOOL

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

DOI： 10.18926/AMO/30980

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

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

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

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

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

DOI： 10.1016/j.febslet.2007.09.046

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