start-ver=1.4 cd-journal=joma no-vol=12 cd-vols= no-issue=4 article-no= start-page=894 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2023 dt-pub=20230406 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Multifunctional Metallothioneins as a Target for Neuroprotection in Parkinson's Disease en-subtitle= kn-subtitle= en-abstract= kn-abstract=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 alpha-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, alpha-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 alpha-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. en-copyright= kn-copyright= en-aut-name=MiyazakiIkuko en-aut-sei=Miyazaki en-aut-mei=Ikuko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=AsanumaMasato en-aut-sei=Asanuma en-aut-mei=Masato kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= affil-num=1 en-affil=Department of Medical Neurobiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil=Department of Medical Neurobiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= en-keyword=metallothionein kn-keyword=metallothionein en-keyword=Parkinson's disease kn-keyword=Parkinson's disease en-keyword=neuroprotection kn-keyword=neuroprotection en-keyword=antioxidant kn-keyword=antioxidant en-keyword=metal kn-keyword=metal en-keyword=synuclein kn-keyword=synuclein en-keyword=astrocyte kn-keyword=astrocyte en-keyword=enteric glial cell kn-keyword=enteric glial cell END start-ver=1.4 cd-journal=joma no-vol=22 cd-vols= no-issue=16 article-no= start-page=8689 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2021 dt-pub=20210813 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Glutathione and Related Molecules in Parkinsonism en-subtitle= kn-subtitle= en-abstract= kn-abstract=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. en-copyright= kn-copyright= en-aut-name=AsanumaMasato en-aut-sei=Asanuma en-aut-mei=Masato kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=MiyazakiIkuko en-aut-sei=Miyazaki en-aut-mei=Ikuko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= affil-num=1 en-affil=Department of Medical Neurobiology, Okayama University Graduate School of Medical, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil=Department of Medical Neurobiology, Okayama University Graduate School of Medical, Dentistry and Pharmaceutical Sciences kn-affil= en-keyword=glutathione kn-keyword=glutathione en-keyword=neuroprotection kn-keyword=neuroprotection en-keyword=parkinsonism kn-keyword=parkinsonism en-keyword=astrocyte kn-keyword=astrocyte en-keyword=region specificity kn-keyword=region specificity en-keyword=striatum kn-keyword=striatum en-keyword=mesencephalon kn-keyword=mesencephalon en-keyword=oxidative stress kn-keyword=oxidative stress en-keyword=Nrf2 kn-keyword=Nrf2 en-keyword=metallothionein kn-keyword=metallothionein en-keyword=serotonin 5-HT1A receptor kn-keyword=serotonin 5-HT1A receptor END start-ver=1.4 cd-journal=joma no-vol=20 cd-vols= no-issue=3 article-no= start-page=598 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2019 dt-pub=20190130 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Region-Specific Neuroprotective Features of Astrocytes against Oxidative Stress Induced by 6-Hydroxydopamine en-subtitle= kn-subtitle= en-abstract= kn-abstract=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. en-copyright= kn-copyright= en-aut-name=AsanumaMasato en-aut-sei=Asanuma en-aut-mei=Masato kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=Okumura-TorigoeNao en-aut-sei=Okumura-Torigoe en-aut-mei=Nao kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=MiyazakiIkuko en-aut-sei=Miyazaki en-aut-mei=Ikuko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=MurakamiShinki en-aut-sei=Murakami en-aut-mei=Shinki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=KitamuraYoshihisa en-aut-sei=Kitamura en-aut-mei=Yoshihisa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=SendoToshiaki en-aut-sei=Sendo en-aut-mei=Toshiaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= affil-num=1 en-affil=Department of Medical Neurobiology, Okayama University Graduate School of Medical, Dental and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil=Department of Clinical Pharmacy, Okayama University Graduate School of Medical, Dental and Pharmaceutical Sciences kn-affil= affil-num=3 en-affil=Department of Medical Neurobiology, Okayama University Graduate School of Medical, Dental and Pharmaceutical Sciences kn-affil= affil-num=4 en-affil=Department of Medical Neurobiology, Okayama University Graduate School of Medical, Dental and Pharmaceutical Sciences kn-affil= affil-num=5 en-affil=Department of Clinical Pharmacy, Okayama University Graduate School of Medical, Dental and Pharmaceutical Sciences kn-affil= affil-num=6 en-affil=Department of Clinical Pharmacy, Okayama University Graduate School of Medical, Dental and Pharmaceutical Sciences kn-affil= en-keyword=astrocyte kn-keyword=astrocyte en-keyword=neuroprotection kn-keyword=neuroprotection en-keyword=region-specificity kn-keyword=region-specificity en-keyword=striatum kn-keyword=striatum en-keyword=mesencephalon kn-keyword=mesencephalon en-keyword=oxidative stress kn-keyword=oxidative stress en-keyword=6-hydroxydopamine kn-keyword=6-hydroxydopamine en-keyword=Nrf2 kn-keyword=Nrf2 en-keyword=phase II detoxifying molecules kn-keyword=phase II detoxifying molecules END start-ver=1.4 cd-journal=joma no-vol=9 cd-vols= no-issue=12 article-no= start-page=2623 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2020 dt-pub=20201207 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Neuron-Astrocyte Interactions in Parkinson's Disease en-subtitle= kn-subtitle= en-abstract= kn-abstract=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. en-copyright= kn-copyright= en-aut-name=MiyazakiIkuko en-aut-sei=Miyazaki en-aut-mei=Ikuko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=AsanumaMasato en-aut-sei=Asanuma en-aut-mei=Masato kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= affil-num=1 en-affil=Department of Medical Neurobiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=2 en-affil=Department of Medical Neurobiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= en-keyword=astrocyte kn-keyword=astrocyte en-keyword=Parkinson’s disease kn-keyword=Parkinson’s disease en-keyword=dopaminergic neuron kn-keyword=dopaminergic neuron en-keyword=neuroinflammation kn-keyword=neuroinflammation en-keyword=neuroprotection kn-keyword=neuroprotection en-keyword=alpha-synuclein kn-keyword=alpha-synuclein en-keyword=mitochondria kn-keyword=mitochondria END start-ver=1.4 cd-journal=joma no-vol=10 cd-vols= no-issue=1 article-no= start-page=20698 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2020 dt-pub=20201126 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Mirtazapine exerts astrocyte-mediated dopaminergic neuroprotection en-subtitle= kn-subtitle= en-abstract= kn-abstract=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. en-copyright= kn-copyright= en-aut-name=KikuokaRyo en-aut-sei=Kikuoka en-aut-mei=Ryo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=MiyazakiIkuko en-aut-sei=Miyazaki en-aut-mei=Ikuko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=KubotaNatsuki en-aut-sei=Kubota en-aut-mei=Natsuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=MaedaMegumi en-aut-sei=Maeda en-aut-mei=Megumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=KagawaDaiki en-aut-sei=Kagawa en-aut-mei=Daiki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=MoriyamaMasaaki en-aut-sei=Moriyama en-aut-mei=Masaaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=SatoAsuka en-aut-sei=Sato en-aut-mei=Asuka kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=MurakamiShinki en-aut-sei=Murakami en-aut-mei=Shinki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=KitamuraYoshihisa en-aut-sei=Kitamura en-aut-mei=Yoshihisa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=SendoToshiaki en-aut-sei=Sendo en-aut-mei=Toshiaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=AsanumaMasato en-aut-sei=Asanuma en-aut-mei=Masato kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= affil-num=1 en-affil=Department of Medical Neurobiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil=Department of Medical Neurobiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=3 en-affil=Department of Medical Neurobiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=4 en-affil=Department of Medical Neurobiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=5 en-affil=Department of Medical Neurobiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=6 en-affil=Department of Medical Neurobiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=7 en-affil=Department of Medical Neurobiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=8 en-affil=Department of Medical Neurobiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=9 en-affil=Department of Clinical Pharmacy, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=10 en-affil=Department of Clinical Pharmacy, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=11 en-affil=Department of Medical Neurobiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= END start-ver=1.4 cd-journal=joma no-vol=21 cd-vols= no-issue=11 article-no= start-page=4137 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2020 dt-pub=20200610 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Cerebellar Blood Flow and Gene Expression in Crossed Cerebellar Diaschisis after Transient Middle Cerebral Artery Occlusion in Rats en-subtitle= kn-subtitle= en-abstract= kn-abstract=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. en-copyright= kn-copyright= en-aut-name=KidaniNaoya en-aut-sei=Kidani en-aut-mei=Naoya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=HishikawaTomohito en-aut-sei=Hishikawa en-aut-mei=Tomohito kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=HiramatsuMasafumi en-aut-sei=Hiramatsu en-aut-mei=Masafumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=NishihiroShingo en-aut-sei=Nishihiro en-aut-mei=Shingo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=KinKyohei en-aut-sei=Kin en-aut-mei=Kyohei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=TakahashiYu en-aut-sei=Takahashi en-aut-mei=Yu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=MuraiSatoshi en-aut-sei=Murai en-aut-mei=Satoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=SugiuKenji en-aut-sei=Sugiu en-aut-mei=Kenji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=YasuharaTakao en-aut-sei=Yasuhara en-aut-mei=Takao kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=MiyazakiIkuko en-aut-sei=Miyazaki en-aut-mei=Ikuko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=AsanumaMasato en-aut-sei=Asanuma en-aut-mei=Masato kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=DateIsao en-aut-sei=Date en-aut-mei=Isao kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= affil-num=1 en-affil=Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil=Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=3 en-affil=Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=4 en-affil=Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=5 en-affil=Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=6 en-affil=Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=7 en-affil=Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=8 en-affil=Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=9 en-affil=Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=10 en-affil=Department of Medical Neurobiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=11 en-affil=Department of Medical Neurobiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=12 en-affil=Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= en-keyword=apoptosis kn-keyword=apoptosis en-keyword=cerebral blood flow kn-keyword=cerebral blood flow en-keyword=crossed cerebellar diaschisis kn-keyword=crossed cerebellar diaschisis en-keyword=ischemic stroke kn-keyword=ischemic stroke en-keyword=oxidative stress kn-keyword=oxidative stress END start-ver=1.4 cd-journal=joma no-vol=138 cd-vols= no-issue= article-no= start-page=111235 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2020 dt-pub=20200303 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Effects of maternal bisphenol A diglycidyl ether exposure during gestation and lactation on behavior and brain development of the offspring en-subtitle= kn-subtitle= en-abstract= kn-abstract=Bisphenol A diglycidyl ether (BADGE) is an epoxy resin used for the inner coating of canned food and beverages. BADGE can easily migrate from the containers and become a contaminant. In this study, we examined the effects of BADGE exposure to the dams on the behavioral, structural, and developmental abnormalities in the offspring. Female pregnant mice were fed with a diet containing BADGE (0.15 or 1.5 mg/kg/day) during gestation and lactation periods. In an open field test, the time spent in the corner area significantly increases in male mice of high-dose BADGE group at 5 weeks old. The histological analysis using offspring brain at postnatal day 1 delivered from BADGE (1.5 mg/kg/day)-treated dams demonstrates that positive signals of Forkhead box P2- and COUP-TF interacting protein 2 are restricted in each cortical layer, but not in the control brain. In addition, the maternal BADGE exposure reduces nestin-positive fibers of the radial glia and T-box transcription factor 2-positive intermediate progenitors in the inner subventricular zone. Furthermore, a direct BADGE exposure promotes neurite outgrowth and neuronal connection in the primary cultured cortical neurons. These data suggest that maternal BADGE exposure can accelerate neuronal differentiation in fetuses and induce anxiety-like behavior in juvenile mice. en-copyright= kn-copyright= en-aut-name=MiyazakiIkuko en-aut-sei=Miyazaki en-aut-mei=Ikuko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=KikuokaRyo en-aut-sei=Kikuoka en-aut-mei=Ryo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=IsookaNami en-aut-sei=Isooka en-aut-mei=Nami kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=TakeshimaMika en-aut-sei=Takeshima en-aut-mei=Mika kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=SonobeKanau en-aut-sei=Sonobe en-aut-mei=Kanau kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=AraiRei en-aut-sei=Arai en-aut-mei=Rei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=FunakoshiHidemaru en-aut-sei=Funakoshi en-aut-mei=Hidemaru kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=QuinKyle E. en-aut-sei=Quin en-aut-mei=Kyle E. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=Smart Smart en-aut-sei=Smart en-aut-mei= Smart kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=ZenshoKazumasa en-aut-sei=Zensho en-aut-mei=Kazumasa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=AsanumaMasato en-aut-sei=Asanuma en-aut-mei=Masato kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= affil-num=1 en-affil=Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil=Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=3 en-affil=Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=4 en-affil=Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=5 en-affil=Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=6 en-affil=Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=7 en-affil=Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=8 en-affil=Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=9 en-affil=Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=10 en-affil=Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=11 en-affil=Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= en-keyword=Bisphenol A diglycidyl ether kn-keyword=Bisphenol A diglycidyl ether en-keyword=Epoxy resin kn-keyword=Epoxy resin en-keyword=Brain development kn-keyword=Brain development en-keyword=Neuronal differentiation kn-keyword=Neuronal differentiation en-keyword=Anxiety behavior kn-keyword=Anxiety behavior END start-ver=1.4 cd-journal=joma no-vol=21 cd-vols= no-issue=9 article-no= start-page=3254 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2020 dt-pub=20200504 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Chronic Systemic Exposure to Low-Dose Rotenone Induced Central and Peripheral Neuropathology and Motor Deficits in Mice: Reproducible Animal Model of Parkinson's Disease en-subtitle= kn-subtitle= en-abstract= kn-abstract=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, alpha-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. en-copyright= kn-copyright= en-aut-name=MiyazakiIkuko en-aut-sei=Miyazaki en-aut-mei=Ikuko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=IsookaNami en-aut-sei=Isooka en-aut-mei=Nami kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=ImafukuFuminori en-aut-sei=Imafuku en-aut-mei=Fuminori kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=SunJin en-aut-sei=Sun en-aut-mei=Jin kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=KikuokaRyo en-aut-sei=Kikuoka en-aut-mei=Ryo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=FurukawaChieko en-aut-sei=Furukawa en-aut-mei=Chieko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=AsanumaMasato en-aut-sei=Asanuma en-aut-mei=Masato kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= affil-num=1 en-affil=Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil=Department of Medical Neurobiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=3 en-affil=Department of Medical Neurobiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=4 en-affil=Department of Medical Neurobiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=5 en-affil=Department of Medical Neurobiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=6 en-affil=Department of Medical Neurobiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=7 en-affil=Department of Medical Neurobiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= en-keyword=rotenone kn-keyword=rotenone en-keyword=Parkinson's disease kn-keyword=Parkinson's disease en-keyword=dopaminergic neuron kn-keyword=dopaminergic neuron en-keyword=dorsal motor nucleus of the vagus kn-keyword=dorsal motor nucleus of the vagus en-keyword=myenteric plexus kn-keyword=myenteric plexus en-keyword=neurodegeneration kn-keyword=neurodegeneration en-keyword=α-synuclein kn-keyword=α-synuclein en-keyword=motor deficit kn-keyword=motor deficit END start-ver=1.4 cd-journal=joma no-vol=132 cd-vols= no-issue= article-no= start-page=104608 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2020 dt-pub=20200131 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Dopaminergic neuroprotective effects of rotigotine via 5-HT1A receptors: Possibly involvement of metallothionein expression in astrocytes en-subtitle= kn-subtitle= en-abstract= kn-abstract=Astrocytes exert neuroprotective effects through production of antioxidant molecules and neurotrophic factors. A recent study showed that stimulation of astrocyte serotonin 1A (5-HT1A) receptors promotes astrocyte proliferation and upregulation of the antioxidant molecules metallothionein (MT)-1,2, which protect dopaminergic neurons against oxidative stress. Rotigotine, an anti-parkinsonian drug, can bind to dopamine and 5-HT1A receptors. In this study, we examined neuroprotective effects of rotigotine in models of Parkinson's disease and involvement of astrocyte 5-HT1A receptors in neuroprotective effects of rotigotine against dopaminergic neurodegeneration. Rotigotine increased the number of astrocytes and MT-1,2 expression in cultured astrocytes. Pretreatment with conditioned media from rotigotine-treated astrocytes significantly inhibited 6-hydroxydopamine (6-OHDA)-induced dopaminergic neurotoxicity. These effects were completely blocked by a 5-HT1A antagonist or MT-1,2 specific antibody. Subcutaneous administration of rotigotine increased MT-1,2 expression in striatal astrocytes and prevented reduction of dopaminergic neurons in the substantia nigra of a 6-OHDA-lesioned mouse model of Parkinson's disease. These effects were blocked by co-administration with a 5-HT1A antagonist. These results suggest that rotigotine exerts neuroprotective effects through upregulation of MT expression in astrocytes by targeting 5-HT1A receptors. Our findings provide a possible therapeutic application of rotigotine to prevent dopaminergic neurodegeneration in Parkinson's disease. en-copyright= kn-copyright= en-aut-name=IsookaNami en-aut-sei=Isooka en-aut-mei=Nami kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=MiyazakiIkuko en-aut-sei=Miyazaki en-aut-mei=Ikuko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=KikuokaRyo en-aut-sei=Kikuoka en-aut-mei=Ryo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=WadaKouichi en-aut-sei=Wada en-aut-mei=Kouichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=NakayamaErika en-aut-sei=Nakayama en-aut-mei=Erika kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=ShinKotaro en-aut-sei=Shin en-aut-mei=Kotaro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=YamamotoDaichi en-aut-sei=Yamamoto en-aut-mei=Daichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=KitamuraYoshihisa en-aut-sei=Kitamura en-aut-mei=Yoshihisa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=AsanumaMasato en-aut-sei=Asanuma en-aut-mei=Masato kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= affil-num=1 en-affil=Department of Medical Neurobiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil=Department of Medical Neurobiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=3 en-affil=Department of Medical Neurobiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=4 en-affil=Department of Medical Neurobiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=5 en-affil=Department of Medical Neurobiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=6 en-affil=Department of Medical Neurobiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=7 en-affil=Department of Medical Neurobiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=8 en-affil=Department of Clinical Pharmacy, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=9 en-affil=Department of Medical Neurobiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= en-keyword=Astrocyte kn-keyword=Astrocyte en-keyword=Dopamine agonist kn-keyword=Dopamine agonist en-keyword=Metallothionein kn-keyword=Metallothionein en-keyword=Parkinson's disease kn-keyword=Parkinson's disease en-keyword=Rotigotine kn-keyword=Rotigotine en-keyword=Serotonin 1A receptor kn-keyword=Serotonin 1A receptor END start-ver=1.4 cd-journal=joma no-vol=8 cd-vols= no-issue=6 article-no= start-page=e65983 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2013 dt-pub=20130612 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Transplantation of melanocytes obtained from the skin ameliorates apomorphine-induced abnormal behavior in rodent hemi-parkinsonian models en-subtitle= kn-subtitle= en-abstract= kn-abstract=Tyrosinase, which catalyzes both the hydroxylation of tyrosine and consequent oxidation of L-DOPA to form melanin in melanocytes, is also expressed in the brain, and oxidizes L-DOPA and dopamine. Replacement of dopamine synthesis by tyrosinase was reported in tyrosine hydroxylase null mice. To examine the potential benefits of autograft cell transplantation for patients with Parkinson's disease, tyrosinase-producing cells including melanocytes, were transplanted into the striatum of hemi-parkinsonian model rats or mice lesioned with 6-hydroxydopamine. Marked improvement in apomorphine-induced rotation was noted at day 40 after intrastriatal melanoma cell transplantation. Transplantation of tyrosinase cDNA-transfected hepatoma cells, which constitutively produce L-DOPA, resulted in marked amelioration of the asymmetric apomorphine-induced rotation in hemi-parkinsonian mice and the effect was present up to 2 months. Moreover, parkinsonian mice transplanted with melanocytes from the back skin of black newborn mice, but not from albino mice, showed marked improvement in the apomorphine-induced rotation behavior up to 3 months after the transplantation. Dopamine-positive signals were seen around the surviving transplants in these experiments. Taken together with previous studies showing dopamine synthesis and metabolism by tyrosinase, these results highlight therapeutic potential of intrastriatal autograft cell transplantation of melanocytes in patients with Parkinson's disease. en-copyright= kn-copyright= en-aut-name=AsanumaMasato en-aut-sei=Asanuma en-aut-mei=Masato kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=MiyazakiIkuko en-aut-sei=Miyazaki en-aut-mei=Ikuko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=Francisco J.Diaz-Corrales en-aut-sei=Francisco J. en-aut-mei=Diaz-Corrales kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=HigashiYouichirou en-aut-sei=Higashi en-aut-mei=Youichirou kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=NambaMasayoshi en-aut-sei=Namba en-aut-mei=Masayoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=OgawaNorio en-aut-sei=Ogawa en-aut-mei=Norio kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= affil-num=1 en-affil= kn-affil=Department of Brain Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences affil-num=2 en-affil= kn-affil=Department of Brain Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences affil-num=3 en-affil= kn-affil=Department of Brain Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences affil-num=4 en-affil= kn-affil=Department of Brain Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences affil-num=5 en-affil= kn-affil=Department of Brain Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences affil-num=6 en-affil= kn-affil=Department of Brain Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences END start-ver=1.4 cd-journal=joma no-vol=26 cd-vols= no-issue=3 article-no= start-page=285 end-page=298 dt-received= dt-revised= dt-accepted= dt-pub-year=2014 dt-pub=201410 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Neuroprotective Effects of Metallothionein Against Rotenone-Induced Myenteric Neurodegeneration in Parkinsonian Mice en-subtitle= kn-subtitle= en-abstract= kn-abstract=Parkinson's disease (PD) is a neurodegenerative disease with motor symptoms as well as non-motor symptoms that precede the onset of motor symptoms. Mitochondrial complex I inhibitor, rotenone, has been widely used to reproduce PD pathology in the central nervous system (CNS) and enteric nervous system (ENS). We reported previously that metallothioneins (MTs) released from astrocytes can protect dopaminergic neurons against oxidative stress. The present study examined the changes in MT expression by chronic systemic rotenone administration in the striatum and colonic myenteric plexus of C57BL mice. In addition, we investigated the effects of MT depletion on rotenone-induced neurodegeneration in CNS and ENS using MT-1 and MT-2 knockout (MT KO) mice, or using primary cultured neurons from MT KO mice. In normal C57BL mice, subcutaneous administration of rotenone for 6 weeks caused neurodegeneration, increased MT expression with astrocytes activation in the striatum and myenteric plexus. MT KO mice showed more severe myenteric neuronal damage by rotenone administration after 4 weeks than wild-type mice, accompanied by reduced astroglial activation. In primary cultured mesencephalic neurons from MT KO mice, rotenone exposure induced neurotoxicity in dopaminergic neurons, which was complemented by addition of recombinant protein. The present results suggest that MT seems to provide protection against neurodegeneration in ENS of rotenone-induced PD model mice. en-copyright= kn-copyright= en-aut-name=MurakamiShinki en-aut-sei=Murakami en-aut-mei=Shinki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=MiyazakiIkuko en-aut-sei=Miyazaki en-aut-mei=Ikuko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=SogawaNorio en-aut-sei=Sogawa en-aut-mei=Norio kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=MiyoshiKo en-aut-sei=Miyoshi en-aut-mei=Ko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=AsanumaMasato en-aut-sei=Asanuma en-aut-mei=Masato kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= affil-num=1 en-affil= kn-affil=Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Brain Sci affil-num=2 en-affil= kn-affil=Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Brain Sci affil-num=3 en-affil= kn-affil=Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Dent Pharmacol affil-num=4 en-affil= kn-affil=Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Brain Sci affil-num=5 en-affil= kn-affil=Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Brain Sci en-keyword=Parkinson's disease kn-keyword=Parkinson's disease en-keyword=Rotenone kn-keyword=Rotenone en-keyword=Enteric nervous system kn-keyword=Enteric nervous system en-keyword=Astrocytes kn-keyword=Astrocytes en-keyword=Metallothionein kn-keyword=Metallothionein END start-ver=1.4 cd-journal=joma no-vol=119 cd-vols= no-issue=3 article-no= start-page=235 end-page=239 dt-received= dt-revised= dt-accepted= dt-pub-year=2008 dt-pub=20080104 dt-online= en-article= kn-article= en-subject= kn-subject= en-title=Quinone formation as a common neurotoxic factor in dopaminergic neurotoxicity induced by an excess amount of cytosolic dopamine kn-title=小胞外過剰ドパミンによるドパミン神経障害における共通因子としてのキノン体生成 en-subtitle= kn-subtitle= en-abstract= kn-abstract= en-copyright= kn-copyright= en-aut-name=MiyazakiIkuko en-aut-sei=Miyazaki en-aut-mei=Ikuko kn-aut-name=宮崎育子 kn-aut-sei=宮崎 kn-aut-mei=育子 aut-affil-num=1 ORCID= en-aut-name=AsanumaMasato en-aut-sei=Asanuma en-aut-mei=Masato kn-aut-name=浅沼幹人 kn-aut-sei=浅沼 kn-aut-mei=幹人 aut-affil-num=2 ORCID= en-aut-name= en-aut-sei= en-aut-mei= kn-aut-name=Francisco J.Diaz-Corrales kn-aut-sei=Francisco J. kn-aut-mei=Diaz-Corrales aut-affil-num=3 ORCID= en-aut-name=MiyoshiKo en-aut-sei=Miyoshi en-aut-mei=Ko kn-aut-name=三好耕 kn-aut-sei=三好 kn-aut-mei=耕 aut-affil-num=4 ORCID= en-aut-name=OgawaNorio en-aut-sei=Ogawa en-aut-mei=Norio kn-aut-name=小川紀雄 kn-aut-sei=小川 kn-aut-mei=紀雄 aut-affil-num=5 ORCID= affil-num=1 en-affil= kn-affil=岡山大学大学院医歯薬学総合研究科 神経情報学 affil-num=2 en-affil= kn-affil=岡山大学大学院医歯薬学総合研究科 神経情報学 affil-num=3 en-affil= kn-affil=岡山大学大学院医歯薬学総合研究科 神経情報学 affil-num=4 en-affil= kn-affil=岡山大学大学院医歯薬学総合研究科 神経情報学 affil-num=5 en-affil= kn-affil=岡山大学大学院医歯薬学総合研究科 神経情報学 en-keyword=ドパミンキノン kn-keyword=ドパミンキノン en-keyword=パーキンソン病 kn-keyword=パーキンソン病 en-keyword=メタンフェタミン kn-keyword=メタンフェタミン en-keyword=キノン還元酵素 kn-keyword=キノン還元酵素 en-keyword=チロシナーゼ kn-keyword=チロシナーゼ END start-ver=1.4 cd-journal=joma no-vol= cd-vols= no-issue= article-no= start-page= end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2006 dt-pub=20060324 dt-online= en-article= kn-article= en-subject= kn-subject= en-title=メタンフェタミン誘発ドパミン神経毒性はキノン体形成関連分子により調節されている kn-title=Methamphetamine-induced dopaminergic neurotoxicity is regulated by quinone formation-related molecules en-subtitle= kn-subtitle= en-abstract= kn-abstract=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. en-copyright= kn-copyright= en-aut-name=MiyazakiIkuko en-aut-sei=Miyazaki en-aut-mei=Ikuko kn-aut-name=宮ア育子 kn-aut-sei=宮ア kn-aut-mei=育子 aut-affil-num=1 ORCID= affil-num=1 en-affil= kn-affil=岡山大学 en-keyword=dopamine quinone kn-keyword=dopamine quinone en-keyword=quinone reductase kn-keyword=quinone reductase en-keyword=tyrosinase kn-keyword=tyrosinase END start-ver=1.4 cd-journal=joma no-vol=68 cd-vols= no-issue=6 article-no= start-page=317 end-page=322 dt-received= dt-revised= dt-accepted= dt-pub-year=2014 dt-pub=201412 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Visualization of Astrocytic Primary Cilia in the Mouse Brain by Immunofluorescent Analysis Using the Cilia Marker Arl13b en-subtitle= kn-subtitle= en-abstract= kn-abstract=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. en-copyright= kn-copyright= en-aut-name=KasaharaKyosuke en-aut-sei=Kasahara en-aut-mei=Kyosuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=MiyoshiKo en-aut-sei=Miyoshi en-aut-mei=Ko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=MurakamiShinki en-aut-sei=Murakami en-aut-mei=Shinki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=MiyazakiIkuko en-aut-sei=Miyazaki en-aut-mei=Ikuko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=AsanumaMasato en-aut-sei=Asanuma en-aut-mei=Masato kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= affil-num=1 en-affil= kn-affil=Department of Brain Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences affil-num=2 en-affil= kn-affil=Department of Brain Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences affil-num=3 en-affil= kn-affil=Department of Brain Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences affil-num=4 en-affil= kn-affil=Department of Brain Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences affil-num=5 en-affil= kn-affil=Department of Brain Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences en-keyword=primary cilia kn-keyword=primary cilia en-keyword=astrocyte kn-keyword=astrocyte en-keyword=ADP-ribosylation factor-like protein 13B kn-keyword=ADP-ribosylation factor-like protein 13B END start-ver=1.4 cd-journal=joma no-vol=65 cd-vols= no-issue=5 article-no= start-page=279 end-page=285 dt-received= dt-revised= dt-accepted= dt-pub-year=2011 dt-pub=201110 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Factors That Influence Primary Cilium Length en-subtitle= kn-subtitle= en-abstract= kn-abstract=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-3β 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. en-copyright= kn-copyright= en-aut-name=MiyoshiKo en-aut-sei=Miyoshi en-aut-mei=Ko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=KasaharaKyosuke en-aut-sei=Kasahara en-aut-mei=Kyosuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=MiyazakiIkuko en-aut-sei=Miyazaki en-aut-mei=Ikuko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=AsanumaMasato en-aut-sei=Asanuma en-aut-mei=Masato kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= affil-num=1 en-affil= kn-affil=Department of Brain Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences affil-num=2 en-affil= kn-affil=Department of Brain Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences affil-num=3 en-affil= kn-affil=Department of Brain Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences affil-num=4 en-affil= kn-affil=Department of Brain Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences en-keyword=primary cilium length kn-keyword=primary cilium length en-keyword=lithium kn-keyword=lithium en-keyword=cyclic AMP kn-keyword=cyclic AMP en-keyword=soluble tubulin kn-keyword=soluble tubulin en-keyword=intraflagellar transport kn-keyword=intraflagellar transport END start-ver=1.4 cd-journal=joma no-vol=64 cd-vols= no-issue=4 article-no= start-page=219 end-page=223 dt-received= dt-revised= dt-accepted= dt-pub-year=2010 dt-pub=201008 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Effects of Imipramine and Lithium on the Suppression of Cell Proliferation in the Dentate Gyrus of the Hippocampus in Adrenocorticotropic Hormone-treated Rats en-subtitle= kn-subtitle= en-abstract= kn-abstract=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. en-copyright= kn-copyright= en-aut-name=DoiMaho en-aut-sei=Doi en-aut-mei=Maho kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=MiyazakiIkuko en-aut-sei=Miyazaki en-aut-mei=Ikuko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=NagamachiTomoko en-aut-sei=Nagamachi en-aut-mei=Tomoko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=ShinomiyaKazuaki en-aut-sei=Shinomiya en-aut-mei=Kazuaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=MatsunagaHisashi en-aut-sei=Matsunaga en-aut-mei=Hisashi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=SendoToshiaki en-aut-sei=Sendo en-aut-mei=Toshiaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=KawasakiHiromu en-aut-sei=Kawasaki en-aut-mei=Hiromu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=AsanumaMasato en-aut-sei=Asanuma en-aut-mei=Masato kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=GomitaYutaka en-aut-sei=Gomita en-aut-mei=Yutaka kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=KitamuraYoshihisa en-aut-sei=Kitamura en-aut-mei=Yoshihisa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= affil-num=1 en-affil= kn-affil=Department of Pharmaceutical Care and Health Sciences, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences affil-num=2 en-affil= kn-affil=Department of Brain Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences affil-num=3 en-affil= kn-affil=Department of Pharmacy, Okayama University Hospital affil-num=4 en-affil= kn-affil=Department of Pharmaceutical Care and Health Sciences, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences affil-num=5 en-affil= kn-affil=Department of Pharmacy, Okayama University Hospital affil-num=6 en-affil= kn-affil=Department of Pharmacy, Okayama University Hospital affil-num=7 en-affil= kn-affil=Department of Clinical Pharmacology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences affil-num=8 en-affil= kn-affil=Department of Brain Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences affil-num=9 en-affil= kn-affil=Shujitsu University School of Pharmacy affil-num=10 en-affil= kn-affil=Department of Pharmaceutical Care and Health Sciences, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences en-keyword=ACTH kn-keyword=ACTH en-keyword=imipramine kn-keyword=imipramine en-keyword=lithium kn-keyword=lithium en-keyword=proliferation kn-keyword=proliferation en-keyword=Ki-67 kn-keyword=Ki-67 END start-ver=1.4 cd-journal=joma no-vol=58 cd-vols= no-issue=5 article-no= start-page=221 end-page=233 dt-received= dt-revised= dt-accepted= dt-pub-year=2004 dt-pub=200410 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Quinone formation as dopaminergic neuron-specific oxidative stress in the pathogenesis of sporadic Parkinson's disease and neurotoxin-induced parkinsonism. en-subtitle= kn-subtitle= en-abstract= kn-abstract=

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

en-copyright= kn-copyright= en-aut-name=AsanumaMasato en-aut-sei=Asanuma en-aut-mei=Masato kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=MiyazakiIkuko en-aut-sei=Miyazaki en-aut-mei=Ikuko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=Diaz-CorralesFrancisco J en-aut-sei=Diaz-Corrales en-aut-mei=Francisco J kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=OgawaNorio en-aut-sei=Ogawa en-aut-mei=Norio kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= affil-num=1 en-affil= kn-affil=Okayama University affil-num=2 en-affil= kn-affil=Okayama University affil-num=3 en-affil= kn-affil=Okayama University affil-num=4 en-affil= kn-affil=Okayama University en-keyword=dopamine quinone kn-keyword=dopamine quinone en-keyword=quinoprotein kn-keyword=quinoprotein en-keyword=Parkinson’sdisease kn-keyword=Parkinson’sdisease en-keyword=oxidative stress kn-keyword=oxidative stress en-keyword=neurotoxin kn-keyword=neurotoxin END start-ver=1.4 cd-journal=joma no-vol=55 cd-vols= no-issue=1 article-no= start-page=1 end-page=9 dt-received= dt-revised= dt-accepted= dt-pub-year=2001 dt-pub=200102 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Localization, regulation, and function of metallothionein-III/growth inhibitory factor in the brain. en-subtitle= kn-subtitle= en-abstract= kn-abstract=

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

en-copyright= kn-copyright= en-aut-name=AokiSogawa Chiharu en-aut-sei=Aoki en-aut-mei=Sogawa Chiharu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=AsanumaMasato en-aut-sei=Asanuma en-aut-mei=Masato kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=SogawaNorio en-aut-sei=Sogawa en-aut-mei=Norio kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=MiyazakiIkuko en-aut-sei=Miyazaki en-aut-mei=Ikuko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=NakanishiTohru en-aut-sei=Nakanishi en-aut-mei=Tohru kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=FurutaHiroaki en-aut-sei=Furuta en-aut-mei=Hiroaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=OgawaNoriko en-aut-sei=Ogawa en-aut-mei=Noriko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= affil-num=1 en-affil= kn-affil=Okayama University affil-num=2 en-affil= kn-affil=Okayama University affil-num=3 en-affil= kn-affil=Okayama University affil-num=4 en-affil= kn-affil=Okayama University affil-num=5 en-affil= kn-affil=Okayama University affil-num=6 en-affil= kn-affil=Okayama University affil-num=7 en-affil= kn-affil=Okayama University en-keyword=neuroprotectin kn-keyword=neuroprotectin en-keyword=metal transport kn-keyword=metal transport en-keyword=localization kn-keyword=localization en-keyword=gene expression kn-keyword=gene expression en-keyword=neurodegenerative disease kn-keyword=neurodegenerative disease END start-ver=1.4 cd-journal=joma no-vol=62 cd-vols= no-issue=3 article-no= start-page=141 end-page=150 dt-received= dt-revised= dt-accepted= dt-pub-year=2008 dt-pub=200806 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Dopaminergic neuron-specific oxidative stress caused by dopamine itself en-subtitle= kn-subtitle= en-abstract= kn-abstract=

Oxidative stress, including the reactive oxygen or nitrogen species generated in the enzymatical oxidationor 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 cytotoxicityin 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 dopaminergicneuron-specific oxidative stress. In this article, we primarily review recent studies on the pathogenicity of quinone formation, in addition to several neuroprotective approaches against dopaminequinone-induced dysfunction of dopaminergic neurons.

en-copyright= kn-copyright= en-aut-name=MiyazakiIkuko en-aut-sei=Miyazaki en-aut-mei=Ikuko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=AsanumaMasato en-aut-sei=Asanuma en-aut-mei=Masato kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= affil-num=1 en-affil= kn-affil=Department of Brain Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences affil-num=2 en-affil= kn-affil=Department of Brain Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences en-keyword=dopamine quinone kn-keyword=dopamine quinone en-keyword=quinoprotein kn-keyword=quinoprotein en-keyword=methamphetamine kn-keyword=methamphetamine en-keyword=Parkinson?s disease kn-keyword=Parkinson?s disease en-keyword=L-DOPA kn-keyword=L-DOPA END start-ver=1.4 cd-journal=joma no-vol=60 cd-vols= no-issue=6 article-no= start-page=299 end-page=309 dt-received= dt-revised= dt-accepted= dt-pub-year=2006 dt-pub=200612 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Involvement of STAT3 in Bladder Smooth Muscle Hypertrophy Following Bladder Outlet Obstruction en-subtitle= kn-subtitle= en-abstract= kn-abstract=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 1 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 > or = 2.0 and < or = 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 < or = 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 (1 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. en-copyright= kn-copyright= en-aut-name=FujitaOsamu en-aut-sei=Fujita en-aut-mei=Osamu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=AsanumaMasato en-aut-sei=Asanuma en-aut-mei=Masato kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=YokoyamaTeruhiko en-aut-sei=Yokoyama en-aut-mei=Teruhiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=MiyazakiIkuko en-aut-sei=Miyazaki en-aut-mei=Ikuko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=OgawaNorio en-aut-sei=Ogawa en-aut-mei=Norio kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=KumonHiromi en-aut-sei=Kumon en-aut-mei=Hiromi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= affil-num=1 en-affil= kn-affil=Okayama University affil-num=2 en-affil= kn-affil=Okayama University affil-num=3 en-affil= kn-affil=Okayama University affil-num=4 en-affil= kn-affil=Okayama University affil-num=5 en-affil= kn-affil=Okayama University affil-num=6 en-affil= kn-affil=Okayama University en-keyword=benign prostatic hyperplasia kn-keyword=benign prostatic hyperplasia en-keyword=bladder outlet obstruction kn-keyword=bladder outlet obstruction en-keyword=bladder smooth muscle kn-keyword=bladder smooth muscle en-keyword=signal transducer and activator of transcription 3 (STAT3) kn-keyword=signal transducer and activator of transcription 3 (STAT3) en-keyword=small interfering RNA (siRNA) kn-keyword=small interfering RNA (siRNA) END