title: Iptakalim protects against MPP+-induced degeneration of dopaminergic neurons in association with astrocyte activation.
abstract: Astrocyte activation observed in the MPTP mouse model and Parkinson's disease patients participates in the cascade of deleterious events that ultimately leads to death of dopaminergic neurons in the substantia nigra pars compacta (SNpc). The present study aimed to elucidate whether inhibiting astrocyte activation was involved in the protective effects of iptakalim (Ipt), a novel ATP-sensitive potassium channel opener, on MPP+-induced degeneration of dopaminergic neurons. The results showed that Ipt could decrease MPP+-induced TNF-alpha release and p38 MAPK activation in reactive astrocytes. The effects of Ipt were reversed by the mitochondrial KATP blocker, 5-hydroxydecanoate, indicating that mitochondrial KATP channels participate in the regulation of astrocyte activation. Moreover, systematic administration of Ipt could significantly alleviate MPP+-induced behavioural symptoms in motor coordination, the loss of dopaminergic neurons, and the activation of astrocyte and microglia in the SNpc. Together, these findings suggest that Ipt may protect against MPP+-induced degeneration of dopaminergic neurons by inhibiting astrocyte activation and subsequent release of pro-inflammatory factors.
authors.affiliation: Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu, P.R. China.
authors.forename: Yan-Jing
authors.initials: YJ
authors.lastname: Yang
authors.forename: Shu
authors.initials: S
authors.lastname: Zhang
authors.forename: Jian-Hua
authors.initials: JH
authors.lastname: Ding
authors.forename: Fang
authors.initials: F
authors.lastname: Zhou
authors.forename: Gang
authors.initials: G
authors.lastname: Hu
mesh_terms: D015655:1-Methyl-4-phenylpyridinium; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000378:metabolism / Q000502:physiology*; D001933:Brain Stem / Q000166:cytology; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D003652:Decanoic Acids / Q000494:pharmacology; D003981:Diazoxide / Q000494:pharmacology; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D053331:Ectodysplasins / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006880:Hydroxy Acids / Q000494:pharmacology; D020267:MPTP Poisoning / Q000139:chemically induced / Q000150:complications; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009410:Nerve Degeneration / Q000209:etiology / Q000378:metabolism* / Q000517:prevention & control*; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D026902:Potassium Channel Blockers / Q000494:pharmacology; D011437:Propylamines / Q000494:pharmacology*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013378:Substantia Nigra / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D003652:Decanoic Acids; D053331:Ectodysplasins; D005904:Glial Fibrillary Acidic Protein; D006880:Hydroxy Acids; C502260:N-(1-methylethyl)-1,1,2-trimethylpropylamine; D018696:Neuroprotective Agents; D026902:Potassium Channel Blockers; D011437:Propylamines; D014409:Tumor Necrosis Factor-alpha; C052853:5-hydroxydecanoic acid; D014446:Tyrosine 3-Monooxygenase; D048051:p38 Mitogen-Activated Protein Kinases; D003981:Diazoxide; D015655:1-Methyl-4-phenylpyridinium; D004298:Dopamine