title: Iptakalim alleviates rotenone-induced degeneration of dopaminergic neurons through inhibiting microglia-mediated neuroinflammation.
abstract: Inhibition of microglia-mediated neuroinflammation has been regarded as a prospective strategy for treating neurodegenerative disorders, such as Parkinson's disease (PD). In the present study, we demonstrated that systematic administration with iptakalim (IPT), an adenosine triphosphate (ATP)-sensitive potassium channel (K(ATP)) opener, could alleviate rotenone-induced degeneration of dopaminergic neurons in rat substantia nigra along with the downregulation of microglial activation and mRNA levels of tumor necrosis factor-alpha (TNF-alpha) and cyclooxygenase-2 (COX-2). In rat primary cultured microglia, pretreatment with IPT suppressed rotenone-induced microglial activation evidenced by inhibition of microglial amoeboid morphological alteration, declined expression of ED1 (a marker for activated microglia), and decreased production of TNF-alpha and prostaglandin E2 (PGE(2)). These inhibitory effects of IPT could be reversed by selective mitochondrial K(ATP) (mitoK(ATP)) channel blocker 5-hydroxydecanoate (5-HD). Furthermore, pretreatment with IPT prevented rotenone-induced mitochondrial membrane potential loss and p38/c-jun N-terminal kinase (JNK) mitogen-activated protein kinase (MAPK) activation in microglia, which might in turn regulate microglial activation and subsequent production of TNF-alpha and PGE(2). These data strongly suggest that the K(ATP) opener IPT may be a novel and promising neuroprotective drug via inhibiting microglia-mediated neuroinflammation.
authors.affiliation: Laboratory of Neuropharmacology, Department of Anatomy, Histology and Pharmacology, Nanjing Medical University, Nanjing, Jiangsu, PR China.
authors.forename: Fang
authors.initials: F
authors.lastname: Zhou
authors.forename: Jia-Yong
authors.initials: JY
authors.lastname: Wu
authors.forename: Xiu-Lan
authors.initials: XL
authors.lastname: Sun
authors.forename: Hong-Hong
authors.initials: HH
authors.lastname: Yao
authors.forename: Jian-Hua
authors.initials: JH
authors.lastname: Ding
authors.forename: Gang
authors.initials: G
authors.lastname: Hu
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001522:Behavior, Animal; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D046352:Freezing Reaction, Cataleptic / Q000187:drug effects; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D017628:Microglia / Q000187:drug effects / Q000502:physiology*; D009043:Motor Activity / Q000187:drug effects; D009410:Nerve Degeneration / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D011437:Propylamines / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012402:Rotenone; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: C502260:N-(1-methylethyl)-1,1,2-trimethylpropylamine; D018696:Neuroprotective Agents; D011437:Propylamines; D014409:Tumor Necrosis Factor-alpha; D012402:Rotenone; D051546:Cyclooxygenase 2; D015232:Dinoprostone; D004298:Dopamine