Iptakalim alleviates rotenone-induced degeneration of Dopaminergic neurons through inhibiting microglia-mediated neuroinflammation

作者：Zhou, Fang; Wu, Jia-Yong; Sun, Xiu-Lan; Yao, Hong-Hong; Ding, Jian-Hua; Hu, Gang^*

来源：Neuropsychopharmacology, 2007, 32(12): 2570-2580.

DOI：10.1038/sj.npp.1301381

• iptakalim
• ATP-sensitive potassium channel
• microglia
• rotenone
• neuroinflammation
• Parkinson's disease

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 EDl (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 KATP (mitoKATP) 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 microgliamediated neuroinflammation.

• 出版日期2007-12
• 单位南京医科大学