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. Inhibition of microglia-mediated neuroinflammation has been considered 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). In rat primary cultured microglia, pretreatment with IPT suppressed rotenone-induced microglial activation evidence by 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). Further, 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 inhibited microgliamediated neuroinflammation.