ATP-sensitive potassium channel opener iptakalim protects against MPP +-induced astrocytic apoptosis via mitochondria and mitogen-activated protein kinase signal pathways

Abstract

Inhibition of astrocytic apoptosis has been regarded as a novel prospective strategy for treating neurodegenerative disorders such as Parkinson's disease. In the present study, we demonstrated that iptakalim (IPT), an ATP-sensitive potassium channel (KATP channel) opener, exerted protective effect on MPP+-induced astrocytic apoptosis, which was reversed by selective mitochondrial KATP channel blocker 5-hydroxydecanoate. Further study revealed that IPT inhibited glutathione (GSH) depletion, mitochondrial membrane potential loss and subsequent release of pro-apoptotic factors (cytochrome c and apoptosis-inducing factor (AIF), and c-Jun NH2-terminal kinase/mitogen-activated protein kinases (MAPK) phosphorylation induced by MPP+. Meanwhile, extracellular signal-regulated kinase (ERK) 1/2 inhibitor inhibited the protective effect of IPT on MPP+-induced astrocytic apoptosis. Furthermore, IPT could also activate ERK/MAPK and maintain increased phospho-ERK1/2 level after MPP+ exposure. Taken together, these findings reveal for the first time that IPT protects against MPP +-induced astrocytic apoptosis via inhibition of mitochondria apoptotic pathway and regulating the MAPK signal transduction pathways by opening mitochondrial ATP-sensitive potassium (mitoKATP) channels in astrocytes. And targeting KATP channels expressed in astrocytes may provide a novel therapeutic strategy for neurodegenerative disorders. © 2007 The Authors.