Opening of microglial KATP channels inhibits rotenone-induced neuroinflammation

Abstract

As activated microglia (MG) is an early sign that often precedes and triggers neuronal death, inhibition of microglial activation and reduction of subsequent neurotoxicity may offer therapeutic benefit. The present study demonstrates that rat primary cultured MG expressed Kir6.1 and SUR2 subunits of KATP channel, which was identical to that expressed in BV-2 microglial cell line. The classic KATP channel opener pinacidil and selective mitochondrial KATP (mito-KATP) channel opener diazoxide prevented rotenone-induc microglial activation and production of pro-inflammatory factors (tumour necrosis factor[TNF]-α and prostaglandin E2 [PGE2]). And the effects of pinacidil and diazoxide were reversed by mito-KATP blocker 5-hydroxydecanoate (5-HD), indicating that mito-KATP channels participate in the regulation of microglial activation. Moreover, the underlying mechanisms involved the stabilization of mitocho drial membrane potential and inhibition of p38/c-Jun-N-terminal kinase (JNK) activation in microglia. Furthermore, the in vivo study confirmed that diazoxide exhibited neuroprotective effects against rotenone along with the inhibition of microglial activation and neuroinflammation. Thus, microglial mito-KATP channel might be a novel prospective target for the treatment of neuroinflammation-related degenerative disorders such as Parkinson's disease. © 2008 The Authors.