KATP Channel Openers Protect Mesencephalic Neurons Against MPP+-Induced Cytotoxicity Via Inhibition of ROS Production

Opening of ATP-sensitive potassium (K-ATP) channels has been demonstrated to exert significant neuroprotection in in vivo and in vitro models of Parkinson's disease (PD), but the exact mechanism remains unclear. In the present study, various K-ATP channel openers (KCOs) sensitive to diverse K-ATP subunits were used to clarify the protective role of K-ATP channel opening in 1 methyl-4-phenylpyridinium (MPP+)-induced oxidative stress injury in mouse primary cultured mesencephalic neurons. The results showed that pretreatment with nonselective KCO pinacidil (Pin) or diazoxide (Dia), a KCO sensitive to Kir6.2/SUR1 K-ATP channels, protected mesencephalic neurons, especially dopaminergic neurons, against MPP+-induced injury in a concentration-dependent manner. However, cromakalim (Cro), an opener of Kir6.1/SUR2 but not Kir6.2/SUR1 K-ATP channels, failed to protect against MPP+-induced cytotoxicity. Furthermore, Pin and Dia but not Cro significantly suppressed the elevation of reactive oxygen species (ROS) triggered by MPP+ and prevented the loss of mitochondrial member potential (Delta Psi m) and the release of mitochondrial cyotchrome c. Consequently, opening of K-ATP channels expressed in neurons could protect primary mesencephalic neurons against MPP+-induced cytotoxicity via inhibiting ROS overproduction and subsequently ameliorating mitochondrial function. (C) 2009 Wiley-Liss, Inc.