K(ATP) 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 cytochrome 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.
Xie
Juan
J
Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu, People's Republic of China.
Duan
Lei
L
Qian
Xia
X
Huang
Xu
X
Ding
Jianhua
J
Hu
Gang
G
D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity*; D000818:Animals; D002478:Cells, Cultured; D019806:Cromakalim / Q000008:administration & dosage / Q000494:pharmacology; D045304:Cytochromes c / Q000378:metabolism; D003981:Diazoxide / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism; D054086:KATP Channels / Q000378:metabolism*; D049990:Membrane Transport Modulators / Q000008:administration & dosage / Q000494:pharmacology; D008636:Mesencephalon / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology*; D009498:Neurotoxins / Q000633:toxicity*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D020110:Pinacidil / Q000008:administration & dosage / Q000494:pharmacology; D024661:Potassium Channels, Inwardly Rectifying / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D000099161:Kcnj11 Channel
D015655:1-Methyl-4-phenylpyridinium; D019806:Cromakalim; D045304:Cytochromes c; D003981:Diazoxide; D004298:Dopamine; D054086:KATP Channels; D049990:Membrane Transport Modulators; D018696:Neuroprotective Agents; D009498:Neurotoxins; D020110:Pinacidil; D024661:Potassium Channels, Inwardly Rectifying; D017382:Reactive Oxygen Species; D000099161:Kcnj11 Channel; C023586:cytochrome C, maleylated; C092520:uK-ATP-1 potassium channel