Nicorandil prevents oxidative stress-induced apoptosis in neurons by activating mitochondrial ATP-sensitive potassium channels.
Nicorandil, a clinically useful drug for the treatment of ischemic heart disease, has an anti-apoptotic effect in cardiomyocytes, and activation of mitochondrial ATP-sensitive potassium (mitoKATP) channels underlies this effect. Recently, several studies showed that nicorandil reduced brain injury in animal models of brain ischemia. Based on these facts, we hypothesized that nicorandil may have anti-apoptotic effects in neurons mediated by mitoKATP channels. We investigated the effect of nicorandil on apoptosis induced by oxidative stress using cultured cerebellar granule neurons. Nicorandil (100 micromol/l) significantly suppressed the number of cells with TUNEL-positive nuclei and the increase in caspase-3 activity induced by 20 micromol/l H2O2. An indicator dye for mitochondrial inner membrane potential (DeltaPsim) revealed that nicorandil prevented the loss of DeltaPsim induced by H2O2 in a concentration-dependent manner. These effects were abolished by 5-hydroxydecanoate (5HD; 500 micromol/l), a mitoKATP channel blocker. The present results showed that nicorandil has anti-apoptotic effects in neurons, at least in part, by preserving DeltaPsim.
Institute of Molecular Cardiobiology, The Johns Hopkins University, Baltimore, MD 21205, USA.
Yasushi
Y
Teshima
Masaharu
M
Akao
William A
WA
Baumgartner
Eduardo
E
Marbán
D018528:ATP-Binding Cassette Transporters; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology / Q000187:drug effects; D003652:Decanoic Acids / Q000494:pharmacology; D005434:Flow Cytometry; D006880:Hydroxy Acids / Q000494:pharmacology; D020287:In Situ Nick-End Labeling; D054086:KATP Channels; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects*; D020108:Nicorandil / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D015221:Potassium Channels / Q000819:agonists*; D024661:Potassium Channels, Inwardly Rectifying; D051381:Rats; D017207:Rats, Sprague-Dawley
D018528:ATP-Binding Cassette Transporters; D000889:Anti-Arrhythmia Agents; D003652:Decanoic Acids; D006880:Hydroxy Acids; D054086:KATP Channels; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; C092520:uK-ATP-1 potassium channel; D020108:Nicorandil; C052853:5-hydroxydecanoic acid; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases