title: Diazoxide induces delayed pre-conditioning in cultured rat cortical neurons.
abstract: We investigated the effect of diazoxide on neuronal survival in primary cultures of rat cortical neurons against oxygen-glucose deprivation (OGD). Diazoxide pre-treatment induced delayed pre-conditioning and almost entirely attenuated the OGD-induced neuronal death. Diazoxide inhibited succinate dehydrogenase and induced mitochondrial depolarization, free radical production and protein kinase C activation. The putative mitochondrial ATP-sensitive potassium channel blocker 5-hydroxydecanoate abolished the protective effect of diazoxide while the non-selective KATP channel blocker glibenclamide did not. The non-selective KATP channel openers nicorandil and cromakalim did not improve viability. Superoxide dismutase mimetic, M40401, or protein kinase C inhibitor, chelerythrine, prevented the neuroprotective effect of diazoxide. Diazoxide did not increase reduced glutathione and manganese-superoxide dismutase levels but we found significantly higher reduced glutathione levels in diazoxide-pre-conditioned neurons after OGD. In pre-conditioned neurons free radical production was reduced upon glutamate stimulation. The succinate dehydrogenase inhibitor 3-nitropropionic acid also induced pre-conditioning and free radical production in neurons. Here, we provide the first evidence that diazoxide induces delayed pre-conditioning in neurons via acute generation of superoxide anion and activation of protein kinases and subsequent attenuation of oxidant stress following OGD. The succinate dehydrogenase-inhibiting effect of diazoxide is more likely to be involved in this neuroprotection than the opening of mitochondrial ATP-sensitive potassium channels.
authors: Department of Physiology and Pharmacology, Wake Forest University, Winston-Salem, North Carolina 27157, USA. bkis@wfubmc.edu
authors: Bela
authors: B
authors: Kis
authors: Nishadi C
authors: NC
authors: Rajapakse
authors: James A
authors: JA
authors: Snipes
authors: Krisztina
authors: K
authors: Nagy
authors: Takashi
authors: T
authors: Horiguchi
authors: David W
authors: DW
authors: Busija
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects; D015687:Cell Hypoxia / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D019806:Cromakalim / Q000494:pharmacology; D003652:Decanoic Acids / Q000494:pharmacology; D003981:Diazoxide / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005947:Glucose / Q000172:deficiency / Q000378:metabolism; D005905:Glyburide / Q000494:pharmacology; D006880:Hydroxy Acids / Q000494:pharmacology; D019194:Ischemic Preconditioning / Q000379:methods*; D008928:Mitochondria / Q000187:drug effects; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D018696:Neuroprotective Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology; D020108:Nicorandil / Q000494:pharmacology; D009574:Nitro Compounds; D018384:Oxidative Stress / Q000187:drug effects; D011422:Propionates / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013385:Succinate Dehydrogenase / Q000037:antagonists & inhibitors; D013481:Superoxides / Q000378:metabolism; D013997:Time Factors
chemical_list: D003652:Decanoic Acids; D004791:Enzyme Inhibitors; D006880:Hydroxy Acids; D018696:Neuroprotective Agents; D009574:Nitro Compounds; D011422:Propionates; D019806:Cromakalim; D013481:Superoxides; D020108:Nicorandil; C052853:5-hydroxydecanoic acid; D013385:Succinate Dehydrogenase; D005947:Glucose; D003981:Diazoxide; C015392:3-nitropropionic acid; D005905:Glyburide