Diazoxide induces delayed pre-conditioning in cultured rat cortical neurons

Bela Kis, Nishadi C. Rajapakse, James A. Snipes, Krisztina Nagy, Takashi Horiguchi, David W. Busija

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119 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)969-980
Number of pages12
JournalJournal of Neurochemistry
Volume87
Issue number4
DOIs
Publication statusPublished - 2003 Nov
Externally publishedYes

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Keywords

  • Diazoxide
  • Free radicals
  • Mitochondrial ATP-sensitive potassium channels
  • Neurons
  • Pre-conditioning
  • Succinate dehydrogenase

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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