Diazoxide pretreatment induces delayed preconditioning in astrocytes against oxygen glucose deprivation and hydrogen peroxide-induced toxicity

Nishadi Rajapakse, Bela Kis, Takashi Horiguchi, James Snipes, David Busija

研究成果: Article査読

45 被引用数 (Scopus)

抄録

Recent studies suggest that activation of mitochondrial ATP-sensitive potassium channels (mKATP) with diazoxide can protect neurons against ischemic stress. However, it is not yet known whether astrocytes, which are more resilient against ischemia, respond similarly to diazoxide. We exposed cultured astrocytes to oxygen-glucose deprivation (OGD) or hydrogen peroxide (H2O2) with or without pretreatment with the mKATP opener diazoxide. Marked decreases in astrocyte viability were evident after 9 and 12 hr of OGD [76% ± 3% (n = 50) and 60% ± 1% (n = 50)] and 400 and 600 μM H2O2 [40% ± 2% (n = 16) and 25% ± 2% (n = 16)], respectively, compared with no treatment (100% ± 1%). Diazoxide treatment (3 days of sequential application) dramatically reversed the negative effects of OGD and H2O2, resulting in complete blockade of astrocyte cell death. Effects of diazoxide were blocked by the mKATP blocker 5-hydroxydecanoic acid (5-HD). Furthermore, incubation of astrocytes with diazoxide resulted in loss of mitochondrial membrane potential monitored by tetramethylrhodamineethylester fluorescence. Additionally, generation of reactive oxygen species was observed in response to diazoxide, assessed using the oxidation-sensitive dye hydroethidine, and this effect was abolished by antioxidants, catalase, and a superoxide dismutase mimetic, M40401. Finally, diazoxide increased the protein level of phosphorylated protein kinase C (PKC) revealed by immunoblot analysis. Our findings demonstrate that opening of mKATP by diazoxide identifies a delayed preconditioning effect that is protective against two types of injury in astrocytes and that diazoxide may deliver protection via mitochondrial depolarization, free radical production, and PKC activation.

本文言語English
ページ(範囲)206-214
ページ数9
ジャーナルJournal of neuroscience research
73
2
DOI
出版ステータスPublished - 2003 7 15
外部発表はい

ASJC Scopus subject areas

  • 細胞および分子神経科学

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