期刊
JOURNAL OF NEUROCHEMISTRY
卷 134, 期 5, 页码 845-856出版社
WILEY
DOI: 10.1111/jnc.13181
关键词
diazoxide preconditioning; ischemic stroke; mTOR pathway; oxygen glucose deprivation; rapamycin; S6 Kinase
资金
- National Institutes of Health [HL-077731, HL093554]
- Louisiana Board of Regents Support Fund-Research Competitiveness Subprogram [LEQSF(2014-17)-RD-A-11]
- American Heart Association National Center NRCP Scientist Development Grant [14SDG20490359]
- American Heart Association Post-Doctoral Fellowship Grant [15POST23040005]
- Louisiana Board of Regents Endowed Chairs for Eminent Scholars program
We examined the role of the mechanistic target of rapamycin (mTOR) pathway in delayed diazoxide (DZ)-induced preconditioning of cultured rat primary cortical neurons. Neurons were treated for 3days with 500M DZ or feeding medium and then exposed to 3h of continuous normoxia in Dulbecco's modified eagle medium with glucose or with 3h of oxygen-glucose deprivation (OGD) followed by normoxia and feeding medium. The OGD decreased viability by 50%, depolarized mitochondria, and reduced mitochondrial respiration, whereas DZ treatment improved viability and mitochondrial respiration, and suppressed reactive oxygen species production, but did not restore mitochondrial membrane potential after OGD. Neuroprotection by DZ was associated with increased phosphorylation of protein kinase B (Akt), mTOR, and the major mTOR downstream substrate, S6 Kinase (S6K). The mTOR inhibitors rapamycin and Torin-1, as well as S6K-targeted siRNA abolished the protective effects of DZ. The effects of DZ on mitochondrial membrane potential and reactive oxygen species production were not affected by rapamycin. Preconditioning with DZ also changed mitochondrial and non-mitochondrial oxygen consumption rates. We conclude that in addition to reducing reactive oxygen species (ROS) production and mitochondrial membrane depolarization, DZ protects against OGD by activation of the Akt-mTOR-S6K pathway and by changes in mitochondrial respiration.
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