Journal
BRAIN RESEARCH
Volume 1321, Issue -, Pages 1-12Publisher
ELSEVIER
DOI: 10.1016/j.brainres.2010.01.046
Keywords
Estradiol; PI3K/Akt/signaling; Neuronal death; Apoptosis; Global ischemia
Categories
Funding
- NIH [NS045693]
- American Heart Association Development [0335285N]
- ISCIII RETICS-RENEVAS [RD06/0026/0006]
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Global ischemia arising during cardiac arrest or cardiac surgery causes highly selective, delayed death of hippocampal CA1 neurons. Exogenous estradiol ameliorates global ischemia-induced neuronal death and cognitive impairment in male and female rodents. However, the molecular mechanisms by which a single acute injection of estradiol administered after the ischemic event intervenes in global ischemia-induced apoptotic cell death are unclear. Here we show that acute estradiol acts via the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling cascade to protect CA1 neurons in ovariectomized female rats. We demonstrate that global ischemia promotes early activation of glycogen synthase kinase-3 beta (GSK3 beta) and forkhead transcription factor of the O class (FOXO)3A, known Akt targets that are related to cell survival, and activation of caspase-3. Estradiol prevents ischemia-induced dephosphorylation and activation of GSK3 beta and FOXO3A, and the caspase death cascade. These findings support a model whereby estradiol acts by activation of PI3K/Akt signaling to promote neuronal survival in the face of global ischemia. (C) 2010 Elsevier B.V. All rights reserved.
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