4.3 Article

17 β-estradiol prevents focal cerebral ischemic damages via activation of Akt and CREB in association with reduced PTEN phosphorylation in rats

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FUNDAMENTAL & CLINICAL PHARMACOLOGY
卷 18, 期 5, 页码 547-557

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WILEY
DOI: 10.1111/j.1472-8206.2004.00284.x

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apoptosis; Bax; Bcl-2; cytochrome c; 17 beta-estradiol; ischemic brain damage; middle cerebral artery occlusion

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This study aimed to assess the signaling pathway of the neuroprotective action of estrogen in the cerebral ischemic injury evoked by subjecting rats to 2-h occlusion of the middle cerebral artery (MCA) followed by 24-h reperfusion. Rats received beta-estradiol (1, 4 and 10 mg/kg, i.p.) 24 h before and 5 min after the completion of 2-h MCA occlusion. The cerebral infarct area was consistently observed in the cortex and striatum of the left hemisphere. Increased terminal deoxynucleotidyl transferase-mediated deoxyuridine-biotin nick-end labeling (TUNEL)-positive cells and DNA fragmentation in the penumbral zone were significantly reduced by 17 beta-estradiol. In line with these results, 17 beta-estradiol significantly increased Akt and cyclic AMP response element binding protein (CREB) with increased Bcl-2 protein in the ischemic area, whereas the elevated the phosphatase and tensin homolog deleted from chromosome10 (PTEN) phosphorylation was significantly reduced with decreased Bax protein and cytochrome c release. Inhibition of DNA fragmentation, PTEN phosphorylation, and Akt activation by 17 beta-estradiol were antagonized by iberiotoxin, a maxi-K channel blocker. Taken together, it is suggested that suppression of cerebral ischemic injury by 17 beta-estradiol may be ascribed to the maxi-K channel opening-coupled downregulation of PTEN phosphorylation and upregulation of Akt and CREB phosphorylation with resultant increase in Bcl-2 protein and decrease in Bax protein and cytochrome c release.

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