Estradiol prevents the injury-induced decrease of Akt/glycogen synthase kinase 3β phosphorylation

Estradiol prevents neuronal cell death through the activation of cell survival signals and the inhibition of apoptotic signals. This study investigated whether estradiol modulates the anti-apoptotic signal through the phosphorylation of Akt and its downstream target, glycogen synthase kinase 3β (GSK3β). Adult female rats were ovariectomized and treated with estradiol prior to middle cerebral artery occlusion (MCAO). Brains were collected 24 h after MCAO and infarct volumes were analyzed. Estradiol administration significantly reduced infarct volume and decreased the positive cells of TUNEL staining in the cerebral cortex. Potential activation was measured by phosphorylation of Akt at Ser473 and GSK3β at Ser9 using Western blot analysis and immunohistochemistry. Estradiol prevented the injury-induced decrease of pAkt and pGSK3β. Furthermore, pretreatment with estradiol decreased glutamate toxicity-induced cell death in a hippocampal cell line (HT22). Also, estradiol prevented the glutamate toxicity-induced decrease of pAkt and pGSK3β in HT22 cells. Our findings suggest that estradiol plays a potent protective role against brain injury and that phosphorylation of Akt and GSK3β by estradiol mediated these protective effects.