Estradiol modulates bcl-2 in cerebral ischemia: A potential role for estrogen receptors

We have shown that physiological levels of estradiol exert profound protect ive effects on the cerebral cortex in ischemia induced by permanent middle cerebral artery occlusion. The major goal of this study was to begin to elu cidate potential mechanisms of estradiol action in injury. Bcl-2 is a proto oncogene that promotes cell survival in a variety of tissues including the brain. Because estradiol is known to promote cell survival via Bcl-2 in non -neural tissues, we tested the hypothesis that estradiol decreases cell dea th by influencing bcl-2 expression in ischemic brain injury. Furthermore, b ecause estradiol may protect the brain through estrogen receptor-mediated m echanisms, we examined expression of both receptor subtypes ER alpha and ER beta in the normal and injured brain. We analyzed gene expression by RT-PC R in microdissected regions of the cerebral cortex obtained from injured an d sham female rats treated with estradiol or oil. We found that estradiol p revented the injury-induced downregulation of bcl-2 expression. This effect was specific to bcl-2, as expression of other members of the bcl-2 family (bax, bcl-x(L), bcl-x(S), and bad) was unaffected by estradiol treatment. W e also found that estrogen receptors were differentially modulated in injur y, with ER beta expression paralleling bcl-2 expression. Finally, we provid e the first evidence of functional ER beta protein that is capable of bindi ng ligand within the region of the cortex where estradiol-mediated neuropro tection was observed in cerebral ischemia. These findings indicate that est radiol modulates the expression of bcl-2 in ischemic injury. Furthermore, o ur data suggest that estrogen receptors may be involved in hormone-mediated neuroprotection.