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The Journal of Neuroscience, August 1, 1999, 19(15):6385-6393

Estradiol Modulates bcl-2 in Cerebral Ischemia: A Potential Role for Estrogen Receptors

Dena B. Dubal¹, Paul J. Shughrue², Melinda E. Wilson¹, Istvan Merchenthaler², and Phyllis M. Wise¹

¹ Department of Physiology, College of Medicine, University of Kentucky, Lexington, Kentucky 40536, and ² The Women's Health Research Institute, Wyeth-Ayerst Research, Radnor, Pennsylvania 19087

We have shown that physiological levels of estradiol exert profound protective effects on the cerebral cortex in ischemia induced by permanent middle cerebral artery occlusion. The major goal of this study was to begin to elucidate 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 death by influencing bcl-2 expression in ischemic brain injury. Furthermore, because estradiol may protect the brain through estrogen receptor-mediated mechanisms, we examined expression of both receptor subtypes ER and ER in the normal and injured brain. We analyzed gene expression by RT-PCR in microdissected regions of the cerebral cortex obtained from injured and sham female rats treated with estradiol or oil. We found that estradiol prevented 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. We also found that estrogen receptors were differentially modulated in injury, with ER expression paralleling bcl-2 expression. Finally, we provide the first evidence of functional ER protein that is capable of binding ligand within the region of the cortex where estradiol-mediated neuroprotection was observed in cerebral ischemia. These findings indicate that estradiol modulates the expression of bcl-2 in ischemic injury. Furthermore, our data suggest that estrogen receptors may be involved in hormone-mediated neuroprotection.

Key words: estradiol; estrogen; neuroprotection; cerebral ischemia; stroke; menopause; bcl-2; bcl-2 family; estrogen receptors; ER; ER; receptor binding; RT-PCR; in situ hybridization

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Copyright © 1999 Society for Neuroscience  0270-6474/99/19156385-09$05.00/0

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