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Differential Modulation of Estrogen Receptors (ERs) in Ischemic Brain Injury: A Role for ER in Estradiol-Mediated Protection against Delayed Cell Death

Department of Physiology (D.B.D., S.W.R., M.B.B., S.B.D., P.M.W.), University of Kentucky College of Medicine, Lexington, Kentucky 40536; Department of Neurology (D.B.D.), University of California at San Francisco, San Francisco, California 94143; Department of Psychiatric Medicine (S.W.R.), University of Virginia Health System, Charlottesville, Virginia 22908; Department of Pharmacology (P.J.S.), Merck Research Laboratories, West Point, Pennsylvania 19486; Department of Physiology and Neuroscience (H.Z., J.Y., M.S.K.), Medical College of South Carolina, Charleston, South Carolina 29425; WHRI (P.J.S., I.M.), Wyeth Research, Collegeville, Pennsylvania 19426; Department of Neurobiology, Physiology, and Behavior (A.B.C., S.S., L.M.G., M.B.B., P.M.W.), Division of Biological Sciences, University of California, Davis, Davis, California 95616; Department of Clinical and Experimental Endocrinology (M.B.B.), University of Gottingen, 37075 Gottingen, Germany; and Department of Physiology and Biophysics (P.M.W.), University of Washington, Seattle, Washington 98195

Address all correspondence and requests for reprints to: Phyllis M. Wise, Ph.D., University of Washington, 301 Gerberding Hall, Box 351237, Seattle, Washington 98195-1237. E-mail: pmwise{at}u.washington.edu.

Estradiol enhances plasticity and survival of the injured brain. Our previous work demonstrates that physiological levels of estradiol protect against cerebral ischemia in the young and aging brain through actions involving estrogen receptors (ERs) and alterations in gene expression. The major goal of this study was to establish mechanisms of neuroprotective actions induced by low levels of estradiol. We first examined effects of estradiol on the time-dependent evolution of ischemic brain injury. Because estradiol is known to influence apoptosis, we hypothesized that it acts to decrease the delayed phase of cell death observed after middle cerebral artery occlusion (MCAO). Furthermore, because ERs are pivotal to neuroprotection, we examined the temporal expression profiles of both ER subtypes, ER and ERß, after MCAO and delineated potential roles for each receptor in estradiol-mediated neuroprotection. We quantified cell death in brains at various times after MCAO and analyzed ER expression by RT-PCR, in situ hybridization, and immunohistochemistry. We found that during the first 24 h, the mechanisms of estradiol-induced neuroprotection after MCAO are limited to attenuation of delayed cell death and do not influence immediate cell death. Furthermore, we discovered that ERs exhibit distinctly divergent profiles of expression over the evolution of injury, with ER induction occurring early and ERß modulation occurring later. Finally, we provide evidence for a new and functional role for ER in estradiol-mediated protection of the injured brain. These findings indicate that physiological levels of estradiol protect against delayed cell death after stroke-like injury through mechanisms requiring ER.

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