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This version published online on March 9, 2006
Endocrinology, doi:10.1210/en.2005-1177
A more recent version of this article appeared on June 1, 2006
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*Compound via MeSH
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*ESTRADIOL

Submitted on September 14, 2005
Accepted on February 23, 2006

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

Dena B. Dubal, Shane W. Rau, Paul J. Shughrue, Hong Zhu, Jin Yu, Adrienne B. Cashion, Shotaro Suzuki, Lynnette M. Gerhold, Martina B. Bottner, Sam B. Dubal, Istvan Merchanthaler, Mark S. Kindy, and Phyllis M. Wise*

Department of Physiology, University of Kentucky College of Medicine, Lexington, KY 40536; Department of Neurology, University of California at San Francisco, San Francisco CA 94143; Department of Psychiatric Medicine, University of Virginia Health System, Charlottesville, VA 22908; Department of Pharmacology, Merck Research Labs, West Point PA 19486; Department of Physiology and Neuroscience, Medical College of South Carolina, Charleston SC 29425; WHRI, Wyeth Research, Collegeville PA 19426; Department of Neurobiology, Physiology and Behavior, Division of Biological Sciences, University of California Davis, Davis CA 95616; Department of Clinical and Experimental Endocrinology, University of Gottingen, 37075 Gottingen, Germany; Department of Physiology and Biophysics, University of Washington, Seattle WA 98195

* To whom correspondence should be addressed. 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. Since estradiol is known to influence apoptosis, we hypothesized that it acts to decrease the delayed phase cell death observed after middle cerebral artery occlusion (MCAO). Furthermore, since ERs are pivotal to neuroprotection, we examined the temporal expression profiles of both estrogen receptor subtypes, ER{alpha} and ER{beta}, following 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 following MCAO are limited to attenuation of delayed cell death and do not influence immediate cell death. Further, we discovered that ERs exhibit distinctly divergent profiles of expression over the evolution of injury, with ER{alpha} induction occurring early and ER{beta} modulation occurring later. Finally, we provide evidence for a new and functional role for ER{alpha} in estradiol-mediated protection of the injured brain. These findings indicate that physiological levels of estradiol protect against delayed cell death following stroke-like injury through mechanisms requiring ER{alpha}.
Key words: estrogen • estradiol • stroke • ischemia • neuroprotection • apoptosis




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