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The Journal of Neuroscience, October 1, 2001, 21(19):7543-7550
Estrogen and Bcl-2: Gene Induction and Effect of Transgene in Experimental Stroke
Nabil J. Alkayed1, Shozo Goto1, Nubuo Sugo1, Hung-Dong Joh1, Judith Klaus1, Barbara J. Crain2, Ora Bernard3, Richard J. Traystman1, and Patricia D. Hurn1 Departments of 1 Anesthesiology and Critical Care Medicine and 2 Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, and 3 Molecular Neurobiology Laboratory, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia 3050
Female rodents producing endogenous estrogens are protected from stroke damage in comparison with male counterparts. This natural protection is lost after ovariectomy or reproductive senescence. The aim of this study is to determine whether estrogen reduces early neuronal injury and cell loss after ischemia by increasing the expression of Bcl-2. Male, intact female, ovariectomized, and estrogen-repleted ovariectomized rats were subjected to middle cerebral artery occlusion, and 22 hr later the level and localization of Bcl-2 mRNA and protein were determined. The levels of post-ischemic bcl-2 mRNA and protein were increased exclusively in neurons within the peri-infarct region. Intact females and estrogen-treated castrates demonstrated increased bcl-2 mRNA and protein expression compared with males and estrogen-deficient females, accompanied by a decrease in infarct size. To test the hypothesis that the neuroprotective mechanism of estrogen functions via Bcl-2, we compared ischemic outcome in male, female, and ovariectomized wild-type mice and mice overexpressing Bcl-2 exclusively in neurons. Wild-type female mice sustained smaller infarcts compared with males. Bcl-2 overexpression reduced infarct size in males, but provided no added protection in the female. Moreover, ovariectomy exacerbated infarction in wild-type females, but had no effect in Bcl-2 overexpressors. These data indicate that overexpression of Bcl-2 simulates the protection against ischemic injury conferred by endogenous female sex steroids. We concluded that estrogen rescues neurons after focal cerebral ischemia by increasing the level of Bcl-2 in peri-infarct regions and that estrogen-induced bcl-2 gene expression is an important downstream component of neuronal protection in female stroke.
Key words: estrogen; stroke; cerebral ischemia; bcl-2; neuroprotection; neuronal cell death; male; female; sex; gender differences
Copyright © 2001 Society for Neuroscience 0270-6474/01/21197543-08$05.00/0
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