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(Stroke. 1999;30:1665-1670.)
© 1999 American Heart Association, Inc.

Original Contributions

17ß-Estradiol Reduces Stroke Injury in Estrogen-Deficient Female Animals

Renata Rusa, MD; Nabil J. Alkayed, MD, PhD; Barbara J. Crain, MD, PhD; Richard J. Traystman, PhD; Alane S. Kimes, PhD; Edythe D. London, PhD; Judy A. Klaus, RN Patricia D. Hurn, PhD

From the Department of Anesthesiology and Critical Care Medicine (R.R., N.J.A., R.J.T., J.A.K., P.D.H.) and Department of Pathology (B.J.C.), Johns Hopkins University School of Medicine, and National Institute on Drug Abuse (A.S.K., E.D.L.), Baltimore, Md.

Correspondence to Dr Patricia D. Hurn, Department of Anesthesiology and Critical Care Medicine, Johns Hopkins Medical Institutions, 600 N Wolfe St/Blalock 1404, Baltimore, MD 21287. E-mail: phurn{at}jhmi.edu

Background and Purpose—The importance of postmenopausal estrogen replacement therapy for stroke in females remains controversial. We previously showed that female rats sustain less infarction in reversible middle cerebral artery occlusion (MCAO) than their ovariectomized counterparts and that vascular mechanisms are partly responsible for improved tissue outcomes. Furthermore, exogenous estrogen strongly protects the male brain, even when administered in a single injection before MCAO injection. The present study examined the hypothesis that replacement of 17ß-estradiol to physiological levels improves stroke outcome in ovariectomized, estrogen-deficient female rats, acting through blood flow–mediated mechanisms.

Methods—Age-matched, adult female Wistar rats were ovariectomized and treated with 0, 25, or 100 µg of 17ß-estradiol administered through a subcutaneous implant or with a single Premarin (USP) injection (1 mg/kg) given immediately before ischemia was induced (n=10 per group). Each animal subsequently underwent 2 hours of MCAO by the intraluminal filament technique, followed by 22 hours of reperfusion. Ipsilateral parietal cortex perfusion was monitored by laser-Doppler flowmetry throughout ischemia. Cortical and caudate-putamen infarction volumes were determined by 2,3,5-triphenyltetrazolium chloride staining and digital image analysis. End-ischemic regional cerebral blood flow was measured in ovariectomized females with 0- or 25-µg implants (n=4 per group) by ¹⁴C-iodoantipyrine quantitative autoradiography.

Results—Plasma estradiol levels were 3.0±0.6, 20±8, and 46±10 pg/mL in the 0-, 25-, and 100-µg groups, respectively. Caudate-putamen infarction (% of ipsilateral caudate-putamen) was reduced by long-term, 25-µg estrogen treatment (13±4% versus 31±6% in the 0-µg group, P<0.05, and 22±3% in the 100-µg group). Similarly, cortical infarction (% of ipsilateral cortex) was reduced only in the 25-µg group (3±2% versus 12±3% in the 0-µg group, P<0.05, and 6±3% in the 100-µg group. End-ischemic striatal or cortical blood flow was not altered by estrogen treatment at the neuroprotective dose. Infarction volume was unchanged by acute treatment before MCAO when estrogen-treated animals were compared with saline vehicle–treated animals.

Conclusions—Long-term estradiol replacement within a low physiological range ameliorates ischemic brain injury in previously ovariectomized female rats. The neuroprotective mechanism is flow-independent, not through preservation of residual ischemic regional cerebral blood flow. Furthermore, the therapeutic range is narrow, because the benefit of estrogen in transient vascular occlusion is diminished at larger doses, which yield high, but still physiologically relevant, plasma 17ß-estradiol levels. Lastly, unlike in the male brain, single-injection estrogen exposure does not salvage ischemic tissue in the female brain. Therefore, although exogenous steroid therapy protects both male and female estrogen-deficient brain, the mechanism may not be identical and depends on long-term hormone augmentation in the female.

Editorial Comment

Costantino Iadecola, MD, Guest Editor

Laboratory of Cerebrovascular Biology and Stroke, Department of Neurology, University of Minnesota, Minneapolis, Minnesota

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