17β-Estradiol Reduces Stroke Injury in Estrogen-Deficient Female Animals
- 1 August 1999
- journal article
- research article
- Published by Ovid Technologies (Wolters Kluwer Health) in Stroke
- Vol. 30 (8), 1665-1670
- https://doi.org/10.1161/01.str.30.8.1665
Abstract
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 17β-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 17β-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 14 C-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 P 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 17β-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.Keywords
This publication has 28 references indexed in Scilit:
- Cerebral vasodilating capacity during forebrain ischemiaNeuroReport, 1998
- Differential effects of low- and high-dose estrogen treatments on vascular responses in female ratsLife Sciences, 1997
- ERβ: Identification and characterization of a novel human estrogen receptorFEBS Letters, 1996
- Postischemic Cerebral Blood Flow Recovery in the Female: Effect of 17β-EstradiolJournal of Cerebral Blood Flow & Metabolism, 1995
- Steroid Hormone Actions on the Brain: When Is the Genome Involved?Hormones and Behavior, 1994
- Estrogen and the blood vessel wallCurrent Opinion in Cardiology, 1994
- Distribution of androgen and estrogen receptor mRNA‐containing cells in the rat brain: An in situ hybridization studyJournal of Comparative Neurology, 1990
- Postmenopausal oestrogen treatment and stroke: a prospective study.BMJ, 1988
- Postmenopausal Estrogen Use, Cigarette Smoking, and Cardiovascular Morbidity in Women over 50New England Journal of Medicine, 1985
- Estradiol-Concentrating Neurons: Topography in the Hypothalamus by Dry-Mount AutoradiographyScience, 1968