Timing of estrogen therapy after ovariectomy dictates the efficacy of its neuroprotective and antiinflammatory actions

Departments of *Physiology and Biophysics and
^‡Biology, University of Washington, Seattle, WA 98195; and
^†Department of Neurobiology, Physiology, and Behavior, University of California, Davis, CA 95616

Edited by Bruce S. McEwen, The Rockefeller University, New York, NY, and approved February 17, 2007 (received for review November 22, 2006)

Abstract

Recent studies describing the seemingly contradictory actions of estrogens in ischemic stroke injury have led us to reevaluate the circumstances under which estrogen therapy (ET) provides benefits against cerebral stroke and decipher its mechanisms of action. One prominent feature that follows stroke injury is massive central and peripheral inflammatory responses. Evidence now suggests that postischemic inflammatory responses strongly contribute to the extent of brain injury, and 17β-estradiol (E₂) may protect the ischemic brain by exerting antiinflammatory actions. In an attempt to explain recently reported dichotomous effects of E₂ in stroke injury, we tested the hypothesis that an extended period of hypoestrogenicity both prevents E₂ from protecting the brain against ischemia and simultaneously suppresses its antiinflammatory actions. We report that E₂ exerts profound neuroprotective action when administered immediately upon ovariectomy, but not when administered after 10 weeks of hypoestrogenicity. Consistently, E₂ treatment given immediately at the time of ovariectomy attenuated central and peripheral production of proinflammatory cytokines after ischemic stroke. In contrast, E₂ did not suppress production of proinflammatory molecules when it was administered after 10 weeks postovariectomy. These results demonstrate that a prolonged period of hypoestrogenicity disrupts both neuroprotective and antiinflammatory actions of E₂. Our findings may help to explain the results of the Women's Health initiative that reported no beneficial effect of ET against stroke because the majority of the subjects initiated ET after an extended period of hypoestrogenicity.

Footnotes

^§To whom correspondence should be addressed. E-mail: pmwise{at}u.washington.edu
Author contributions: S.S. and P.M.W. designed research; S.S. and C.M.B. performed research; C.D.D. and E.Y. contributed new reagents/analytic tools; S.S., C.M.B., C.D.D., E.Y., and D.A.B. analyzed data; and S.S. and P.M.W. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/cgi/content/full/0610394104/DC1.
Abbreviations:

CSF,

cerebrospinal fluid;

E2,

17β-estradiol;

ERα,

estrogen receptor alpha;

ET,

estrogen therapy;

MCAO,

middle cerebral artery occlusion;

TTC,

2,3,5-triphenyltetrazolium chloride;

WEST,

Women Estrogen Stroke Trial;

WHI,

Women's Health initiative.