Estradiol is a protective factor in the adult and aging brain: Understanding of mechanisms derived from in vivo and in vitro studies

Phyllis M. Wise, Dena B. Dubal, Melinda E. Wilson, Shane W. Rau, Martina Böttner, Katherine L. Rosewell

Research output: Contribution to journalReview articlepeer-review

203 Scopus citations


We have shown that 17β-estradiol exerts profound protective effects against stroke-like ischemic injury in female rats. These effects are evident using physiological levels of estradiol replacement in ovariectomized rats and require hormone treatment prior to the time of injury. The protective actions of estradiol appear to be most prominent in the cerebral cortex, where cell death is not apparent until at least 4 h after the initiation of ischemic injury and where cell death is thought to be apoptotic in nature. Middle-aged rats remain equally responsive to the protective actions of estradiol. The maintenance of responsiveness of the cerebral cortex to the neuroprotective actions of estradiol was unexpected since responsiveness of the hypothalamus to estradiol decreases dramatically by the time animals are middle-aged. We believe that the protective actions of estradiol require the estrogen receptor-α, since estradiol does not protect in estrogen receptor-α knockout mice. We have also implemented a method of culturing cerebral cortical explants to assess the protective effects of estradiol in vitro. This model exhibits remarkable parallelisms with our in vivo model of brain injury. We have found that 17β-estradiol decreases the extent of cell death and that this protective effect requires hormone pretreatment. Finally, 17α-estradiol, which does not interact effectively with the estrogen receptor, does not protect; and addition of ICI 182,780, an estrogen receptor antagonist, blocks the protective actions of estradiol. We have begun to explore the molecular and cellular mechanisms of estradiol-mediated protection. In summary, our findings demonstrate that estradiol exerts powerful protective effects both in vivo and in vitro and suggest that these actions are mediated by estrogen receptors.

Original languageEnglish
Pages (from-to)313-319
Number of pages7
JournalBrain Research Reviews
Issue number1-3
StatePublished - 2001

Bibliographical note

Funding Information:
Supported by NIH AG02224 and AG17164 (PMW), AG05818 (MEW), Glenn Foundation/American Federation for Aging Research Scholarship (DBD). DBD and SWR are predoctoral trainees on NIH Training Grant AG00242 (PMW).


  • Cell death
  • Estradiol
  • In vitro
  • In vivo
  • Ischemia
  • Neuroprotection

ASJC Scopus subject areas

  • General Neuroscience
  • Clinical Neurology


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