Estradiol modulates bcl-2 in cerebral ischemia: A potential role for estrogen receptors

Dena B. Dubal, Paul J. Shughrue, Melinda E. Wilson, Istvan Merchenthaler, Phyllis M. Wise

Research output: Contribution to journalArticlepeer-review

439 Scopus citations

Abstract

We have shown that physiological levels of estradiol exert profound protective effects on the cerebral cortex in ischemia induced by permanent middle-cerebral artery occlusion. The major goal of this study was to begin to elucidate potential mechanisms of estradiol action in injury. Bcl-2 is a proto-oncogene that promotes cell survival in a variety of tissues including the brain. Because estradiol is known to promote cell survival via Bcl-2 in non-neural tissues, we tested the hypothesis that estradiol decreases cell death by influencing bcl-2 expression in ischemic brain injury. Furthermore, because estradiol may protect the brain through estrogen receptor-mediated mechanisms, we examined expression of both receptor subtypes ERα and ERβ in the normal and injured brain. We analyzed gene expression by RT-PCR in microdissected regions of the cerebral Cortex obtained from injured and sham female rats treated with estradiol or oil. We found that estradiol prevented the injury-induced downregulation of bcl-2 expression. This effect was specific to bcl-2, as expression of other members of the bcl-2 family (bax, bcl-x(L), bcl-x(S), and bad) was unaffected by estradiol treatment. We also found that estrogen receptors were differentially modulated in injury, with ERβ expression paralleling bcl-2 expression. Finally, we provide the first evidence of functional ERβ protein that is capable of binding ligand within the region of the cortex where estradiol-mediated neuroprotection was observed in cerebral ischemia. These findings indicate that estradiol modulates the expression of bcl-2 in ischemic injury. Furthermore, our data suggest that estrogen receptors may be involved in hormone-mediated neuroprotection.

Original languageEnglish
Pages (from-to)6385-6393
Number of pages9
JournalJournal of Neuroscience
Volume19
Issue number15
DOIs
StatePublished - Aug 1 1999

Keywords

  • Cerebral ischemia
  • ERα
  • ERβ
  • Estradiol
  • Estrogen
  • Estrogen receptors
  • In situ hybridization
  • Menopause
  • Neuroprotection
  • RT-PCR
  • Receptor binding
  • Stroke
  • bcl-2
  • bcl-2 family

ASJC Scopus subject areas

  • General Neuroscience

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