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Estrogen receptor alpha, not beta, is a critical link in estradiol-mediated protection against brain injury.

Abstract
Estradiol protects against brain injury, neurodegeneration, and cognitive decline. Our previous work demonstrates that physiological levels of estradiol protect against stroke injury and that this protection may be mediated through receptor-dependent alterations of gene expression. In this report, we tested the hypothesis that estrogen receptors play a pivotal role in mediating neuroprotective actions of estradiol and dissected the potential biological roles of each estrogen receptor (ER) subtype, ER alpha and ER beta, in the injured brain. To investigate and delineate these mechanisms, we used ER alpha-knockout (ER alpha KO) and ER beta-knockout (ER beta KO) mice in an animal model of stroke. We performed our studies by using a controlled endocrine paradigm, because endogenous levels of estradiol differ dramatically among ER alpha KO, ER beta KO, and wild-type mice. We ovariectomized ER alpha KO, ER beta KO, and the respective wild-type mice and implanted them with capsules filled with oil (vehicle) or a dose of 17 beta-estradiol that produces physiological hormone levels in serum. One week later, mice underwent ischemia. Our results demonstrate that deletion of ER alpha completely abolishes the protective actions of estradiol in all regions of the brain; whereas the ability of estradiol to protect against brain injury is totally preserved in the absence of ER beta. Thus, our results clearly establish that the ER alpha subtype is a critical mechanistic link in mediating the protective effects of physiological levels of estradiol in brain injury. Our discovery that ER alpha mediates protection of the brain carries far-reaching implications for the selective targeting of ERs in the treatment and prevention of neural dysfunction associated with normal aging or brain injury.
AuthorsD B Dubal, H Zhu, J Yu, S W Rau, P J Shughrue, I Merchenthaler, M S Kindy, P M Wise
JournalProceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 98 Issue 4 Pg. 1952-7 (Feb 13 2001) ISSN: 0027-8424 [Print] United States
PMID11172057 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Estrogen Receptor alpha
  • Estrogen Receptor beta
  • Receptors, Estrogen
  • Estradiol
Topics
  • Animals
  • Brain (blood supply, pathology)
  • Brain Injuries (pathology, prevention & control)
  • Brain Ischemia (pathology, prevention & control)
  • Cerebral Infarction (pathology, prevention & control)
  • Cerebrovascular Circulation
  • Estradiol (blood, physiology)
  • Estrogen Receptor alpha
  • Estrogen Receptor beta
  • Female
  • Hormone Replacement Therapy
  • Mice
  • Mice, Inbred C57BL
  • Receptors, Estrogen (physiology)
  • Stroke (pathology, prevention & control)

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