title: Estrogen receptors and ischemic neuroprotection: who, what, where, and when?
abstract: Estrogens, particularly 17β-estradiol (E2), are powerful neuroprotective agents in animal models of cerebral ischemia. Loss of endogenous E2 in women at menopause or after surgical oopherectomy leads to an increase risk of stroke, neurodegenerative disease, and cognitive decline. However, several clinical trials found detrimental effects of E2 therapy after menopause, including increased stroke risk and dementia. Recent animal and human studies now support the "critical period" hypothesis for E2 neuroprotection whereby E2 therapy must begin soon after the loss of endogenous E2 production to have a beneficial effect. Although a wide array of mechanisms has been proposed for estradiol (E2)-dependent neuroprotection in cerebral ischemia and neurodegenerative disease, most of these mechanisms involve interactions of E2 with one of its cognate receptors, estrogen receptor alpha (ERα), estrogen receptor beta (ERβ), or the G protein-coupled estrogen receptor (GPER). However, these receptors are not uniformly distributed throughout the brain, across different cell types, and within cellular compartments. Such differences likely play a role in the ability of E2 and ER selective ligands to protect the brain from ischemia. This review examines the changes in ER expression and location that may underlie the loss of E2 neuroprotection seen with aging and long-term estrogen deprivation (LTED). Recent results suggest that the loss of ERα that accompanies aging and LTED plays an important role in the loss of E2-dependent neuroprotection. This article is part of a Special Issue entitled Hormone Therapy.
authors.affiliation: Department of Pharmacology and Neuroscience, Institute for Aging and Alzheimer's Disease Research, University of North Texas Health Science Center at Fort Worth, 3500 Camp Bowie Boulevard, Fort Worth, TX 76107, USA. derek.schreihofer@unthsc.edu
authors.forename: Derek A
authors.initials: DA
authors.lastname: Schreihofer
authors.forename: Yulin
authors.initials: Y
authors.lastname: Ma
mesh_terms: D000375:Aging / Q000187:drug effects; D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy*; D005260:Female; D006728:Hormones / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008593:Menopause / Q000187:drug effects; D058632:Neuroprostanes / Q000627:therapeutic use*; D011960:Receptors, Estrogen / Q000378:metabolism*
chemical_list: D006728:Hormones; D058632:Neuroprostanes; D011960:Receptors, Estrogen