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␣ and ER␤, in the injured brain. To investigate and delineate these mechanisms, we used ER␣-knockout (ER␣KO) and ER␤-knockout (ER␤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␣KO, ER␤KO, and wild-type mice. We ovariectomized ER␣KO, ER␤KO, and the respective wild-type mice and implanted them with capsules filled with oil (vehicle) or a dose of 17␤-estradiol that produces physiological hormone levels in serum. One week later, mice underwent ischemia. Our results demonstrate that deletion of ER␣ 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␤. Thus, our results clearly establish that the ER␣ subtype is a critical mechanistic link in mediating the protective effects of physiological levels of estradiol in brain injury. Our discovery that ER␣ 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. Menopause marks the end of female reproduction and is accompanied by a dramatic and permanent decrease in estrogen levels. Although the life span of women has increased significantly in the past century, the average age of menopause has remained constant. Consequently, women may now spend more than one-third of their lives in a chronic hypoestrogenic postmenopausal state. Because estradiol is an important trophic and protective factor in the adult brain (1, 2), hypoestrogenic postmenopausal women may be more vulnerable to brain injury and dysfunction caused by neurodegenerative conditions and cognitive decline. It is, therefore, crucial that we gain a complete understanding of the mechanisms underlying the neuroprotective actions of estradiol.A growing body of evidence has begun to reveal that estrogen replacement therapy may ameliorate neural dysfunctions resulting from Alzheimer's disease (3-5) and stroke (6, 7) through multiple and complex cellular and molecular mechanisms of action. The protective role of estrogen in brain function has been examined by using a variety of in vivo and in vitro models of brain injury that mimic neurotoxic environments found in Alzheimer's disease, stroke, and other neurodegenerative conditions (8-13). These studies demonstrate that physiological and pharmacological concentrations of...

Estrogen Enhances Neurogenesis and Behavioral Recovery after Stroke

“…Previous studies have shown no physiological differences between groups (Dubal et al, 2001;McCullough et al, , 2005. At either 14 or 42 days of reperfusion, the brain was harvested for histological examination.…”

“…Female ERKO and BERKO mice, back crossed onto a C57BL/6J genetic background (Dubal et al, 2001;reviewed in Hewitt et al (2005)) and aromatase-deficient (ArKO on SV129) mice were compared directly to their respective gonadally intact agematched female WT littermates.…”

Membrane-initiated estrogen signaling in hypothalamic neurons

“…One view is that both nuclear and plasma membrane-associated ERs might be products of the same genes (Razandi et al, 1999, Boulware et al, 2005, Pedram et al, 2006, Szegõ et al, 2006, Dewing et al, 2007. This belief stems primarily from the fact that many of the rapid effects of E2 can be induced by selective ERα or ERβ ligands, antagonized by the ER antagonist, ICI 182,780, or are lost in animals bearing mutations in ERα and/or ERβ genes (Couse and Korach, 1999, Singer et al, 1999, Dubal et al, 2001, Wade et al, 2001, Abraham et al, 2003, Boulware et al, 2005. Another view is that estrogen activates a unique membrane ER (mER) (Gu et al, 1999, Toran-Allerand, 2004, Toran-Allerand, 2005, Qiu et al, 2006b).…”

Modulation of hypothalamic neuronal activity through a novel G-protein-coupled estrogen membrane receptor

“…This belief stems primarily from the fact that many of the rapid effects of E 2 can be induced by selective ERα or ERβ ligands, antagonized by the ER antagonist, ICI 182,780 or are lost in animals bearing mutations in ERα and/or ERβ genes [15,46,[49][50][51][52]. In ERα-deficient mice, rapid estrogen responses in certain regions of the mouse brain are lost [53], whereas the rapid action of estradiol in mouse hippocampal and arcuate neurons is not [18,54].…”