Clinical studies demonstrate that estrogen replacement therapy in postmenopausal women may enhance cognitive function and reduce neurodegeneration associated with Alzheimer's disease and stroke. This study assesses whether physiologic levels of estradiol prevent brain injury in an in vivo model of permanent focal ischemia. Sprague-Dawley rats were ovariectomized; they then were implanted, immediately or at the onset of ischemia, with capsules that produced physiologically low or physiologically high 17beta-estradiol levels in serum (10 or 60 pg/mL, respectively). One week after ovariectomy, ischemia was induced. Estradiol pretreatment significantly reduced overall infarct volume compared with oil-pretreated controls (mean+/-SD: oil = 241+/-88; low = 139+/-91; high = 132+/-88 mm3); this protective effect was regionally specific to the cortex, since no protection was observed in the striatum. Baseline and ischemic regional CBF did not differ between oil and estradiol pretreated rats, as measured by laser Doppler flowmetry. Acute estradiol treatment did not protect against ischemic injury. Our finding that estradiol pretreatment reduces injury demonstrates that physiologic levels of estradiol can protect against neurodegeneration.

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...

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Estradiol enhances plasticity and survival of the injured brain. Our previous work demonstrates that physiological levels of estradiol protect against cerebral ischemia in the young and aging brain through actions involving estrogen receptors (ERs) and alterations in gene expression. The major goal of this study was to establish mechanisms of neuroprotective actions induced by low levels of estradiol. We first examined effects of estradiol on the time-dependent evolution of ischemic brain injury. Because estradiol is known to influence apoptosis, we hypothesized that it acts to decrease the delayed phase of cell death observed after middle cerebral artery occlusion (MCAO). Furthermore, because ERs are pivotal to neuroprotection, we examined the temporal expression profiles of both ER subtypes, ERalpha and ERbeta, after MCAO and delineated potential roles for each receptor in estradiol-mediated neuroprotection. We quantified cell death in brains at various times after MCAO and analyzed ER expression by RT-PCR, in situ hybridization, and immunohistochemistry. We found that during the first 24 h, the mechanisms of estradiol-induced neuroprotection after MCAO are limited to attenuation of delayed cell death and do not influence immediate cell death. Furthermore, we discovered that ERs exhibit distinctly divergent profiles of expression over the evolution of injury, with ERalpha induction occurring early and ERbeta modulation occurring later. Finally, we provide evidence for a new and functional role for ERalpha in estradiol-mediated protection of the injured brain. These findings indicate that physiological levels of estradiol protect against delayed cell death after stroke-like injury through mechanisms requiring ERalpha.