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.

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