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

Estradiol protects against brain injury, neurodegeneration, and cognitive d ecline. Our previous work demonstrates that physiological levels of estradi ol protect against stroke injury and that this protection may be mediated t hrough receptor-dependent alterations of gene expression. In this report, w e tested the hypothesis that estrogen receptors play a pivotal role in medi ating neuroprotective actions of estradiol and dissected the potential biol ogical roles of each estrogen receptor (ER) subtype, ER alpha and ER beta, in the injured brain. To investigate and delineate these mechanisms, we use d 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 controlle d endocrine paradigm, because endogenous levels of estradiol differ dramati cally 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 th em with capsules filled with oil (vehicle) or a dose of 17 beta -estradiol that produces physiological hormone levels in serum. One week later, mice u nderwent ischemia. Our results demonstrate that deletion of ER alpha comple tely abolishes the protective actions of estradiol in all regions of the br ain; whereas the ability of estradiol to protect against brain injury is to tally preserved in the absence of ERP, Thus, our results clearly establish that the ER alpha subtype is a critical mechanistic link in mediating the p rotective effects of physiological levels of estradiol in brain injury. Our discovery that ERa mediates protection of the brain carries far-reaching i mplications for the selective targeting of ERs in the treatment and prevent ion of neural dysfunction associated with normal aging or brain injury.