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 alpha and ER beta, in the injured brain. To investigate and delineate these mechanisms, we used 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 controlled endocrine paradigm, because endogenous levels of
estradiol differ dramatically 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 them with capsules filled with oil (vehicle) or a dose of
17 beta-estradiol that produces physiological
hormone levels in serum. One week later, mice underwent
ischemia. Our results demonstrate that deletion of ER alpha 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 beta. Thus, our results clearly establish that the ER alpha subtype is a critical mechanistic link in mediating the protective effects of physiological levels of
estradiol in
brain injury. Our discovery that ER alpha 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.