Mechanisms of neuroprotection by estrogen

Over the past decade our recognition that estrogens function as important neurotrophic and neuroprotective factors has grown rapidly. Accumulating evidence from basic science studies demonstrates that estrogens exert profound protective actions against various forms of neurodegenerative diseases and injury. Although a thorough understanding of the mechanisms underlying the protective effect of estrogens is far from complete, significant progress has been achieved through the use of in vivo as well as in vitro models. Here we review the results from our laboratory demonstrating that low physiological levels of estradiol therapy exert powerful protection against ischemic stroke-like injury. Using an animal model of cerebrovascular stroke and in vitro explant cultures, we have begun to decipher under what circumstances 17β-estradiol protects against neuronal death and to uncover its mechanisms of action. In addition, we will review recent work demonstrating that estradiol may additionally enhance the ability of the adult brain to undergo repair by influencing the production of new neurons under neuropathological conditions, as well as by promoting an anti-inflammatory response. As we uncover the important protective roles of ovarian steroid hormones in brain disease and injury, we increasingly appreciate that the mechanisms by which estrogens achieve these effects are diverse and complex.