Neuroprotection by estradiol

This review highlights recent evidence from clinical and basic science stud ies supporting a role for estrogen in neuroprotection. Accumulated clinical evidence suggests that estrogen exposure decreases the risk and delays the onset and progression of Alzheimer's disease and schizophrenia, and may al so enhance recovery from traumatic neurological injury such as stroke. Rece nt basic science studies show that not only does exogenous estradiol decrea se the response to various forms of insult, but the brain itself upregulate s both estrogen synthesis and estrogen receptor expression at sites of inju ry. Thus, our view of the role of estrogen in neural function must be broad ened to include not only its function in neuroendocrine regulation and repr oductive behaviors, but also to include a direct protective role in respons e to degenerative disease or injury. Estrogen may play this protective role through several routes. Key among these are estrogen dependent alterations in cell survival, axonal sprouting, regenerative responses, enhanced synap tic transmission and enhanced neurogenesis. Some of the mechanisms underlyi ng these effects are independent of the classically defined nuclear estroge n receptors and involve unidentified membrane receptors, direct modulation of neurotransmitter receptor function, or the known anti-oxidant activities of estrogen. Other neuroprotective effects of estrogen do depend on the cl assical nuclear estrogen receptor, through which estrogen alters expression of estrogen responsive gents that play a role in apoptosis, axonal regener ation, or general trophic support. Yet another possibility is that estrogen receptors in the membrane or cytoplasm alter phosphorylation cascades thro ugh direct interactions with protein kinases or that estrogen receptor sign aling may converge with signaling by other trophic molecules to confer resi stance to injury. Although there is clear evidence that estradiol exposure can be deleterious to some neuronal populations, the potential clinical ben efits of estrogen treatment for enhancing cognitive function may outweigh t he associated central and peripheral risks. Exciting and important avenues for future investigation into the protective effects of estrogen include th e optimal ligand and doses that can be used clinically to confer benefit wi thout undue risk, modulation of neurotrophin and neurotrophin receptor expr ession, interaction of estrogen with regulated cofactors and coactivators t hat couple estrogen receptors to basal transcriptional machinery, interacti ons of estrogen with other survival and regeneration promoting factors, pot ential estrogenic effects on neuronal replenishment, and modulation of phen otypic choices by neural stem cells. (C) 2000 Elsevier Science Ltd. All rig hts reserved.