Mechanism of estrogen-mediated neuroprotection: Regulation of mitochondrial calcium and Bcl-2 expression

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Abstract
Estrogens are neuroprotective against glutamate excitotoxicity caused by an excessive rise in intracellular calcium ([Ca 2+ ] i ). In this study, we demonstrate that 17β-estradiol (E 2 ) treatment of hippocampal neurons attenuated the excitotoxic glutamate-induced rise in bulk-free [Ca 2+ ] i despite potentiating the influx of Ca 2+ induced by glutamate. E 2 -induced attenuation of bulk-free [Ca 2+ ] i depends on mitochondrial sequestration of Ca 2+ , which is blocked in the presence of the combination of rotenone and oligomycin or in the presence of antimycin, which collapse the mitochondrial membrane potential, thereby preventing mitochondrial Ca 2+ transport. Release of mitochondrial Ca 2+ by carbonyl cyanide p -trifluoromethoxyphenylhydrazone (FCCP) after excitotoxic glutamate treatment resulted in a greater [Ca 2+ ] i in E 2 -treated cells, indicating an E 2 -induced increase in the mitochondrial calcium ([Ca 2+ ] m ) load. The increased [Ca 2+ ] m load was accompanied by increased expression of Bcl-2, which can promote mitochondrial Ca 2+ load tolerance. These findings provide a mechanism of E 2 -induced neuronal survival by attenuation of excitotoxic glutamate [Ca 2+ ] i rise via increased mitochondrial sequestration of cytosolic Ca 2+ coupled with an increase in Bcl-2 expression to sustain mitochondrial Ca 2+ load tolerance and function.