| 12604781 |
Nilsen J, Diaz Brinton R: Mechanism of estrogen-mediated neuroprotection: regulation of mitochondrial calcium and Bcl-2 expression. Proc Natl Acad Sci U S A. 2003 Mar 4;100(5):2842-7. Epub 2003 Feb 25.
Estrogens are neuroprotective against glutamate excitotoxicity caused by an excessive rise in intracellular calcium ([Ca (2+)](i)). In this study, we demonstrate that 17 beta-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. |
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