17β-Estradiol protects cortical neurons against oxidative stress-induced cell death through reduction in the activity of mitogen-activated protein kinase and in the accumulation of intracellular calcium

Abstract

Although many studies have suggested that estrogen acts as a neuroprotective agent in oxidative stress, the underlying mechanism has not been fully elucidated. In the present study, we examined the effect of 17β-estradiol (17β-E2) on H2O2-induced death signaling in cultured cortical neurons. Exposure of the cortical neurons to H2O2 triggered a series of events, including overactivation of p44/42 MAPK and intracellular Ca2+ accumulation via voltage-gated Ca2+ channels and ionotropic glutamate receptors, resulting in apoptotic-like cell death. The MAPK pathway might work as death signaling in our system, because the MAPK pathway inhibitor, U0126, blocked H2O2-induced MAPK activation, Ca2+ overload, and cell death. Interestingly, a similar inhibitory effect on H 2O2-triggered MAPK activation, Ca2+ accumulation, and cell death was observed in cultures incubated with 17β-E2 for 24 h before exposure to H2O2, suggesting that the protective effect of 17β-E2 is induced via attenuating overactivation of the MAPK pathway. Furthermore, we found that ionotropic glutamate receptor subunits, including NR2A and GluR2/3, but not NR2B and GluR1, were down-regulated in the 17β-E2-treated cultures. The down-regulation of these glutamate receptor subunits was also observed after chronic treatment with U0126. Therefore, it is possible that 17β-E2 down-regulates the expression of the ionotropic glutamate receptors by reducing activity of the MAPK pathway, which might be important for the protective effect of 17β-E2 against oxidative stress-induced toxicity. Copyright © 2007 by The Endocrine Society.