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17ß-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

Human Stress Signal Research Center (Y.N., E.N.), Neuronics Research Group, Special Division for Human Life Technology (T.M., D.Y., T.T., T.N.), National Institute of Advanced Industrial Science and Technology, Ikeda, Osaka 563-8577, Japan; Division of Protein Biosynthesis (Y.N., T.M., D.Y., H.H., T.N.), Institute for Protein Research, Osaka University, Suita, Osaka 565-0871, Japan; and Department of Mental Disorder Research (H.K., T.N.), National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo 187-8502, Japan

Address all correspondence and requests for reprints to: Tomoya Matsumoto, Division of Pharmacology/Neurobiology, Biozentrum, University of Basel, Klingelbergstrasse 50/70, CH-4056 Basel, Switzerland. E-mail: Tomoya.Matsumoto{at}unibas.ch.

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 17ß-estradiol (17ß-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 H₂O₂-triggered MAPK activation, Ca²⁺ accumulation, and cell death was observed in cultures incubated with 17ß-E2 for 24 h before exposure to H₂O₂, suggesting that the protective effect of 17ß-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 17ß-E2-treated cultures. The down-regulation of these glutamate receptor subunits was also observed after chronic treatment with U0126. Therefore, it is possible that 17ß-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 17ß-E2 against oxidative stress-induced toxicity.

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