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Estrogen Receptor-Mediated Neuroprotection from Oxidative Stress Requires Activation of the Mitogen-Activated Protein Kinase Pathway

Departments of Pharmacology (A.L.M.) and Psychiatry and Behavioral Sciences (R.A.S., D.M.D.), University of Washington, Seattle, Washington 98195; and Department of Physiology and Pharmacology (R.A.S., D.M.D.), Oregon Health Science University, Portland, Oregon 97201

Address all correspondence and requests for reprints to: Robert A. Shapiro, Ph.D., Oregon Health Science University, Department of Physiology and Pharmacology, 3181 SW Sam Jackson Park Road, Portland, Oregon 97201. E-mail: shapiror{at}ohsu.edu.

It is well documented that estrogen mediates responses by both genomic and nongenomic mechanisms, both of which are important for cell survival. Because direct evidence showing that the estrogen receptors (ERs) and/or ß can activate rapid signaling that may mediate neuroprotection is lacking, the hippocampal-derived cell line, HT22, was stably transfected with ER (HTER), ERß (HTERß), or a mutated form of ER (HTERHE27), which lacks the ability to mediate ER element-mediated transcription. Treatment of HT22, HTER, HTERß, and HTERHE27 cells with glutamate (5 mM) resulted in a significant decrease in cell viability. Pretreatment for 15 min with 10 nM 17ß-estradiol resulted in a 50% increase in the number of living cells in HTER and HTERß cells but not in HT22 cells. The ER antagonist ICI 182,780 and the MEK inhibitor PD98059 prevented 17ß-estradiol-mediated protection. In HTERHE27 cells, 17ß-estradiol rapidly phosphorylated ERK2 (within 15 min), in the absence of estrogen response element-mediated transcription. Treatment of HTERHE27 cells with 10 nM 17ß-estradiol partially reversed the cell death produced by glutamate treatment. This study demonstrates that activation of either ER or ERß can result in neuroprotection and that activation of the MAPK pathway is an important part of the neuroprotective mechanism.

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