Estrogen receptor-mediated neuroprotection from oxidative stress requires activation of the mitogen-activated protein kinase pathway

Abstract

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) α and/or β can activate rapid signaling that may mediate neuroprotection is lacking, the hippocampal-derived cell line, HT22, was stably transfected with ERα (HTERα), ERβ (HTERβ), or a mutated form of ERα (HTERαHE27), which lacks the ability to mediate ER element-mediated transcription. Treatment of HT22, HTERα, HTERβ, and HTERαHE27 cells with glutamate (5 mM) resulted in a significant decrease in cell viability. Pretreatment for 15 min with 10 nM 17β-estradiol resulted in a 50% increase in the number of living cells in HTERα and HTERβ cells but not in HT22 cells. The ER antagonist ICI 182,780 and the MEK inhibitor PD98059 prevented 17β-estradiol-mediated protection. In HTERαHE27 cells, 17β-estradiol rapidly phosphorylated ERK2 (within 15 min), in the absence of estrogen response element-mediated transcription. Treatment of HTERαHE27 cells with 10 nM 17β-estradiol partially reversed the cell death produced by glutamate treatment. This study demonstrates that activation of either ERα or ERβ can result in neuroprotection and that activation of the MAPK pathway is an important part of the neuroprotective mechanism.