Estradiol at physiological concentrations intervenes in apoptotic death cascades and ameliorates neuronal death in experimental models of focal and global ischemia. The cellular targets that mediate estradiol protection of hippocampal neurons in global ischemia are, however, unclear. The present study examined the hypothesis that estradiol protects hippocampal neurons in ovariectomized rats via estrogen receptor (ER)␣ and/or ␤. Estradiol (14 d pretreatment) afforded robust protection of CA1

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... ons against global ischemiainduced death. The broad-spectrum ER antagonist ICI 182,780 (intracerebroventricularly, 0 and 12 h after ischemia) abolished estrogen protection, consistent with a role for ERs. To evaluate the potential roles of ER␣ vs. ER␤ in estrogen protection, we administered subtype-selective agonists for 14 d before and 7 d after ischemia. The ER␣-selective agonist pro-pyl pyrazole triol (PPT, 10 mg/kg) and ER␤-selective agonist WAY 200070 -3 (1 mg/kg) produced nearly complete protection of CA1 neurons in approximately 50% of the animals. PPT, but not WAY 200070 -3, at doses used for protection, elicited lordosis, induced negative feedback inhibition of LH release, and reduced weight gain. These findings establish the efficacy of the PPT dose in neuroendocrine assays and specificity of WAY 200070 -3 for ER␤. We also examined the ability of estradiol and neuronal injury to regulate ER␣ and ER␤ expression. Both estradiol and global ischemia markedly increased ER␣, but not ER␤, protein in CA1. These data indicate that estradiol can act via ER␣ and ER␤ to protect CA1 neurons from global ischemia-induced death and that both estradiol and global ischemia modulate ER␣ expression in hippocampal CA1. (Endocrinology 146: 3070 -3079, 2005)