Estrogen can act via estrogen receptor α and β to protect hippocampal neurons against global ischemia-induced cell death

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)alpha and/ or beta. Estradiol (14 d pretreatment) afforded robust protection of CA1 neurons against global ischemia-induced 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 alpha vs. ER beta in estrogen protection, we administered subtype-selective agonists for 14 d before and 7 d after ischemia. The ER alpha-selective agonist propyl pyrazole triol (PPT, 10 mg/kg) and ER beta-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 beta. We also examined the ability of estradiol and neuronal injury to regulate ER alpha and ER beta expression. Both estradiol and global ischemia markedly increased ER alpha, but not ER beta, protein in CA1. These data indicate that estradiol can act via ER alpha and ER beta to protect CA1 neurons from global ischemia-induced death and that both estradiol and global ischemia modulate ER alpha expression in hippocampal CA1.