ABSTRACT
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 ERalpha vs. ERbeta in estrogen protection, we administered subtype-selective agonists for 14 d before and 7 d after ischemia. The ERalpha-selective agonist propyl pyrazole triol (PPT, 10 mg/kg) and ERbeta-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 ERbeta. We also examined the ability of estradiol and neuronal injury to regulate ERalpha and ERbeta expression. Both estradiol and global ischemia markedly increased ERalpha, but not ERbeta, protein in CA1. These data indicate that estradiol can act via ERalpha and ERbeta to protect CA1 neurons from global ischemia-induced death and that both estradiol and global ischemia modulate ERalpha expression in hippocampal CA1.
Subject(s)
Brain Ischemia/physiopathology , Estradiol/pharmacology , Estrogen Receptor alpha/physiology , Estrogen Receptor beta/physiology , Hippocampus/physiopathology , Neuroprotective Agents/pharmacology , Animals , Brain Ischemia/pathology , Cell Survival/drug effects , Cell Survival/physiology , Dose-Response Relationship, Drug , Estrogen Receptor alpha/agonists , Estrogen Receptor beta/agonists , Feedback, Physiological , Female , Hippocampus/drug effects , Hippocampus/pathology , Lordosis/chemically induced , Luteinizing Hormone/antagonists & inhibitors , Neurons/drug effects , Neurons/pathology , Neuroprotective Agents/administration & dosage , Oxazoles/administration & dosage , Oxazoles/pharmacology , Phenols/administration & dosage , Phenols/pharmacology , Pyrazoles/administration & dosage , Pyrazoles/pharmacology , Rats , Rats, Sprague-Dawley , Time Factors , Weight Gain/drug effectsABSTRACT
OBJECTIVE: To determine whether maternal serum levels of androgens are associated with preeclampsia in primigravid women. STUDY DESIGN: A case-control study of primigravid women with singleton pregnancies. Women diagnosed with preeclampsia (n = 15) were matched with normotensive controls (n = 30) for age and gestational age. Serum testosterone, sex hormone binding globulin, estradiol and dehydroepiandrosterone sulfate were measured before delivery. The study had 80% power to detect a 30% difference in mean testosterone concentration between cases and controls using a two-tailed test and alpha level of .05. The Student t test, Mann-Whitney U test, Wilcoxon signed ranks test and chi 2 analysis of proportions were used for analysis. RESULTS: Cases and controls did not differ in maternal age, gestational age, body mass index, tobacco use or neonatal sex. As compared with normotensive controls, preeclamptic women exhibited no statistically significant differences in median levels of total testosterone, free androgen index, sex hormone binding globulin, estradiol or dehydroepiandrosterone sulfate. CONCLUSION: Maternal serum levels of androgens do not exhibit an association with preeclampsia in primigravid women.
