Miller Nora R, Jover Teresa, Cohen Hillel W, Zukin R Suzanne, Etgen Anne M
Department of Obstetrics, Gynecology and Women's Health, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Endocrinology. 2005 Jul;146(7):3070-9. doi: 10.1210/en.2004-1515. Epub 2005 Apr 7.
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.
生理浓度的雌二醇可干预凋亡死亡级联反应，并改善局灶性和全脑缺血实验模型中的神经元死亡。然而，介导雌二醇对全脑缺血中海马神经元保护作用的细胞靶点尚不清楚。本研究检验了以下假设：雌二醇通过雌激素受体（ER）α和/或β保护去卵巢大鼠的海马神经元。雌二醇（预处理14天）对CA1神经元免受全脑缺血诱导的死亡提供了强大的保护作用。广谱ER拮抗剂ICI 182,780（脑室内注射，缺血后0和12小时）消除了雌激素的保护作用，这与ERs的作用一致。为了评估ERα与ERβ在雌激素保护中的潜在作用，我们在缺血前14天和缺血后7天给予亚型选择性激动剂。ERα选择性激动剂丙基吡唑三醇（PPT，10mg/kg）和ERβ选择性激动剂WAY 200070-3（1mg/kg）在约50%的动物中对CA1神经元产生了几乎完全的保护作用。用于保护的剂量下，PPT而非WAY 200070-3引起了脊柱前凸，诱导了对促黄体激素释放的负反馈抑制，并减少了体重增加。这些发现确定了PPT剂量在神经内分泌测定中的有效性以及WAY 200070-3对ERβ的特异性。我们还研究了雌二醇和神经元损伤调节ERα和ERβ表达的能力。雌二醇和全脑缺血均显著增加了CA1区的ERα蛋白，但未增加ERβ蛋白。这些数据表明，雌二醇可通过ERα和ERβ发挥作用，保护CA1神经元免受全脑缺血诱导的死亡，并且雌二醇和全脑缺血均调节海马CA1区的ERα表达。
