Jover Teresa, Tanaka Hidenobu, Calderone Agata, Oguro Keiji, Bennett Michael V L, Etgen Anne M, Zukin R Suzanne
Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
J Neurosci. 2002 Mar 15;22(6):2115-24. doi: 10.1523/JNEUROSCI.22-06-02115.2002.
The importance of postmenopausal estrogen replacement therapy in affording protection against the selective and delayed neuronal death associated with cardiac arrest or cardiac surgery in women remains controversial. Here we report that exogenous estrogen at levels that are physiological for hormone replacement in postmenopausal women affords protection against global ischemia-induced neuronal death and prevents activation of apoptotic signaling cascades in the hippocampal CA1 of male gerbils. Global ischemia induced a marked increase in activated caspase-3 in CA1, evident at 6 hr after ischemia. Global ischemia induced a marked upregulation of the proapoptotic neurotrophin receptor p75(NTR) in CA1, evident at 48 hr. p75(NTR) expression was induced primarily in terminal deoxynucleotidyl transferase-mediated UTP nick-end labeling-positive cells, indicating expression in neurons undergoing apoptosis. Global ischemia also induced a marked downregulation of mRNA encoding the AMPA receptor GluR2 subunit in CA1. Caspase-3, p75(NTR), and GluR2 were not significantly changed in CA3 and dentate gyrus, indicating that the ischemia-induced changes in gene expression were cell specific. Exogenous estrogen attenuated the ischemia-induced increases in activated caspase-3 and blocked the increase in p75(NTR) in post-ischemic CA1 neurons but did not prevent ischemia-induced downregulation of GluR2. These findings demonstrate that long-term estrogen at physiological levels ameliorates ischemia-induced hippocampal injury and indicate that estrogen intervenes at the level of apoptotic signaling cascades to prevent onset of death in neurons otherwise "destined to die."
绝经后雌激素替代疗法对于预防女性因心脏骤停或心脏手术导致的选择性和延迟性神经元死亡的重要性仍存在争议。在此我们报告，绝经后女性激素替代生理水平的外源性雌激素可预防全脑缺血诱导的神经元死亡，并防止雄性沙鼠海马CA1区凋亡信号级联反应的激活。全脑缺血诱导CA1区活化的半胱天冬酶-3显著增加，缺血后6小时即可明显观察到。全脑缺血诱导CA1区促凋亡神经营养因子受体p75(NTR)显著上调，48小时时明显可见。p75(NTR)表达主要在末端脱氧核苷酸转移酶介导的UTP缺口末端标记阳性细胞中诱导产生，表明在发生凋亡的神经元中表达。全脑缺血还诱导CA1区编码AMPA受体GluR2亚基的mRNA显著下调。CA3区和齿状回中的半胱天冬酶-3、p75(NTR)和GluR2没有明显变化，表明缺血诱导的基因表达变化具有细胞特异性。外源性雌激素可减轻缺血诱导的活化半胱天冬酶-3的增加，并阻断缺血后CA1神经元中p75(NTR)的增加，但不能预防缺血诱导的GluR2下调。这些发现表明，生理水平的长期雌激素可改善缺血诱导的海马损伤，并表明雌激素在凋亡信号级联反应水平上发挥干预作用，以防止原本“注定死亡”的神经元发生死亡。
