Jover-Mengual Teresa, Zukin R Suzanne, Etgen Anne M
Department of Neuroscience, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA.
Endocrinology. 2007 Mar;148(3):1131-43. doi: 10.1210/en.2006-1137. Epub 2006 Nov 30.
The importance of hormone therapy in affording protection against the sequelae of global ischemia in postmenopausal women remains controversial. Global ischemia arising during cardiac arrest or cardiac surgery causes highly selective, delayed death of hippocampal CA1 neurons. Exogenous estradiol ameliorates global ischemia-induced neuronal death and cognitive impairment in male and female rodents. However, the molecular mechanisms by which estrogens intervene in global ischemia-induced apoptotic cell death are unclear. Here we show that estradiol acts via the classical estrogen receptors, the IGF-I receptor, and the ERK/MAPK signaling cascade to protect CA1 neurons in ovariectomized female rats and gerbils. We demonstrate that global ischemia promotes early dephosphorylation and inactivation of ERK1 and the transcription factor cAMP-response element binding protein (CREB), subsequent down-regulation of the antiapoptotic protein Bcl-2, a known gene target of estradiol and CREB, and activation of caspase-3. Estradiol treatment increases basal phosphorylation of both ERK1 and ERK2 in hippocampal CA1 and prevents ischemia-induced dephosphorylation and inactivation of ERK1 and CREB, down-regulation of Bcl-2 and activation of the caspase death cascade. Whereas ERK/MAPK signaling is critical to CREB activation and neuronal survival, the impact of estradiol on Bcl-2 levels is ERK independent. These findings support a model whereby estradiol acts via the classical estrogen receptors and IGF-I receptors, which converge on activation of ERK/MAPK signaling and CREB to promote neuronal survival in the face of global ischemia.
激素疗法在预防绝经后女性全脑缺血后遗症方面的重要性仍存在争议。心脏骤停或心脏手术期间发生的全脑缺血会导致海马CA1神经元高度选择性、延迟性死亡。外源性雌二醇可改善雄性和雌性啮齿动物全脑缺血诱导的神经元死亡和认知障碍。然而，雌激素干预全脑缺血诱导的凋亡性细胞死亡的分子机制尚不清楚。在此，我们表明，雌二醇通过经典雌激素受体、IGF-I受体和ERK/MAPK信号级联发挥作用，以保护去卵巢雌性大鼠和沙鼠的CA1神经元。我们证明，全脑缺血促进ERK1和转录因子cAMP反应元件结合蛋白（CREB）的早期去磷酸化和失活，随后下调抗凋亡蛋白Bcl-2（已知的雌二醇和CREB的基因靶点），并激活caspase-3。雌二醇处理可增加海马CA1中ERK1和ERK2的基础磷酸化，并防止缺血诱导的ERK1和CREB去磷酸化和失活、Bcl-2下调以及caspase死亡级联的激活。虽然ERK/MAPK信号传导对CREB激活和神经元存活至关重要，但雌二醇对Bcl-2水平的影响不依赖于ERK。这些发现支持了一种模型，即雌二醇通过经典雌激素受体和IGF-I受体发挥作用，这些受体汇聚于ERK/MAPK信号传导和CREB的激活，以促进在全脑缺血情况下的神经元存活。
