Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY, USA.
Brain Res. 2010 Mar 19;1321:1-12. doi: 10.1016/j.brainres.2010.01.046. Epub 2010 Jan 28.
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 a single acute injection of estradiol administered after the ischemic event intervenes in global ischemia-induced apoptotic cell death are unclear. Here we show that acute estradiol acts via the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling cascade to protect CA1 neurons in ovariectomized female rats. We demonstrate that global ischemia promotes early activation of glycogen synthase kinase-3beta (GSK3beta) and forkhead transcription factor of the O class (FOXO)3A, known Akt targets that are related to cell survival, and activation of caspase-3. Estradiol prevents ischemia-induced dephosphorylation and activation of GSK3beta and FOXO3A, and the caspase death cascade. These findings support a model whereby estradiol acts by activation of PI3K/Akt signaling to promote neuronal survival in the face of global ischemia.
心脏骤停或心脏手术期间发生的全球缺血导致海马 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的全脑缺血诱导的神经元死亡和认知障碍。然而，在缺血事件发生后单次给予雌二醇可干预全脑缺血诱导的细胞凋亡性死亡的分子机制尚不清楚。在这里，我们表明急性雌二醇通过磷酸肌醇 3-激酶 (PI3K)/蛋白激酶 B (Akt) 信号级联反应发挥作用，以保护去卵巢雌性大鼠的 CA1 神经元。我们证明，全脑缺血会促进糖原合酶激酶-3β (GSK3β) 和叉头转录因子 O 类 (FOXO)3A 的早期激活，这是 Akt 的已知靶标，与细胞存活有关，以及 caspase-3 的激活。雌二醇可防止缺血诱导的 GSK3β 和 FOXO3A 去磷酸化和激活，以及半胱天冬酶死亡级联。这些发现支持这样一种模型，即雌二醇通过激活 PI3K/Akt 信号通路来发挥作用，以促进面对全脑缺血时神经元的存活。
