Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York, United States of America.
PLoS One. 2010 Jan 8;5(1):e8642. doi: 10.1371/journal.pone.0008642.
Pretreatment with 17beta-estradiol (E2) is profoundly neuroprotective in young animals subjected to focal and global ischemia. However, whether E2 retains its neuroprotective efficacy in aging animals, especially when administered after brain insult, is largely unknown.
METHODOLOGY/PRINCIPAL FINDINGS: We examined the neuroprotective effects of E2 and two agonists that bind to non-classical estrogen receptors, G1 and STX, when administered after ischemia in middle-aged rats after prolonged ovarian hormone withdrawal. Eight weeks after ovariectomy, middle-aged female rats underwent 10 minutes of global ischemia by four vessel occlusion. Immediately after reperfusion, animals received a single infusion of either E2 (2.25 microg), G1 (50 microg) or STX (50 microg) into the lateral ventricle (ICV) or a single systemic injection of E2 (100 microg/kg). Surviving pyramidal neurons in the hippocampal CA1 were quantified 1 week later. E2 and both agonists that target non-classical estrogen receptors (G1 and STX) administered ICV at the time of reperfusion provided significant levels of neuroprotection, with 55-60% of CA1 neurons surviving vs 15% survival in controls. A single systemic injection of a pharmacological dose of E2 also rescued approximately 50% of CA1 pyramidal neurons destined to die. To determine if E2 and G1 have similar mechanisms of action in hippocampal neurons, we compared the ability of E2 and G1 to modify CA1 pyramidal neuron responses to excitatory inputs from the Schaffer collaterals recorded in hippocampal slices derived from female rats not subjected to global ischemia. E2 and G1 (10 nM) significantly potentiated pyramidal neuron responses to excitatory inputs when applied to hippocampal slices.
CONCLUSIONS/SIGNIFICANCE: These findings suggest (1) that middle-aged female rats retain their responsiveness to E2 even after a long period of hormone withdrawal, (2) that non-classical estrogen receptors may mediate the neuroprotective actions of E2 when given after ischemia, and (3) that the neuroprotective efficacy of estrogens may be related to their modulation of synaptic activity in hippocampal slices.
在接受局部和全脑缺血的年轻动物中，17β-雌二醇（E2）预处理具有显著的神经保护作用。然而，E2 是否在衰老动物中保留其神经保护作用，特别是在脑损伤后给予时，在很大程度上尚不清楚。
方法/主要发现：我们检查了 E2 及其两种与非经典雌激素受体结合的激动剂 G1 和 STX 在经过长时间卵巢激素剥夺后，在中年大鼠脑缺血后给予时的神经保护作用。卵巢切除 8 周后，中年雌性大鼠通过四血管闭塞接受 10 分钟的全脑缺血。再灌注后立即将 E2（2.25 微克）、G1（50 微克）或 STX（50 微克）单次输注到侧脑室（ICV）或 E2（100 微克/公斤）单次全身注射到动物体内。1 周后定量海马 CA1 中的存活锥体神经元。再灌注时给予 ICV 的 E2 和两种靶向非经典雌激素受体（G1 和 STX）的激动剂均提供了显著水平的神经保护作用，CA1 神经元的存活率为 55-60%，而对照组的存活率为 15%。单次全身给予药理剂量的 E2 也可挽救约 50%注定死亡的 CA1 锥体神经元。为了确定 E2 和 G1 在海马神经元中是否具有相似的作用机制，我们比较了 E2 和 G1 改变未接受全脑缺血的雌性大鼠海马切片中来自 Schaffer 侧支的兴奋性输入对 CA1 锥体神经元反应的能力。E2 和 G1（10 nM）显著增强了海马切片中兴奋性输入对锥体神经元反应的作用。
结论/意义：这些发现表明（1）中年雌性大鼠即使在长时间的激素剥夺后仍保留对 E2 的反应性，（2）非经典雌激素受体可能介导 E2 在缺血后给予时的神经保护作用，以及（3）雌激素的神经保护作用可能与其在海马切片中调节突触活性有关。
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