Harukuni I, Hurn P D, Crain B J
Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Brain Res. 2001 May 4;900(1):137-42. doi: 10.1016/s0006-8993(01)02278-8.
Estrogen has demonstrated great potential as a therapeutic agent in focal ischemic brain injury, as exogenous beta-estradiol has proven beneficial in a variety of focal stroke models. In contrast, the relatively few studies of estrogen's efficacy in transient forebrain ischemia have produced inconsistent results. The present study was therefore designed to clarify estrogen's neuroprotective potential in selective hippocampal neuronal injury resulting from four-vessel occlusion in the rat. Female Wistar rats (normal, ovariectomized, or ovariectomized and estradiol-treated) received 5 or 10 min of ischemia. No differences in hippocampal cell loss were found amongst the groups with 10 min of ischemia. Amongst the groups with 5 min of ischemia, the mildest injury was found in the ovariectomized animals, which lost only 32% of their CA1 pyramidal cells. In comparison, mean cell losses were 54% and 49%, respectively, in intact females and in ovariectomized animals with estradiol replacement. Linear regression analysis demonstrated a highly significant relationship between cell loss and plasma estradiol levels. The mechanism by which exogenous and endogenous estrogen exacerbated the injury is unclear, as estrogen has many neuroprotective effects. On the other hand, many other reported effects of estrogen in hippocampal area CA1 might confer increased sensitivity to ischemia, either by modulating the excitatory effects of glutamate or by modifying the inhibitory effects of GABA. Determining how to modulate the various competing effects of estrogen is of both theoretical and practical importance, as it is now clear that one cannot assume that estrogen administration will always improve outcome in cerebral ischemia.
雌激素已被证明在局灶性缺血性脑损伤中作为治疗剂具有巨大潜力，因为外源性β-雌二醇已在多种局灶性中风模型中被证明是有益的。相比之下，关于雌激素在短暂性前脑缺血中疗效的研究相对较少，结果也不一致。因此，本研究旨在阐明雌激素在大鼠四血管闭塞所致选择性海马神经元损伤中的神经保护潜力。雌性Wistar大鼠（正常、去卵巢或去卵巢并用雌二醇治疗）经历5或10分钟的缺血。缺血10分钟的各组之间未发现海马细胞丢失有差异。在缺血5分钟的各组中，去卵巢动物的损伤最轻，仅损失了32%的CA1锥体细胞。相比之下，完整雌性大鼠和接受雌二醇替代的去卵巢动物的平均细胞损失分别为54%和49%。线性回归分析表明细胞丢失与血浆雌二醇水平之间存在高度显著的关系。外源性和内源性雌激素加剧损伤的机制尚不清楚，因为雌激素具有许多神经保护作用。另一方面，雌激素在海马CA1区的许多其他已报道的作用可能会通过调节谷氨酸的兴奋作用或改变γ-氨基丁酸的抑制作用而增加对缺血的敏感性。确定如何调节雌激素的各种相互竞争的作用具有理论和实际意义，因为现在很清楚，不能假定给予雌激素总能改善脑缺血的结局。
