Soy phytoestrogen neuroprotection in cerebral ischemia

描述（由申请人提供）：雌激素是一种强大的神经保护激素，在减少中风中的脑缺血性损伤方面特别有效。内源性和外源性雌激素也与保护人类免受神经退行性疾病有关。然而，最近的临床结果表明激素替代疗法（HRT）对健康有影响，从而减轻了雌激素的益处。对激素依赖性癌症的担忧将继续阻止妇女接受替代疗法。药理学选择性雌激素受体调节剂（SERM）在保留雌激素的有益作用而不增加癌症风险方面显示出希望。然而，许多女性已经选择了“天然”SERM，如含有大豆和其他植物雌激素的植物衍生物，并认为这种疗法比HRT更有效和安全。流行病学和实验数据表明，大豆植物雌激素含量高的饮食提供了许多与雌激素相同的益处，具有减少传统HRT所见的负面副作用的潜力。然而，人们对大豆植物雌激素在大脑中的作用知之甚少。在体外，大豆植物雌激素可以模拟一些雌激素的神经保护作用，但这些相同的化合物也被证明可以抑制大脑中的一些雌激素作用。 本研究旨在确定大豆植物雌激素是否在体外和体内保护神经元免受缺血性损伤。我们假设生理相关剂量的大豆植物雌激素通过模拟雌激素的基因组和非基因组作用而具有神经保护作用。 目的1将测试大豆植物雌激素genestein，大豆黄酮，雌马酚抑制脑缺血的神经元细胞系模型中的雌激素受体依赖性的方式细胞凋亡的假设。目的2将检验在缺乏内源性雌激素的情况下，高大豆饮食将减少与大鼠大脑中动脉闭塞相关的梗死面积和细胞死亡的假设。目的3将检验以下假设：在内源性雌激素不存在的情况下，摄入高大豆饮食将诱导神经保护基因BDNF、NGF、Bcl-2、BCl-xL和TrkB的表达，并减少大脑中动脉闭塞损伤的脑区域中促凋亡p75 NTR的表达。该建议旨在提供关于植物雌激素保护大脑免于局灶性脑缺血的能力的重要新信息。

DESCRIPTION (provided by applicant): Estrogen is a powerful neuroprotective hormone that is particularly effective in reducing cerebral ischemic damage in stroke. Endogenous and exogenous estrogen is also associated with protection from neurodegenerative disease in humans. However, the benefits of estrogen are mitigated by recent clinical results suggesting that hormone replacement therapy (HRT) has health consequences. Concerns about hormone dependent cancer will continue to deter women from taking replacement therapy. Pharmacological selective estrogen receptor modulators (SERMs) show promise in preserving the beneficial effects of estrogen without increasing cancer risk. However, many women are already opting for "natural" SERMs such as plant derivatives containing soy and other phytoestrogens with the presumption that such therapies are both effective and safer than HRT. Epidemiological and experimental data suggest that diets high in soy phytoestrogens provide many of the same benefits as estrogen with the potential for decreased negative side effects seen with traditional HRT. Nevertheless, very little is known about the effects of dietary soy phytoestrogens in the brain. In vitro, soy phytoestrogens can mimic some of estrogen's neuroprotective actions, but these same compounds have also been shown to inhibit some estrogen actions in the brain. The present proposal seeks to determine the whether of soy phytoestrogens protect neurons from ischemic damage in vitro and in vivo. We hypothesize that physiologically relevant doses of soy phytoestrogens are neuroprotective by mimicking both genomic and non-genomic actions of estrogen. Aim 1 will test the hypothesis that the soy phytoestrogens genestein, daidzein, and equol inhibit apoptotic cell death in neuronal cell line models of cerebral ischemia in an estrogen receptor-dependent manner. Aim 2 will test the hypothesis that in the absence of endogenous estrogen a high soy diet will decrease infarct size and cell death associated with middle cerebral artery occlusion in rats. Aim 3 will test the hypothesis that in the absence of endogenous estrogen, ingestion of a high soy diet will induce the expression of the neuroprotective genes BDNF, NGF, Bcl-2, BCl-xL, and TrkB and reduce expression of the pro-apoptotic p75 NTR in brain regions damaged by middle cerebral artery occlusion. This proposal seeks to provide critical new information about the ability of phytoestrogens to protect the brain from focal cerebral ischemia.