Soy phytoestrogen neuroprotection in cerebral ischemia

说明(申请人提供)：雌激素是一种强大的神经保护激素，对减少中风患者的脑缺血损害特别有效。内源性和外源性雌激素也与人类神经退行性疾病的保护有关。然而，最近的临床结果表明激素替代疗法(HRT)具有健康后果，雌激素的好处被减轻了。对激素依赖型癌症的担忧将继续阻止女性接受替代疗法。药理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，许多妇女已经选择了“天然”的SERM，例如含有大豆和其他植物雌激素的植物衍生品，他们认为这种疗法比HRT既有效又安全。流行病学和实验数据表明，高大豆植物雌激素饮食提供了许多与雌激素相同的好处，并有可能减少传统HRT的负面副作用。然而，人们对食用大豆植物雌激素对大脑的影响知之甚少。在体外，大豆植物雌激素可以模仿雌激素的一些神经保护作用，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。 目前的建议试图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，生理上相关剂量的大豆植物雌激素通过模仿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验证大豆植物雌激素genstein、daidzein和equol以雌激素受体依赖的方式抑制脑缺血神经细胞系的细胞凋亡的假说。目的2将验证一个假设，即在缺乏内源性雌激素的情况下，高大豆饮食将减少与大脑中动脉闭塞相关的大鼠脑梗塞范围和细胞死亡。目的3将验证一种假说，即在缺乏内源性雌激素的情况下，摄入高大豆饮食会诱导大脑中动脉闭塞损伤的脑区神经保护基因BDNF、NGF、Bcl2、bclxl和TrkB的表达，并减少促凋亡基因p75NTR的表达。这项提案试图提供有关植物雌激素保护大脑免受局灶性脑缺血影响的关键新信息。

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.