Soy phytoestrogen neuroprotection in cerebral ischemia

大豆植物雌激素对脑缺血的神经保护作用

• 批准号: 7022332
• 负责人: DEREK A SCHREIHOFER
• 金额: $ 27.4万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-02-15 至 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7022332
• 关键词: BCL2 gene /protein; alternative medicine; apoptosis; brain derived neurotrophic factor; cerebral ischemia /hypoxia; cerebrovascular occlusions; estrogen receptors; laboratory rat; nerve growth factors; neuropharmacology; neuroprotectants; phytoestrogens; soybeans

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.

描述（由申请人提供）：雌激素是一种强大的神经保护激素，在减少脑缺血性损害中尤其有效。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，从而减轻了雌激素的益处。对依赖激素的癌症的担忧将继续阻止女性接受替代疗法。药理学选择性雌激素受体调节剂（SERMS）在保留雌激素的有益作用而不会增加癌症风险方面显示出希望。但是，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物，并认为这种疗法既有效又更安全。流行病学和实验数据表明，大豆植物雌激素中高饮食的饮食具有与雌激素相同的许多益处，并有可能减少传统HRT的负面副作用。然而，对于大脑饮食中的大豆植物雌激素的影响知​​之甚少。在体外，大豆植物雌激素可以模仿雌激素的神经保护作用，但是这些相同的化合物也已被证明可以抑制大脑中的某些雌激素作用。 本提案旨在确定大豆植物雌激素是否保护神经元免受体外和体内缺血性损害的影响。我们假设通过模仿雌激素的基因组和非基因组作用，大豆植物雌激素与生理相关的大豆植物雌激素具有神经保护作用。 AIM 1将检验以下假设：在雌激素受体依赖性方式的神经元细胞系模型中，大豆植物雌激素基因，大豆和雌激素抑制凋亡细胞死亡。 AIM 2将检验以下假设：在没有内源性雌激素的情况下，高大豆饮食将降低与大鼠中大脑中动脉闭塞相关的梗塞大小和细胞死亡。 AIM 3将检验以下假设：在没有内源性雌激素的情况下，摄入高大豆饮食将诱导神经保护基因BDNF，NGF，BCL-2，BCL-2，BCL-XL和TRKB的表达，并减少促凋亡的表达脑区域中大脑中动脉阻塞受损的脑区域的P75 NTR。该建议旨在提供有关植物雌激素保护大脑免受局灶性脑缺血能力的关键新信息。