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Neuroprotective mechanisms of EGb-761

EGb-761 的神经保护机制

基本信息

批准号：
6947923
负责人：
Sylvain DORE
金额：
$ 20.44万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-09-15 至 2006-08-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Ginkgo biloba extract (EGb 761 ; EGb) is a standardized extract and one of the most renowned natural compounds specifically to treat neurological conditions. The constituents from the extract are likely to have synergistic effects that have been shown to be protective against oxidative stress injury. However, the cellular mechanisms of protection afforded by Ginkgo biloba are still unclear. We tested the hypothesis that the neuroprotective action of EGb could be due partially to an induction of heme oxygenase 1 (HO1). We and others have reported that modulation of HO activity may well have direct physiological implications in stroke and in Alzheimer disease. Through the use of cultured neurons, we demonstrated that EGb induces HO1 in a dose-dependent manner. Interestingly, our preliminary results indicate that pre-treatment of primary neurons with EGb followed by washing out the cells and then inducing toxicity, either by H202 or glutamate, EGb revealed neuroprotection. This effect is abolished with the heme oxygenase inhibitor (SnPPIX). We are proposing that several of the protective effects of EGb in ischemic conditions could be mediated through beneficial actions of heme degradation and its metabolites. We will first determine the cerebral blood flow, the infarct size, and the neuronal death following cardiac arrest in EGb-treated WT mice and test whether these effects are significantly decreased in the HOI-/- mice. Then, we will determine whether EGb-induced changes in HO1 expression result in changes in iron homeostasis and cell survival in neuronal cultures derived from WT and HOI-/- mice. To further address possible cellular mechanisms of action, primary cultured neurons derived from WT and HOI-/- mice will be used to test their susceptibility to heme toxicity and their role in controlling the iron efflux. These results should indicate if EGb pretreatment can be protective against iron toxicity and cell death and if this protection is abolished in HOI-/- cells. Together, we will test this new hypothesis that some of the beneficial effects attributed to EGb could be attributed to HO1 induction itself and its biological actions. It could provide new pathways to support the theory that EGb could provide brain's resistance in conditions of ischemia and aged-related dementia.

描述(申请人提供)：银杏叶提取物(EGb 761；EGb)是一种标准化提取物，是专门用于治疗神经系统疾病的最著名的天然化合物之一。提取物中的成分可能具有协同作用，已被证明对氧化应激损伤具有保护作用。然而，银杏叶所提供的细胞保护机制仍不清楚。我们验证了EGB的神经保护作用可能部分归因于诱导血红素加氧酶1(HO1)的假说。我们和其他人已经报道，HO活性的调节很可能在中风和阿尔茨海默病中具有直接的生理学意义。通过使用培养的神经元，我们证明了EGb以剂量依赖的方式诱导HO1。有趣的是，我们的初步结果表明，EGb预先处理原代神经元，然后清洗细胞，然后用H202或谷氨酸诱导毒性，EGb显示出神经保护作用。这种作用可被血红素加氧酶抑制剂(SnPIX)消除。我们提出，银杏叶提取物在缺血条件下的一些保护作用可能是通过血红素降解及其代谢物的有益作用来调节的。我们将首先确定EGB处理的WT小鼠的脑血流量、梗塞范围和心脏骤停后的神经元死亡，并测试这些影响在HoI-/-小鼠中是否显著减少。然后，我们将确定EGB诱导的HO1表达的变化是否会导致WT和HoI-/-小鼠神经细胞培养中铁稳态和细胞存活率的变化。为了进一步探讨可能的细胞作用机制，来自WT和HoI-/-小鼠的原代培养神经元将被用来测试它们对血红素毒性的敏感性以及它们在控制铁外流中的作用。这些结果表明银杏叶提取物对铁毒性和细胞死亡是否具有保护作用，以及这种保护在HOI-/-细胞中是否被取消。我们将共同检验这一新的假设，即银杏叶提取物的一些有益作用可能归因于HO1诱导本身及其生物学作用。这可能为银杏叶提取物在脑缺血和老年性痴呆条件下提供脑抵抗的理论提供新的途径。