In vivo Studies of Ginkgo biloba Neuroprotection

描述（由申请人提供）：随着我们的平均寿命延长，阿尔茨海默病（AD）的发病率在美国稳步上升。因此，预防或降低这种疾病的发生率是医学研究的高度优先事项。银杏叶的标准化提取物（EGb 761）已被用于治疗某些与衰老和AD相关的脑功能障碍和痴呆。大量证据表明EGb 761具有神经保护作用。然而，提取物的作用机制知之甚少。我们之前的研究由美国国立卫生研究院资助，提供了证据，证明EGb 761在体外具有抗淀粉样蛋白β（A β）聚集和抗凋亡特性，这有望成为潜在的重要神经保护作用机制。 这个跨学科项目的目标是进一步了解EGb 761在体内的神经保护机制。我们将继续检验EGb 761的神经保护作用是通过抑制A β寡聚化、抗氧化特性和增强生物体内源性应激反应来实现的假设。我们将使用转基因C。elegans模型与AD的转基因小鼠模型相结合，以研究A β聚集、氧化和毒性之间的可能联系。本项目的具体目标是：1）通过A β沉积物的荧光染色和A β诱导的转基因C.表达人A β的线虫; 2）通过诱导型转基因C. 3）EGb 761诱导的野生型和转基因C. elegans，采用基因芯片技术; 4）通过检测AD转基因小鼠模型的海马依赖性空间学习能力来确定EGb 761对认知障碍的影响。前期研究结果和初步数据表明了该项目的可行性。更好地理解EGb 761的神经保护机制对于理解潜在的神经退行性疾病过程和设计针对神经退行性疾病的治疗策略非常重要

DESCRIPTION (provided by applicant): The incidence of Alzheimer's disease (AD) has steadily increased in the United States as our average lifespan has lengthened. Thus, the means to prevent or reduce the rate of this disorder is a high priority for medical research. A standardized extract of Ginkgo biloba leaves (EGb 761) has been used for treatment of certain cerebral dysfunctions and dementias associated with aging and AD. Substantial evidence indicates that EGb 761 has neuroprotective effects. The action mechanisms of the extract are, however, poorly understood. Our previous studies funded by the National Institutes of Health provided evidence for the anti-amyloid beta (A beta) aggregation and anti-apoptotic properties of EGb 761 in vitro, which hold promise as potentially important neuroprotective mechanisms of action. The goal of this interdisciplinary project is to further our understanding of the neuroprotective mechanisms of EGb 761 in vivo. We will continue to test the hypothesis that the neuroprotective effect of EGb 761 is achieved by inhibition of A beta oligomerization, antioxidative properties and augmentation of an organism's endogenous stress-response. We will use transgenic C. elegans models in conjunction with a transgenic mouse model of AD to study possible links between A beta aggregation, oxidation and toxicity. The specific aims of the present project are: 1) to correlate effects of EGb 761 on A beta aggregation and toxicity through fluorescence staining of A beta deposits and behavioral analysis of A beta-induced paralysis in the transgenic C. elegans expressing human A beta; 2) to define activities of single constituents of Egb 761 against A beta-induced oxidation through kinetic study of protein carbonyls in an inducible transgenic C. elegans; 3) to implicate changes in gene transcription profile induced by EGb 761 in the wild type and the transgenic C. elegans, using DNA microarray method, 4) to determine effects of EGb 761 on cognitive impairment through testing hippocampus-dependent spatial learning in a transgenic mouse model of AD. Previous results and preliminary data show the feasibility of this project. A better understanding of the 'mechanisms of EGb 761 neuroprotection will be important for understanding of the underlying neurodegenerative processes and for designing therapeutic strategies that target neurodegenerative disorders