Neuromodulatory Effects of Ginkgolides and Bilobalide

银杏内酯和白果内酯的神经调节作用

• 批准号: 6672208
• 负责人: KOJI NAKANISHI
• 金额: $ 23.26万
• 依托单位: COLUMBIA UNIV NEW YORK MORNINGSIDE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-12 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6672208
• 关键词: alternative medicine; brain mapping; central nervous system; chemical models; circular dichroism; flavonoids; ginkgo biloba; glycine receptors; ligands; mass spectrometry; medicinal plants; neural degeneration; neuroprotectants; neuroregulation; pharmacokinetics; plant extracts; platelet activating factor; positron emission tomography; radiotracer; receptor binding; terpenes; tissue /cell culture

DESCRIPTION (provided by applicant): This proposal is focused on the mode of action of the ginkgolides and bilobalide (terpenoid trilactones) from the tree Ginkgo biloba. The crude extract of G. biloba, a complex mixture composed of many different compounds, have shown effects on the diseased as well as healthy state of the mammalian brain. Clinical studies, animal studies, and various in vitro studies of the extracts have demonstrated beneficial effects against various neurodegenerative diseases, particularly Alzheimer's disease, as well as memory enhancing effects in the normal brain. However, very little is known about effects of individual constituents, especially at the molecular structural level. In this proposal, we will focus on the most unique constituents of the Ginkgo biloba extract, the ginkgolides and bilobalide, but not on the action of the crude extract which clearly involves synergistic effects, e.g., between the flavonoids (a major component) and the terpenoid trilactones. Some ginkgolides are antagonists of the platelet-activating factor receptor (PAFR), and appear to have antioxidant and neuroprotective properties. We have also found that ginkgolide B is a glycine receptor antagonist, while bilobalide is a potent GABAA receptor antagonist. Our goal is to determine the neuromodulatory effects of terpene trilactones on the mammalian central nervous system, using bioorganic and spectroscopic methods, including those under development in our laboratory on a molecular level. The specific topics to be studied include synthesis of radiotracers for positron emission tomography (PET) and ex vivo autoradiography studies, design and preparation of novel photolabile and fluorescent terpene trilactones analogs to be used to elucidate the interactions of terpene trilactones and PAFR. During these studies we will develop and apply novel methodologies such as ultra-microscale photolabeling and sequencing using unconventional mass spectrometric and circular dichroic techniques, as well as "membrane scissors". Using radioligand binding and microphysiometry, we will initiate studies on the effects of terpene trilactones on the cloned PAFR, using PAFR expressed in Chinese hamster ovary cells. The effects of terpene trilactones on long-term potentiation will be examined in vitro as well as in animal models. These studies can potentially provide new targets for terpene trilactones in the central nervous system that require the synthesis of new ginkgolide and bilobalide ligands.

描述（由申请人提供）：该提案集中于从树银杏鸟biloba的Ginkgolides和Biolobalide（Terpenoid Trilactones）的作用方式上。由许多不同化合物组成的复杂混合物G. biloba的粗提取物对哺乳动物大脑的患病和健康状态显示了影响。提取物的临床研究，动物研究和各种体外研究表明，针对各种神经退行性疾病，尤其是阿尔茨海默氏病以及正常大脑的记忆力增强作用。但是，关于个体成分的影响，尤其是在分子结构水平上，知之甚少。在此提案中，我们将重点关注银杏叶提取物，银杏和双核酸的最独特成分，但不关注粗糙提取物的作用，这些作用清楚地涉及协同作用，例如黄酮类动物（主要成分）和terpenoid trilactone之间。一些银杏是血小板激活因子受体（PAFR）的拮抗剂，似乎具有抗氧化剂和神经保护性质。我们还发现Ginkgolide B是甘氨酸受体拮抗剂，而双洛巴生物是有效的GABAA受体拮抗剂。我们的目标是使用生物有机和光谱法（包括分子水平上的实验室中正在开发的方法）来确定萜烯三轮酮对哺乳动物中枢神经系统的神经调节作用。要研究的特定主题包括用于正电子发射断层扫描（PET）和离体自显影研究的合成，设计和制备了新型的光片和荧光萜烯三轮酮类似物，以阐明构成三烯三轮酮和PaFR的相互作用。在这些研究中，我们将开发和采用新的方法，例如使用非常规质谱和圆形二分性技术以及“膜剪刀”等新方法和测序。使用放射性物体结合和微分生理测量法，我们将使用在中国仓鼠卵巢细胞中表达的PAFR来开始研究萜烯三酯对克隆PAFR的影响。将在体外和动物模型中检查萜烯三轮酮对长期增强的影响。这些研究可能会为中枢神经系统中的萜烯三轮酮提供新的靶标，该靶标需要合成新的Ginkgolide和Biolobalide配体。