Anti-edema and neuroprotective effects of Ginkgo extract EGb761 and bilobalide

性状（由申请方提供）：银杏和贯叶连翘（圣约翰草，SJW）草药提取物，分别广泛用于治疗认知功能障碍和轻度至中度抑郁症。负责治疗效果的成分（一种或多种）正在接受严格的审查。在过去的几年里，我们已经收集了这两种植物的两种主要成分的神经保护特性的新证据：白果内酯（来自银杏）和贯叶金丝桃素（来自金丝桃）。银杏内酯被发现在体外和体内抑制缺氧和兴奋性毒性过程中的膜破裂。在初步实验中，它还减少了小鼠中风模型中的梗死面积和水肿形成。发现贯叶连翘素拮抗由NMDA受体激活引起的细胞反应，如钙内流和细胞肿胀。目前的建议是基于这样的假设，银杏和SJW提取物，和它们的成分，在急性脑缺血模型中具有神经保护特性。本研究拟采用离体脑片研究银杏叶和三金汤提取物及其纯组分的脑水肿形成和抗脑水肿作用。对于体内研究，我们将采用小鼠大脑中动脉闭塞（MCAO）来测试提取物和纯化合物对梗塞面积和水肿形成的影响。此外，我们将使用微透析结合中风监测缺血的代谢参数（葡萄糖，乳酸盐，谷氨酸盐，钾，甘油，胆碱），我们将测试预处理与植物对这些参数的影响。这些实验将（a.）研究两种广泛使用的草药提取物和（B.）分别确定银杏内酯和贯叶金丝桃素对银杏和SJW提取物的神经保护作用的作用。

DESCRIPTION (provided by applicant): Extracts of Ginkgo biloba and Hypericum perforatum (St. John's wort, SJW) herbal medicines that are widely used for the treatment of cognitive dysfunctions and for mild to moderate depression, respectively. The constituents (one or many) that are responsible for therapeutic effects are under intensive scrutiny. Over the last few years, we have collected novel evidence for neuroprotective properties of two major constituents of these two plants: bilobalide (from Ginkgo) and hyperforin (from Hypericum). Bilobalide was found to inhibit membrane breakdown during hypoxia and excitotoxicity in vitro and in vivo. In preliminary experiments, it also reduced infarct area and edema formation in a stroke model in mice. Hyperforin was found to antagonize cellular responses initiated by NMDA receptor activation such as calcium influx and cellular swelling. The present proposal is based on the hypothesis that Ginkgo and SJW extracts, and their constituents, have neuroprotective properties in acute models of brain ischemia. We will use in vitro-studies in brain slices to study edema formation and anti-edema effects of Ginkgo and SJW extracts and their pure constituents. For in vivo-studies, we will employ middle cerebral artery occlusion (MCAO) in mice to test effects of extracts and pure compounds on infarct area and edema formation. In addition, we will use microdialysis in combination with stroke to monitor metabolic parameters of ischemia (glucose, lactate, glutamate, potassium, glycerol, choline), and we will test the effects of pretreatment with botanicals on these parameters. These experiments will (a.) investigate the potential clinical utility of neuroprotective effects of two widely used herbal extracts and (b.) define the role of bilobalide and hyperforin for neuroprotective effects of Ginkgo and SJW extracts, respectively.