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

描述（由申请人提供）：银杏叶和贯叶连翘（St. John's wort， 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）受到严格审查。在过去的几年里，我们收集了新的证据，证明这两种植物的两种主要成分：双叶碱（来自银杏）和金丝桃素（来自金丝桃）的神经保护作用。在体外和体内实验中发现双胆碱可抑制缺氧和兴奋性毒性时的膜破坏。在初步实验中，它还减少了小鼠中风模型的梗死面积和水肿形成。研究发现，hyperperin可拮抗由NMDA受体激活引起的细胞反应，如钙内流和细胞肿胀。目前的建议是基于银杏和SJW提取物及其成分对急性脑缺血模型具有神经保护作用的假设。我们将使用体外脑切片研究银杏和SJW提取物及其纯成分的水肿形成和抗水肿作用。对于体内研究，我们将在小鼠大脑中动脉闭塞（MCAO）中测试提取物和纯化合物对梗死面积和水肿形成的影响。此外，我们将使用微透析联合卒中监测缺血代谢参数（葡萄糖，乳酸，谷氨酸，钾，甘油，胆碱），我们将测试预处理植物药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的神经保护作用的潜在临床应用，(b)分别确定银杏和SJW提取物中双叶碱和超根素的神经保护作用。

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.