活血利窍，开通玄府干预血脑屏障腺苷受体促进益脑方药脑靶向作用机理研究

项目名称： 活血利窍，开通玄府干预血脑屏障腺苷受体促进益脑方药脑靶向作用机理研究

项目编号： No.81473588

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 贝伟剑

作者单位： 广东药科大学

项目金额： 66万元

中文摘要： 血脑屏障（BBB）是治疗脑部疾病药物的瓶颈。中医脑玄府与BBB关系密切。通玄府治脑疾历史久远，效果显著。我们根据活血利窍-开通玄府理论，首次提出非芳香活血药与补益药配伍也有脑靶向作用，发现银杏叶配伍补益药人参首乌，能促进活性成分数十倍透过BBB、提高脑组织内浓度，增强药效，但其物质基础和分子机制还不清楚。进一步实验显示其脑靶向有P-糖蛋白非依赖性，推测其可能与腺苷受体通路有关。本项目拟利用体外BBB模型，跨内皮电阻检测、紧密结构电镜检查、分子抑制剂和RNA干扰阻断腺苷受体，研究银杏叶活性成分对BBB结构功能和相关腺苷受体、ZO-1、Occludin3和 Claudin-5表达的影响，旨在获得银杏叶干预腺苷受体调节BBB通透性的可靠证据，将明确银杏叶脑靶向作用机理及其物质基础，科学阐析活血利窍、开通玄府的生物学本质。为益气活血利窍开通玄府提高疗效、研发治疗脑部疾病创新中药提供新思路和科学依据

中文关键词： 血脑屏障；活血利窍；配伍机制；脑靶向；腺苷受体

英文摘要： The blood brain barrier (BBB) is the bottleneck of drugs for the treatment of brain diseases. The brain Xuanfu in Traditional Chinese medicine(TCM) is closely correlated with BBB. Tong Xuan Fu to treat brain disease has a long history and excellent effect. Based on the TCM theoryHuoXue（Activating Blood circulation）LiQiao(benefit 'qiao')- Kai Tong 'XuanFu' , We first suggest that Combination of non-aromatic HuoXue Yao(Herbs for invigorating blood circulation ) and Tonic agent might also promote the opening of BBB to realize the brain-targeting distribution of the active components of the TCM herbs. Our previous study demonstrated that the composition of non-aromatic blood circulation- activating herb ginkgo leaf with tonic ginseng and fleece flower root, promoted their active components to penetrate through BBB and increase their concentration in the brain tissue by 10 more times, and then enhanced the therapeutic efficacy. But the material base and the molecular mechanism of the above effect is not yet clear. Further experiments showed that selective inhibition of P-G glycoprotein only partly weaken its brain targeting effect, suggesting that the mechanism is P-glycoprotein independent, and might be related to adenosine receptor pathway. This project intends to use the in vitro BBB model of the co-culture of the brain microvascular endothelial cells and astrocytes, the transendothelial electrical resistance detection, electron microscopy of BBB tight junction （TJ） structure, selective inhibitors and siRNA interference blocking adenosine receptor, and LC-MS methods to study the effects of active components of Ginkgo biloba leaves on the BBB structure,function and related BBB protein ，such as adenosine receptor, ZO-1, Occludin3 and Claudin-3/5 expression, then to obtain reliable evidence that Ginkgo biloba leaves regulate the permeability of BBB by interfering with adenosine receptor. Our project will clarify the mechanism and material basis of brain targeting effect of Ginkgo biloba leaves, scientifically elucidate the biological essence of the hypothesis HuoXue（Activating Blood circulation）LiQiao(benefit 'qiao')-Kai Tong 'XuanFu'. That might provide new ideas and experimental supports for improving the efficacy of the therapeutic strategy of BuQi HuoXue Li'Qiao' -KaiTong 'XuanFu' and the research and development of innovative Chinese drugs for the treatment of brain disease.

英文关键词： blood brain barrier;HuoXue LiQiao;Machanism of TCM Prescription formulating;brain targeting;adenosine receptor