马先蒿属植物中环烯醚萜的抗焦虑活性及其作用机制

Extensive study on pharmacological activities of the isolated iridoids revealed that many of them are the bioactive principles of the plants for which these plants are used in traditional medicines. Iridoids have been isolated from many anxiolytic natural medicinal plants and some of them showed obvious anxiolytic effect. Pedicularis is one of the largest genera of angiosperms and comprises over 600 species in the world and about 300 species in China, in which some have been used to treat diseases. Many compounds were isolated from Pedicularis, including more than 50 iridoids. During investigation on chemical constituents of the whole of ethanol extracts of five Pedicularis, more than 90 compounds including 40 iridoids were isolated by our research group. The ethanol extracts of two Pedicularis plants (P. spicata and P. rex) were tested on anxiety model of rat. Results indicated that two plants showed anxiolytic activity in vivo. Densispicnin C isolated from Pedicularis densispica showed same bioactivity.. Based on the reported pharmacological activities of some of the isolated iridoids from different anxiolytic species which are used in folklore and from Pedicularis , it can be concluded that extensive research in the fields of iridoids is very much essential for quantification of these anxiolytic components and determination of their mechanism of biological action in anxiolytic models before use of these pharmaceuticals as prospective herbal drugs and clinical trials in humans. The project takes two said Pedicularis plants with effect of reinforcing yin and calming the nerves as a research object.Our research group would carry out four main aspects about the project. First, the iridoid constituents would be isolated by various chromatographic methods and determinted by chemical evidence and spectra data. Second, adopting the international common-used anxiety animal model with the elevated plus-maze test (EPM), the effect of anti-anxiety of iridoids from Pedicularis would be observed. Third, to find out potent anxiolytic iridoids derivatives, some compounds would be prepared on the basis of iridoids from Pedicularis by the chemical reaction and examined their anxiolytic activity. Finally, determination of mechanism of biological action is important to explore the natural anxiolytic drugs. In order to explain related anxiolytic mechanisms, the ethology and neurotransmitter in the brain such as 5-hydroxytryp tamine (5-HT), noradrenaline (NE) and dopamine (DA) would be observed. The intended results would provide the experimental and theorical data on anxiolytic drugs and on bioactive principles of the Pedicularis plants for which these plants are used in traditional medicines.

环烯醚萜是一类具有广泛生物活性的天然产物，是许多抗焦虑天然药物的特征性成分，已成为开发抗焦虑药物的一个重要来源。项目组前期研究表明马先蒿属植物富含环烯醚萜成分，并从中分离出40多个环烯醚萜类化合物。预实验研究发现，穗花、大王两种马先蒿属植物乙醇提取物具有抗焦虑活性，同时也证明环烯醚萜单体densispicnin C具有抗焦虑活性。本项目拟以马先蒿属植物中环烯醚萜作为研究对象，对其进行抗焦虑活性及作用机制研究。采用化学筛选的方法对两种马先蒿属植物中环烯醚萜成分进行针对性系统分离，并利用大鼠高架十字迷宫等模型进行抗焦虑活性评价。在活性筛选的基础上，利用化学方法对天然环烯醚萜进行结构修饰，结合神经递质在大鼠脑组织中的含量变化，对该类化合物进行构效关系及作用机制研究。本项目研究成果可为阐明马先蒿属植物的药用功效及作用物质基础提供实验依据，也为开发具有抗焦虑活性天然药物提供理论指导。

马先蒿属植物富含环烯醚萜类成分，该类化合物具有明显的抗焦虑活性。本项目以穗花、大王两种马先蒿作为研究对象，利用分离方法从中得到天然环烯醚萜20多种。在此基础上，对京尼平苷、桃叶珊瑚苷和梓醇等环烯醚萜代表物进行了结构修饰，得到30多种结构修饰物。利用高架十字迷宫、明暗箱等抗焦虑模型对天然及结构修饰物进行了活性评价，京尼平苷、桃叶珊瑚苷、梓醇及其苷元、乙酰化产物显示了明显的抗焦虑活性。另外，利用高效液相-电化学检测方法测定小鼠脑组织中γ-氨基丁酸、谷氨酸、去甲肾上腺素、多巴胺、5-羟色胺的含量，与模型对照组比较，γ-氨基丁酸含量的升高显示抗焦虑作用；去甲肾上腺素、多巴胺、5-羟色胺的含量降低也预示着受试物具有抗焦虑活性。利用分光光度计对焦虑小鼠血清中NO的含量进行了测定，其结果也预示着上述环烯醚萜通过改变其血清中NO的浓度而发挥抗焦虑作用。本项目阐明了两种马先蒿属植物的化学成分，筛选了环烯醚萜抗焦虑先导化合物，为进一步开放该类抗焦虑药物提供了理论基础。