基于体内过程的奥克梯隆型人参皂苷抗老年痴呆活性物质基础研究

Ocotillol type ginsenosides ocotillol、RT5、F11 have been regarded as the active components for the treatment of Alzheimer's disease. However, few data are available regarding their pharmacokinetic behaviors, which affect the application in clinic. The results from previous experiments indicated that most of the intact ginsenosides could be metabolized in stomach and/or in gastrointestinal tract to secondary saponins and aglycones, which further to form oxidation metabolite with more bioactive. Here, we hypothesize that ocotillol type ginsenosides may be generate deglycosidation and aglycone biotransformation metabolites, which were the real constituents against AD. This project focused on developing a method based on qualitative, quantitative, isolation and identification to understand absorption, distribution, metabolism and excretion (ADME) properties of parent compound and their metabolites. And according to nerve cell survival rate and the influence of neuron apoptosis, structure and activity relationship would be summarized. This project results may illustrate the constituents responsible for pharmacological effects, explore new drugs for AD, and provide new ideas for rational use of traditional Chinese medicines in clinic.

奥克梯隆型人参皂苷ocotillol、RT5、F11在防治老年性痴呆(AD)方面有着较好的应用基础，但由于体内代谢过程尚不明确，阻碍了其在临床中的合理应用。前期研究发现，人参皂苷在胃肠道内易被逐级代谢成次级苷和皂苷元，而皂苷元又进一步发生氧化代谢反应而发挥药效。于是我们推测：ocotillol型人参皂苷在体内通过脱糖基化与皂苷元结构变化代谢通路，产生的活性代谢产物是发挥抗AD药效的真正作用物质。本项目拟构建原形药物与代谢产物定性、定量、分离、鉴定同时进行的检测方法，探讨体内吸收、分布、代谢、排泄特征，同时基于代谢产物结构变化，以细胞存活率及抑制细胞凋亡情况为指标，揭示结构变化与生物学效应之间的关系。综合阐明体内发挥疗效的方式和作用物质，以寻求AD治疗的新药物，为临床合理应用中药提供新思路。

老年性痴呆(Alzheimer's disease，AD)是一种不可逆的、进展性的慢性精神致残及致死性疾病，目前仍缺乏特效的病因治疗方法，奥克梯隆(ocotillol)型人参皂苷在防治AD方面有着一定的研究基础，但由于体内过程尚不明确，阻碍了其在临床中的合理应用。本项目构建了原形药物与代谢产物定性、定量、分离、鉴定的检测方法，系统的探讨了体内吸收、分布、代谢、排泄特征，大鼠灌胃给予ocotillol型人参皂苷后，吸收快，消除缓慢，广泛的分布在各组织中，但血药浓度曲线下面积小，ocotillol和RT5与大鼠血浆蛋白有较强的结合作用，F11与大鼠血浆蛋白属于中等强度结合，3种化合物经尿样和粪样的排泄总量不足给药剂量的30%，在体内ocotillol型人参皂苷通过代谢反应所产生的代谢产物是其重要活性作用形式之一。本研究为探寻基于体内过程的抗AD新治疗药物提供了实验依据，也为临床合理应用中药提供了新思路。