知母皂苷BII抗痴呆的体内药效物质基础及作用机制研究

临床上一些主含皂苷的中药制剂显示了良好的疗效，但皂苷普遍存在生物利用度低的现象。已有研究显示，一些皂苷化合物间存在明显协同作用，据此我们提出了皂苷与其代谢产物，在其有效浓度水平之下通过协同作用发挥药理作用的"协同学说"。知母皂苷BII是中药知母的主要成分，对多种动物模型显示了良好的抗痴呆活性。本课题拟鉴定大鼠灌胃知母皂苷BII后血及脑中的代谢产物，测定原型及主要代谢产物的浓度；利用Aβ诱导的大鼠神经细胞损伤模型、上调胆碱能N及M受体的细胞模型、促神经生长和分化的PC12细胞模型及体外小板聚集实验等，筛选原型及主要代谢产物的活性，观察原型及代谢产物间的协同作用，以此阐明知母皂苷BII抗痴呆的体内药效物质基础及作用机制，从而解释其原型生物利用度低，而抗痴呆活性肯定的质疑。这不仅有利于知母皂苷BII作为抗痴呆药物的研究开发，也为其它中药皂苷的研究提供了一个可以借鉴的新的思路。

The traditional Chinese medicine products mainly containing saponins show satisfactory efficacy in clinic, but their bioavailability is always low. Previous studies showed that there are obvious synergies among some saponins. Accordingly, we propose the "synergistic doctrine" and try to explain the saponin prototype and its metabolites play pharmacological effects together below their individual effective concentration level. Timosaponin BII, the main component of Anemarrhena asphodeloides Bunge, shows potential anti-dementia activity on variety of animal models and low bioavailability too. This project intends to identify metabolites of Timosaponin BII in blood and brain after rats take BII orally, and to determine the concentrations of the prototype and major metabolites. Then synergy between the prototype and its metabolites would be investigated by some in vitro models, such as, the rat nerve cell damage model induced by Aβ, the cholinergic N and M receptors up-regulating cell models, nerve growth and differentiation PC12 model, platelet aggregation in vitro experiments, and the screening the activity of the prototype and its metabolites. In this case, we clarify the substance basis and action mechanism of Tiosaponin BII in vivo, and explain the phenomenon of its potential anti-dementia activity and low bioavailability. The results of this project also provide a new strategy and ideas for investigation of other saponins.