研究从知母中提取的化合物知母皂甙元（ZMS）抗老年痴呆症（AD）的药理学作用。ZMS能显著改善多种动物模型的学习记忆功能,它不抑制胆碱酯酶,不占领M受体的配基结合位点,因此也不是M受体激动剂或拮抗剂。 ZMS主要是调整脑内M受体的密度和它的M1、M2受体亚型,使之从低于正常调整到接近或达到正常,并且脑M受体的改善同学习记忆功能的改善呈正相关。因此,ZMS是一种新型的能显著改善学习记忆功能的药物,它不同于目前已知的胆碱脂酶抑制剂或M受体的激动剂、拮抗剂。其机理研究发现ZMS是通过促进M受体蛋白分子的生成,而使M受体在较高水平上达到新的平衡。这种促进合成是由于ZMS能提高细胞M1和M2受体的mRNA表达和提高mRNA的稳定性,从而促进M受体蛋白的表达。ZMS提高M受体mRNA的稳定性需要细胞合成某种蛋白质。

The purpose of this work is to study the basic pharmacological action of sarsasapogenin, a sapogenin from the Chinese medicinal herb Rhizoma Anemarrhenae, （abbreviated as ZMS in this paper）, on learning ability and memory of three animal models:aged rats and two neurodegeneration models produced either by single unilateral injection of beta-amyloid 1-40（Aβ1-40）plus ibotenic acid（Ibot A）or by bilateral injection of Ibot A alone into nucleus basalis magnocellularis. Y-maze test and step through test revealed that learning ability and memory was impaired in the models and was improved by oral administration of ZMS. ZMS did not inhibit acetylcholinesterase, nor did it occupy the binding sites of muscarinic acetylcholine receptor（M receptor）. On the other hand the densities of total brain M receptor and its M1 and M2 subtypes was significantly lower than control rats and ZMS significantly raised the densities of total M receptors and its M1 and M2 subtype. Linear regression revealed significant correlation between the learning ability/memory and the density of either total M receptor or its M1 and M2 subtypes. Therefore, ZMS seems to represent a new approach to the pharmacological regulation of learning and memory and appears to be not simply palliative but may modify the progression of the disease. Mechanistic studies revealed that the increase of brain M receptor caused by ZMS is due to the increase of synthesis rate of M receptor molecules. The increase of synthesis rate in turn is due to the increase of mRNA of M1 and M2 receptor subtypes.Measurement of the half-life of M1 and M2 receptors by RT-PCR showed that ZMS could prolong the half-life of both subtypes. This effect of ZMS requires a sysnthesis of certain unknown protein since if cycloheximide was added prior to the addition of ZMS in the cultured cells, the effect of ZMS was abolished.

国家自然科学基金资助项目(39320004):知母甙元S调整M、β受体抗衰老的药效及机理研究,负责人:易宁育;国家自然科学基金项目(30070926):知母和黄芪有效成分合并应用时改善老年认知障碍的机理,负责人:胡雅儿。