基于SDAD模型探寻缬草中确有疗效缬草属特有成分治疗阿尔茨海默病及其睡眠障碍协同作用于Aβ蛋白的分子机制

Sleep Disorder (SD) is the cause of Alzheimer's Disease (AD) and is also one of the clinical manifestations of that disease, Aβ is the common way to various causes induced AD, A new study has found that 'SD-Aβ-AD'interaction exists, study of its mechanism is positive significance to the treatment of AD disorders. Comprehensive aging, SD and Aβ in AD cause effect and the corresponding effect of valerian, for the first time proposed and established the mechanism of prevention and cure of SDAD model, confirmed that the valerian total extract treatment SDAD is anti-Aβ injury activity, from the isolation and identification of 18 Valeriana endemic elements, its lignans and new sesquiterpenoids preliminary proved to have anti-Aβ injury activity, its MAPK/ERK signaling pathway and molecular mechanism is not clear, need to be further studied.Therefore, the project plans from the SDAD overall, tissue, cells for pharmacological screening, the application of chinese medicine serum, cerebrospinal fluid drug chemistry method and molecular biology methods, establish and interpretate 'curative effect truly components -Identification of fingerprint' and 'SD-Aβ-AD' relevance interaction of effect mechanism, to elucidate that the molecular mechanism in Aβ protein and its MAPK/ERK signaling pathway to curative effect truly Valeriana endemic elements for synergistic effect treatment of Alzheimer's Disease and Sleep Disorder. Laying foundations for the comprehensive development utilization of Valeriana and provide the new target, new mode and new ideas to study on anti-AD drugs.

睡眠障碍（SD）既是阿尔茨海默病（AD）的病因又是病症的临床表现之一， Aβ是各种原因诱发AD的共同途径，最新研究"SD-Aβ-AD"存在交互作用，其机制研究对治疗AD病症具有积极意义。综合衰老、SD和Aβ在AD成因中作用及缬草相应疗效，首次提出并建立上述防治机理的SDAD模型，证实缬草总提取物治疗SDAD具有抗Aβ损伤活性，从中分离鉴定18个缬草属特有成分，其中木脂素和新倍半萜类前期证实具有抗Aβ损伤活性，其作用于MAPK/ERK信号通路机制尚不明确，有待深入研究。因此，本项目拟在SDAD整体、组织、细胞层面上，应用血清药物化学、分子生物学等方法，诠释"确有疗效成分-可识别指纹图谱"与"SD-Aβ-AD"交互作用的效应机制，阐明确有疗效缬草属特有成分防治SDAD协同作用于Aβ蛋白及其MAPK/ERK信号通路的分子机制，为缬草综合开发利用奠定基础及抗AD药物研究提供新靶点、新模式与新思路。

本项目瞄准“睡眠障碍（SD）-Aβ蛋白-阿尔茨海默病（AD）”存在交互作用的基本问题，围绕“SD既是AD的病因又是病症的临床表现”这一关键科学问题，首次提出并建立以Aβ蛋白为核心“SD-Aβ-AD”交互作用的睡眠障碍阿尔茨海默病（SDAD）的药物筛选模型，确证缬草的20%乙醇洗脱部位（以木脂素苷类成分为主）、40%乙醇洗脱部位（以黄酮类成分为主）、70%乙醇洗脱部位（以环烯醚萜苷元、缬草烷型和吉玛烷型倍半萜类成分为主）的有效部位均能显著改善SDAD模型大鼠空间学习记忆能力，减少自由基对脑组织的氧化损害，减少β-APP和Aβ1-40的阳性细胞表达，能够减轻iNOS过表达，抑制COX-2活性和减少对核因子NF-KB 的激活来降低AD大鼠的脑损伤过程，具有治疗AD的药理作用，提示其抗Aβ损伤作用于NF-KB/MAPK信号通路的蛋白靶点，其分子机制有待进一步深入研究。本课题组利用Aβ25-35致PC12细胞损伤模型对上述有效部位中分离鉴定60多个环烯醚萜类成分、木脂素类成分和黄酮类成分等含量较大的32个化合物进行活性筛选，筛选确定抑制Aβ纤丝产生和阻止其聚集的15个活性成分，为开发抑制Aβ纤丝形成和聚集的自主知识产权新药奠定坚实基础。本课题阐明了缬草治疗AD的药效物质基础，但其有效成分及其移行入血成分以及代谢产物抗Aβ损伤作用于NF-KB/MAPK信号通路的蛋白靶点的分子机制不清楚，有待进一步深入研究。上述研究为缬草的资源开发和合理应用提供系统的科学资料，为开发治疗AD自主知识产权候选新药的研制奠定坚实基础。