抗AD中药火麻仁和束骨姜黄的调节SIRT1有效物质研究

Single-target drugs against Alzheimer's disease (AD) are not effective enough, multi-target drugs raise as a potentially more effective strategy for AD treatment. Recent study revealed that multi-targets of AD (amyloid, tau, oxidative stress, inflammation) could be touched simultaneously by regulating histone deacetylase SIRT1, and that SIRT1 modulators have multi-target effects against AD. During screening SIRT1 modulators from anti-AD herbs, we found that Fructus cannabis and Curcuma xanthorrhiza were potent SIRT1 modulators resources by up-regulating cellular SIRT1 level or activating SIRT1. Presently, the study of anti-AD effect of these two herbs only focused on traditional target amyloid or anti-oxidant effect. This project aimed to search for SIRT1 modulators from the two traditional medicines with the help of fast screening, to study their multi-target anti-AD effects using cell models, and meanwhile to study the possible synergistic effect between compounds regulating SIRT1 expression and SIRT1 activators. At last the multi-target anti-AD effects of SIRT1 modulators or their groups were evaluated using AD animal models. The project will illustrate novel material basis of traditional medicines according to new idea about multi-target drug design. The study has important theory significance and potent application value for anti-AD drug discovery and design.

单靶点药物防治阿尔茨海默症（AD）疗效不理想，多靶点药物成为研究热点，新研究表明对组蛋白去乙酰化酶SIRT1调节能发挥多靶点（淀粉样肽、tau蛋白、氧化应激、炎症）AD防治功能。申请者对具有抗AD潜力的中药进行SIRT1调节活性筛选发现火麻仁、束骨姜黄含有促细胞SIRT1表达或激活SIRT1活性的物质，是潜在的SIRT1调节剂；而文献对两药材抗AD研究仅关注了提取物或主成分抗淀粉样肽毒性或抗氧化作用。本项目拟结合快速活性筛选，发现并获得药材中典型的SIRT1调节剂；细胞水平研究SIRT1调节剂对多个AD病理通路的影响；研究促细胞SIRT1表达与SIRT1激活物质间的协同作用；动物水平评价典型SIRT1调节剂或具有协同作用的调节剂组合的多靶点抗AD作用。本项目将采用多靶点设计的新思路研究中药防治AD的新物质基础与作用机理，对抗AD药物的发现和设计具有重要的理论意义和潜在的应用价值。

传统应用与近期文献显示中药材火麻仁与束骨姜黄具有防治阿尔茨海默症（AD）的潜力，其有效物质有待深入研究。组蛋白去乙酰化酶SIRT1调节能发挥多靶点AD 防治功能。本项目对束骨姜黄、火麻仁进行了化学研究，分离鉴定59个化合物，报道新化合物11个，首次分离化合物23个；优化了火麻仁苯丙酰胺类（木脂素酰胺为主）成分的提取工艺，对火麻仁苯丙酰胺提取物进行了定性定量分析；活性筛选发现束骨姜黄中多个倍半萜、火麻仁木脂素酰胺类成分的SIRT1调节潜力；建立LPS刺激BV2细胞的神经炎症模型，对火麻仁的活性成分Grossamide、Cannabisin F、CLG进行了抗炎、抗氧化作用机制研究，结果表明这些化合物均可抑制NF-κB信号通路，进一步研究表明Grossamide可抑制TLR4而发挥作用，Cannabisin F可激活SIRT1/Nrf-2信号通路，而且其对炎症因子的调节作用具有SIRT1调节依赖性，同时给予SIRT1抑制剂，将抵制其作用，CLG的作用涉及AMPK；通过建立LPS诱导的神经炎症小鼠模型，对火麻仁苯丙酰胺提取物抗AD相关生物活性进行了评价，该提取物可以改善LPS诱导的神经炎症模型小鼠的学习记忆能力、抑制脑组织炎症因子的表达、改善神经细胞的损伤。本项目通过系统的化学研究与体内外生物活性评价，从新的角度揭示了束骨姜黄、火麻仁防治AD的物质基础与作用机理。