基于H/MAD模型探讨栀子治疗阿尔茨海默病药效物质作用于MAPK/ERK和RAGE信号通路的分子机制

Prevention and treatment of Alzheimer′s Disease（AD） has become a global social problem, the disease characteristics and pathogenesis is complex, the existing treatments and pharmacophore models are not ideal. This task group Considering the effect of the aging, cerebral hypoperfusion、 Aβ in AD causes and corresponding effect of Gardenia jasminoides Ellis, "Heterogeneitys/ Multi- factors'AD （H/MAD）" model was established with the above control mechanism, Studies confirmed the total extract and pastille cerebrospinal fluid of the Gardenia jasminoides Ellis has the treatment of H/MAD with anti-Aβ injury and anti-inflammatory activity. more than eighty compounds identified, mainly for the iridoids(thirty-six), flavonoids and triterpenes. But the pharmacodynamic material and molecular mechanism of Gardenia jasminoides Ellis in anti-Aβ injury MAPK/ERK and anti-inflammatory RAGE signal pathway is not clear, need to be further studied. The project plans, from the H/MAD overall, tissue, cells for pharmacological screening , with activity oriented, application of Chinese medicine serum, cerebrospinal fluid drug chemistry method and molecular biology methods, establish "Identification of fingerprint-Effect mechanism-Target point"relevance research, reveal the target compositions and molecular mechanism in anti-Aβ injury MAPK/ERK and anti-inflammatory RAGE signal pathway abuot three types of components (mainly iridoids )from the treatment of H/MAD of Gardenia jasminoides Ellis. Laying foundations for the comprehensive development utilization of Gardenia jasminoides Ellis and provide a new idea to study on anti-AD drugs.

阿尔茨海默病（AD）的防治已成为全球性的社会问题，其病症的特征与发病机制较复杂，现有的治疗药物和药效模型均不理想。本项目综合考虑衰老、脑低灌注和Aβ在AD成因中作用及栀子相应的疗效，建立了符合上述防治机理的H/MAD模型，并证实栀子总提取物及含药脑脊液治疗H/MAD具有抗Aβ损伤和抗炎症的活性，从中分离并鉴定80多个化合物，主要为环烯醚萜类(36个)、黄酮类和三萜类，但栀子作用于抗Aβ损伤MAPK/ERK和抗炎RAGE信号通路的物质基础及分子机制尚不明确，有待深入研究。在前期工作基础上，本项目拟在H/MAD整体、组织、细胞层面上，应用血清、脑脊液药物化学和分子生物学等方法，建立"可识别指纹图谱-效应机制-靶点"的相关性，阐明上述三类成分（主要是环烯醚萜类）防治H/MAD在MAPK/ERK和RAGE信号通路的靶成分和分子机制，为栀子综合开发利用奠定基础及抗AD药物的研究提供新的思路。

本项目瞄准“血管危险因子（VRF）-Aβ蛋白-阿尔茨海默病（AD）”存在交互作用的基本问题，围绕“VRF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“VRF-Aβ-AD”交互作用的异质性及多因性阿尔茨海默病（H/MAD）的药物筛选模型，确证栀子环烯醚萜类有效部位、黄酮类有效部位和京尼平苷单体有效成分均能显著改善H/MAD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MAPK/ERK和RAGE信号通路的NF-KB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细胞损伤模型对从栀子治疗异质性及多因性阿尔茨海默病有效部位中分离鉴定140多个环烯醚萜类成分、单萜类成分、三萜类成分、环烯醚萜苯丙素苷类和黄酮类成分等含量较大的59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16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。本课题阐明了栀子治疗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MAPK/ERK和RAGE信号通路的NF-KB蛋白靶点的分子机制不清楚，有待深入研究。上述研究为栀子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。