金山五味子治疗阿尔茨海默症活性成分及机制

Alzheimer's disease (AD) is a degenerative brain syndrome characterized by a progressive decline in memory, thinking, comprehension, calculation, language, learning capacity and judgment sufficient to impair personal activities of daily living. More than 25 million people in the world suffer from Alzheimer's disease and as many as 8 million Chinese are living with AD. Alzheimer's destroys brain cells, causing problems with memory, thinking and behavior severe enough to affect work, lifelong hobbies or social life. Prevention and treatment of AD has attracted the widespread concern of the society. The discovery of new anti-AD lead compounds and its mechanism study is becoming an important topic for the scientists. Beta amyloid protein (Aβ) forms plaque in which proteins are accumulated and aggregated in brain, and thus has a causal role in the pathogenesis of AD. Therapeutics targeting α,β,γ-scretases could reduce the production of Aβ from the beginning and thus become a new and effective treatment for AD. Schisandra glaucescens mainly distributes in the western of Hubei province and south-eastern of Sichuan province. Its stems were traditionally used for the treatment of insomnia and spontaneous sweating and the fruits for rheumatism and arthritis, etc. Our previous studies revealed that the extracts and some polar fractions of the stems and fruits of S. glaucescens had significant neuro-protective effects on SH-SY5Y cells and inhibiting Aβ42 production on HeLa cell line transfected with human amyloid precursor protein (APP) cultured in DMEM culture medium. Further investigation on the stems of S. glaucescens led to the isolation of a variety of triterpenoids and lignans. Among them, some tetrahydrofuran and dibenzylbutane type lignans had good Aβ42 inhibition effects and neuro-protective effects. Targeting Aβ and related α,β,γ-scretases, this project will seek for the anti-AD agents from S. glaucescens which could potentially decrease or block the production of Aβ. The final purpose is to develop effective anti-AD drugs capable of fundamental treatment without side effects.

阿尔茨海默病(AD)是严重危害老年人身体健康的神经退行性疾病，β淀粉样蛋白(Aβ)在其发病过程中起关键作用，减少Aβ产生或加快其清除已成为AD治疗新策略。作用于分泌酶的药物能从源头上减少Aβ产生，从而根本上阻止AD发展，因此成为AD治疗最有希望的靶点。金山五味子产于湖北西部和四川中南部，民间用其果实治疗心悸失眠、自汗盗汗等症，用其藤茎治疗风湿痹痛、神经衰弱等。前期研究结果显示，金山五味子藤茎和果实提取物均具良好的抑制Aβ42产生及神经保护作用，进一步跟踪分离从金山五味子藤茎得到多种四氢呋喃型和二芳基丁烷型木脂素类成分，且部分木脂素类化合物能显著抑制Aβ42产生，并对氧化损伤和缺氧损伤的SH-SY5Y细胞具保护作用。本课题拟以Aβ及其形成过程中的α，β和γ分泌酶及其它相关物质为靶点，对金山五味子藤茎和果实分别进行深入的抗AD活性成分筛选及机制研究，以期寻找高效低毒抗AD先导化合物。

阿尔茨海默病 (Alzheimer’s disease，AD) 是一种老年人常见的神经退行性疾病。随着社会人口的老龄化，该病的患病率呈急剧上升趋势。针对AD进行的新型先导化合物的发现具有重要的研究意义。该项目对采自湖北神农架地区的金山五味子及相关五味子属植物的果实及藤茎进行了抗AD活性成分的筛选和化学结构研究，从中分离鉴定了332个化合物，包括156个木脂素类成分（含36个新的木脂素）和105个三萜类成分（含39个新的三萜类成分和7个新三萜骨架化合物）。通过理化常数测定及UV、IR、HRESIMS、1H NMR、13C NMR、DEPT、HSQC、HMBC、1H-1H COSY、NOESY、 ECD等波谱数据分析，并结合X-单晶衍射、ECD计算、水解反应、气相分析、标准品对照等方法，确定了所有化合物的化学结构。对所分离得到的化合物进行了抗AD相关的活性研究，结果表明部分木脂素类化合物表现出不同程度的DPPH自由基清除活性和剂量依赖性的FRAP抗氧化活性。另有一些木脂素类化合物在0.08-10 M浓度范围内对其中，对H2O2所致SHSY5Y细胞氧化损伤、CoCl2所致SHSY5Y细胞缺氧损伤、以及Aβ25-35引起的SHSY5Y细胞损伤表现出不同程度的保护作用。部分化合物可致SHSY5Y细胞相对存活率达到95%以上，具有较好的抗AD潜力和进一步开发利用价值。相关研究成果已申请专利并得到授权（201210416957.5，一种木脂素类化合物及其制备方法和应用，2015.08.05授权；201210417900.7，一种木脂素类化合物及其在防治阿尔茨海默症中的应用，2015.09.08授权）。该项目的研究也为金山五味子等五味子属植物治疗神经衰弱、失眠、健忘、盗汗、多梦等传统药用功能提供了理论依据。