赤芍中防治阿尔茨海默病强微量活性成分的发现与功能评价

Paeonia lactiflora (Chishao) is an important traditional Chinese medicine (TCM) that could promote blood circulation to remove blood stasis, and has been used in the clinical treatment of Alzheimer's disease (AD). Generally, peoniflorin is regarded as the indicative bioactive substance against AD in P. lactiflora. In our preliminary research, however, a fraction from P. lactiflora extract after removing out the peoniflorin in vivo and in vitro still showed significant activity against AD with different action mechanism. This result indicated that some potent active minor constituents against AD in P. lactiflora were still unclear. Taking minor constituents as a breakthrough point, based on the integrative application technologies established for solving the technical bottleneck problems with investigation on bioactive minor constituents in complex systems of TCM, e. g. difficult to identify, difficult to obtain, and difficult to evaluate, this project is launched to look for potent active minor constituents against AD in P. lactiflora and evaluate their functions. In addition, the bioactive minor constituents and their derivatives would be synthesized from the major constituents in P. lactiflora by simple reaction on the basis of their biological relations. Further, structure activity relations would be discussed to optimize the lead compounds, which could provide basis for new drug development. Also, this project could provide supportive scientific evidence for the relationship between the minor constituents and functions in TCM, which would be significant for the development of TCM and their quality standards.

活血化瘀中药赤芍在临床上用于防治阿尔茨海默病（AD），疗效确切，高含量芍药苷被认为是赤芍防治AD的指标性成分。本课题组前期发现，赤芍提取物剔除了芍药苷后的分离组分在体内外药理模型上仍显示较强的抗AD活性，活性显著优于芍药苷，且同时具有抑制神经炎症和神经保护作用，表明该组分中还存在抗AD不同作用机制的强微量活性成分。本项目拟在此基础上，以微量成分为切入点，针对中药中微量活性成分“难识别、难获取、难评价”技术瓶颈，通过前期建立的中草药微量成分识别和获取的关键技术和方法体系，深入系统研究赤芍中抗AD强活性组分的微量成分，发现新颖结构类型的强活性化合物，阐明其精确结构、药理活性特点，探索转化合成的制备方法，优选出先导化合物，为新型药物创制奠定基础，也为赤芍的临床应用提供科学依据。本项目对于科学地诠释中药微量活性物质的结构和药理作用，提升我国中草药创新药物研发能力和质量标准，具有重要应用价值。

围绕中药赤芍水提取剔除了芍药苷后的抗AD活性分离组分，以微量成分为切入点，针对中药中微量活性成分“难识别、难获取、难评价”技术瓶颈，通过前期建立的中草药微量成分识别和获取的关键技术和方法体系，深入系统研究赤芍中抗AD强活性组分的微量成分，共分离鉴定了117个化合物，其中新微量成分30个，包括新颖骨架化合物1个，发现具有显著神经保护、抗肝纤维化、抗过敏等显著活性化合物14个；在此基础上，对前期获得具有潜在抗AD活性苯并呋喃单萜化合物进行了全合成和结构衍生化研究，已合成目标化合物及其衍生物共26个。进一步药效评价，遴选出抗肝纤维和抗过敏候选药物2个，并初步阐明了它的作用机制，目前对它已开展深入的成药性研究。同时，优化了中草药微量成分识别和获取的关键技术，提高了中药化学活性成分的发现效率，并得到推广应用。新化合物的发现丰富了中药化学的内容，对中药化学学科的发展和中药材及其制剂质量评价具有重要的学术和应用价值。抗肝纤维化候选药物的发现，阐明了赤芍“活血化瘀”部分药效物质基础，为揭示中药的科学内涵提供了重要依据，也为中药来源创新药物的研究奠定了重要基础。研究结果在国内外重要期刊发表研究论文21篇，申请中国发明专利8项；获得中国专利授权1项。参加编写专业教材1部。先后获得了北京市杰出青年科学基金、中华中医药学会中青年创新人才、青海省“昆仑英才·高端创新创业人才”杰出人才。