藏药矮紫堇治疗缺血性心脏病的药效物质基础与分子机制

Ischemic heart disease brings serious threat to human health, and the drug research and development have been facing with big challenges. The discovery of new leads and effective drug candidates from Tibetan medicine with unique medical theory and the unique habitat ethno medicines are getting more attention and attention...The representative Tibetan medicine Corydalis hendersonii (CH) with heat clearing and detoxifying, drying blood stasis, and blood pressure lowering effect has been used mainly for high altitude polycythemia and vasculitis. The preliminary study found that CH ethanol extract showed significant effect to improve the cardiac function of myocardial ischemic mice, with cardioprotective effect against myocardial ischemic injury. This project employs an acute myocardial infarction (AMI) mice model to evaluate the cardioprotective effect of CH on ischemic heart disease effect, and alkaloids containing quaternary ammonium salts and those non-alkaloids mainly including flavonoids were hypothesized as the effective basis, and to discover potential active molecules or ingredients, also, the myocardial cell model in vitro and various biological methods were established and used to elucidate its molecular mechanism and synergistic mechanisms focusing inflammation, anti-apoptosis, oxidative stress, and antiplatelet aggregation signaling pathways. ..The implementation of the project will expand the scope of clinical application of CH, further explore the precious medicinal resources, enhance the study of therapeutic material, and enrich the traditional Chinese medicine with heat clearing and detoxifying effects for the treatment of ischemic heart disease, and for the enhancement of innovative research of drug discovery from ethno medicine also has an important inspiration and reference...This project will published five to seven papers, including at least three SCI articles. Also application of one patent and training of one doctoral students and four master's degree will be executed based on the grant.

缺血性心脏病(IHD)严重危害着人类健康，其药物研发一直面临挑战。从具有独特医学体系和特有生境来源的藏药中寻找有效候选药物愈渐受青睐。藏药矮紫堇具有清热解毒、干瘀血、降血压功效，传统用于高山多血症、脉管炎等。前期发现，矮紫堇提取物具有显著改善小鼠缺血性心功能作用，因而项目拟采用心梗大、小鼠模型，评价矮紫堇治疗IHD的作用，从包含季铵盐的生物碱与黄酮为主的非生物碱整体上阐明其药效物质；通过体外心肌细胞模型和各种生物学技术，围绕抗血小板聚集、抗炎、抗氧化损伤、抗凋亡等多个环节与信号通路阐明其分子机理及可能的协同机制。项目实施将拓展矮紫堇的临床应用范围，进一步挖掘矮紫堇藏药资源，提升其药效物质基础研究水平，同时对于丰富清热解毒药用于治疗缺血性心脏病的新药发现，提升民族药创新药物研究，亦具有重要的参考。依托本项目将发表5-7篇论文(SCI 3-4篇)，申请专利1项，培养1名博士和4名硕士。

缺血性心脏疾病（IHD）严重危害着人们的健康和生命，因发病机理复杂，造成的后果严重，目前仍无确切行之有效的防治手段，基于传统医药理论和临床实践开展缺血性心脏病的防治研究、药物研发一直是人们所关注的热点。民族医药因其独特的理论体系和特有自然环境中的药物，为IHD的研究和新药开发提供了广阔的视角，越来越受到关注和认可。本项目以藏药矮紫堇Corydalis hendersonii Hemsl. (CH)为研究对象，通过结扎小鼠左冠状动脉，评价CH的乙醇总提取物（TE）、分割部位（富生物碱部位RAF和贫生物碱部位PAF）对缺血性心脏疾病的改善作用，明确药效物质范围。同时通过H9c2心肌细胞体外模型评价RAF的抗心肌缺血作用，采用Westernblot、qPT-PCR及免疫荧光等分子生物学方法，主要从细胞凋亡的角度进行药效机制探讨，并确定其药效物质基础和作用机理。.药效研究结果显示，矮紫堇乙醇提取物TE和富生物碱部位RAF均能改善心梗小鼠心功能，降低血清中升高的CK-MB和LDH水平，减轻心肌组织梗死边缘区炎性细胞浸润程度；体外采用H9c2心肌细胞低糖缺氧模型模拟体内病理环境，检验细胞活力，观察细胞形态，发现在安全剂量范围内，RAF能显著改善细胞活力，上述结果表明RAF具有抗心肌缺血作用，这一发现不仅进一步锁定了矮紫堇抗心肌缺血药效物质的范围，也为临床用药提供了科学阐释。化学成分研究结果显示，从矮紫堇中分离鉴定了59个化合物，包括54个生物碱类成分，5个酚酸或酚苷类化合物，其中16个为新化合物，10个为本属首分，1个为新天然产物。多个化合物和流分对心肌细胞H9c2显示抗氧化、抗缺氧和抗炎作用，为阐明CH保护缺血性心肌损伤的药效物质奠定了基础，为矮紫堇临床治疗缺血性心脏病提供了科学依据，并为中药药效物质研究新的探索积累的经验。.本项目培养了4名硕士研究生，已发表1篇SCI，6篇核心期刊，4篇会议论文，另有2篇SCI与1篇核心正在发表中。