金莲花治疗缺血性脑卒中的药效物质基础及基于铁死亡（ferroptosis）的作用机制研究

Ischemic stroke results from a transient or permanent reduction in cerebral blood flow that is typically restricted to the territory of a major brain artery. Ischemic stroke is the second leading cause of death in industrialized countries and the most important cause of such disease as acquired adult disability. Despite of increasing studies focused on mechanisms of ischemia, few effective therapeutic drugs have been used in clinical practice, leading to a search for agents that might protect neurons against ischemia. Traditional Chinese medicine has accumulated extensive clinical experience in treating stroke with indigenous herbal materials. Our experimental evidence suggested that Flos trollii may be of therapeutic benefit in ischemic stroke. However, the effective components and mechanism of Flos trollii in the treatment of ischemic stroke are not clear. After chemical profiling of Flos trollii, the “active components fishing and knockout” technique, combined with high-throughput in-vitro model, is applied to discover and confirm the effective components of Flos trollii for the treatment of ischemic stroke. Furthermore, the mechanism of the effective components of Flos trollii in curing ischemic stroke is investigated via ferroptosis pathway. This project would be helpful for the clinical application and further development of Flos trollii, and may provide new methods for investigation of the effective components and mechanisms of Traditional Chinese Medicines.

缺血性脑卒中是一种以脑部缺血性损伤症状为主要临床表现的疾病，具有极高的致死率和致残率，是严重危害人类健康和生命安全的常见难治性疾病之一。申请人前期研究结果显示，清热解毒药金莲花具有抗缺血性脑卒中的作用，但其药效物质基础和作用机制尚未阐明。本项目在系统表征金莲花体内外化学成分的基础上，建立多种高通量筛选模型（神经细胞氧糖剥夺/复氧损伤模型、炎症模型、氧化损伤模型），结合“化学成分群缺失-捕获”技术，快速发现与确认金莲花抗缺血性脑卒中主效成分群；在明确金莲花主效成分群基础上，从“铁死亡”角度阐释金莲花作用机制。通过以上研究，以期为金莲花抗缺血性脑卒中的临床应用提供数据支撑；为从金莲花药材中开发出药效成分群明确、作用机制清晰的抗缺血性脑卒中创新药物奠定基础；为中药药效物质基础及作用机制研究提供研究方法与思路。

缺血性脑卒中是一种以脑部缺血性损伤症状为主要临床表现的疾病，具有极高的致残率，严重危害人类健康，降低生活质量。本研究以金莲花为研究对象，首先对金莲花的化学成分进行了全面表征，从中共鉴定出122个化合物，包括黄酮类83个，有机酸类18个，氨基酸类7个，皂苷类5个，苯乙醇苷类3个，香豆素类3个，核苷1个，生物碱1个及内酯1个。并对金莲花体内代谢进行分析，通过对给药后的大鼠血液、尿液、粪便进行解析，建立了金莲花体内物质基础。继而采用动物模型，细胞模型以及网络药理学手段，证实金莲花可通过铁死亡途径治疗缺血性脑卒中，Vitexin，Orientin，Hyperoside，Isoswertisin和Isoswertiajaponin是其主要活性成分。该研究可为金莲花二次开发提供科学依据，为中药药效物质基础及作用机制研究提供研究方法与思路。