咖啡酰白桦醇酯靶向TRPV1/RIP3通路的降温抗炎抗缺血调控机制研究

Ischemic stroke is a leading cause of death worldwide with complicated pathogenesis, but lack of efficacious drugs. Our previous study luckily identified that 28-O-caffeoyl botulin, a novel derivative of naturally occurring caffeoyl triterpene, exhibited potent in vitro and in vivo anti-ischemic effects, and further demonstrated to induce potent hypothermic and anti-inflammatory efficacies. Taken together the recent reports about dual regulative effects of TRPV1 and RIP3 pathways on both hypothermia and inflammation, the current project is designed to validate the relationship among hypothermic, anti-inflammation and anti-ischemic effects of 28-O-caffeoyl botulin, clarify the involvement of TRPV1 and RIP3 signaling in above effects, and further identify the direct pharmacological target of 28-O-caffeoyl botulin, through tool drug/gene intervention, proteomics, metabolomics, as well as FITGE method. This study may shed new light on the pharmacological mechanisms of 28-O-caffeoyl botulin, and provide important clues for validation of key pharmacological target or discovery of promising drug candidate for the treatment of ischemic stroke.

缺血性脑中风发病率高、发病机制复杂、关键药物靶标不明，迄今缺乏高效治疗药物。本项目是基于上述现状，结合我们前期研究发现的新型天然产物结构衍生物咖啡酰白桦醇酯的显著体内外抗缺血作用以及有效降温、抗炎药理作用立项的课题。项目以新近报道发现的兼具降温和抗炎双重调控作用的重要信号通路——TRPV1和RIP3信号通路为切入点，结合咖啡酰白桦醇酯前期发现与TRPV1通路关联性线索，并结合应用工具药/基因干扰、蛋白/代谢组学、分子垂钓(FITGE)等手段，拟开展咖啡酰白桦醇酯降温、抗炎、抗缺血三者的关联性研究，并揭示其调控TRPV1和RIP3通路作用与降温抗炎抗缺血损伤的关联，试图进一步阐明咖啡酰白桦醇酯的分子药理机制和直接药物新靶标。本项目的顺利实施将为发现新型高效抗缺血药物靶标和研发新型抗缺血性脑中风药物提供重要的线索和依据。

缺血性脑中风发病率高、发病机制复杂、关键药物靶标不明，迄今缺乏理想临床治疗药物。本项目针对潜在抗缺血性脑损伤和抗炎作用的咖啡酰白桦醇酯和活性结构衍生物开展体内外抗缺血药理药效和潜在作用机制研究，取得以下进展：1）证实咖啡酰白桦醇酯具有显著抗脑缺血损伤药效，具备显著降温和抗炎药理作用，并揭示降温、抗炎与咖啡酰白桦醇酯化合物结构的潜在构效关联；2）发现咖啡酰白桦醇酯抗脑缺血损伤作用可能间接调控TRPV1和调控RIP3相关信号通路HSP70和ERK表达，并证实其不直接调控TRPV1离子通道；3）揭示咖啡酰白桦醇酯对脑缺血大鼠脑组织NAA、GSH、GABA等小分子代谢物具有显著调控作用；4）发现新型咖啡酰白桦醇酯结构衍生物PDPOB，证实其具有显著体内外抗脑缺血药效，揭示其药理机制涉及AKT、PDGFR、Nrf2多信号通路调控，并证实其可与Nrf2关键调控蛋白Keap1的Kelch结构域发生直接结合。上述研究为解读咖啡酰白桦醇酯药理机制提供了重要线索和依据，并为抗脑缺血候选药物的研发提供了新线索和候选分子。累计发表项目基金标注（基金号81872859）通讯作者SCI论文4篇，获专利授权1项。