基于雪貂模型的常山碱盐呕吐特点及致吐机制研究

疟疾是全球关注的重要公共卫生问题之一。近年来随着一线用药青蒿素耐药性的报道越来越多，亟需研发结构迥异的新型抗疟药。常山为传统抗疟良药，其抗疟效价优于氯喹和青蒿素，但囿于其强烈的致吐副作用，严重制约了其在临床的广泛使用。问题的聚焦点在于：（1）缺乏灵敏且关联临床的呕吐评价模型；（2）致吐机制不清。因此，本项目在前期开创性引入评价呕吐作用金标准的雪貂模型的基础上，通过系统评价DAS诱导呕吐作用特点，以Ca2+/CaMKII/ERK1/2介导的5-HT3和NK1受体通路交互作用为切入点，通过正向激活和反向抑制两个角度，共同探究DAS诱导呕吐的关键环节和分子机制。同时通过脑内直接注射阻断剂对DAS诱导的迷走神经放电行为和呕吐现象的影响，探究DAS到底是通过还是外周，中枢还是两者共同作用诱导的呕吐现象。为临床如何针对性的拮抗常山诱导的呕吐副作用提供科学依据。

Malaria is one of the important public health issues of global concern. In recent years, with more and more reports on the resistance of first-line artemisinin, there is an urgent need to develop new antimalarial drugs with very different structures. Changshan is a traditional antimalarial medicine. Its antimalarial potency is superior to chloroquine and artemisinin, but its strong vomiting side effects severely restrict its widespread clinical use. The focus of the problem is: (1) The lack of a sensitive and clinically relevant vomiting evaluation model; (2)Unclear mechanism of vomiting. Therefore, on the premise of solving the sample preparation in the early stage, this project pioneered the introduction of the ferret model for evaluating the vomiting effect gold standard. -The interaction between HT3 and NK1 receptor pathways is the entry point. Through the two angles of positive activation and reverse inhibition, we will jointly explore the key links and molecular mechanisms of DAS-induced vomiting. At the same time, the effect of DAS-induced vagal discharge and vomiting by direct injection of blockers into the brain is explored to determine whether DAS is through or peripheral, central, or both. Provide scientific basis for how to antagonize the side effects of Changshan induced vomiting clinically.