Ma Lina, Li Sidi, Li Jian, Zhang Guangping, Hou Hongping, Ye Zuguang
Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China.
Post-doctoral Scientific Research Center, China Academy of Chinese Medical Sciences, Beijing, China.
Front Pharmacol. 2021 Apr 22;12:588837. doi: 10.3389/fphar.2021.588837. eCollection 2021.
Dichroa alkali salt (DAS) is the active ingredient of Changshan, a traditional Chinese antimalarial medicine. However, owing to its vomiting side effects, its clinical use is limited. Recently, DAS-induced vomiting has attracted broad attention; however, the mechanisms involved have not yet been elucidated. The present study aimed to explore DAS induced vomiting and decipher the potential role of the 5-serotonin (5-HT) and substance (SP) signaling pathways. We used a combination of approaches in the context of a rat pica model, such as immunoblot analysis, HPLC-ECD, ELISA, quantitative real-time PCR, pharmacological inhibition, and immunohistochemistry assays. We demonstrated that DAS contributed to Changshan-induced vomiting via the activation of the 5-HT and SP signaling pathways. DAS could induce a dose-dependent kaolin intake in the rat pica model. Moreover, DAS caused a similar profile as Cisplatin (DDP): "low-dose double-peak, high-dose single-peak pica phenomenon". Interestingly, treatment with DAS stimulated the peripheral ileum and central medulla oblongata and augmented the release of 5-HT, SP, and preprotachykinin-A and the expression of 5-HT and NK receptors in the two issues in acute phase. Additionally, the 5-HT and NK receptor antagonists effectively alleviated DAS-induced kaolin intake and significantly reduced DAS-induced 5-HT and SP levels in the two issues in acute phase. Similar responses were not observed in the context of dopamine receptor inhibition. This study innovatively revealed that the 5-HT and SP-mediated vomiting network plays an important role in DAS-induced acute vomiting; of note, ondansetron, and aprepitant can effectively antagonize DAS-induced vomiting. Our results suggest a potential therapeutic strategy (based on drugs approved for human use) to prevent the DAS-associated adverse reactions.
常山碱盐（DAS）是传统抗疟中药常山的活性成分。然而，由于其呕吐副作用，其临床应用受到限制。近年来，DAS引起的呕吐已引起广泛关注；然而，其涉及的机制尚未阐明。本研究旨在探讨DAS引起的呕吐，并解读5-羟色胺（5-HT）和P物质（SP）信号通路的潜在作用。我们在大鼠异食癖模型中采用了多种方法相结合，如免疫印迹分析、高效液相色谱-电化学检测法、酶联免疫吸附测定、定量实时聚合酶链反应、药理抑制和免疫组织化学分析。我们证明，DAS通过激活5-HT和SP信号通路导致常山引起呕吐。在大鼠异食癖模型中，DAS可诱导剂量依赖性的高岭土摄取。此外，DAS引起的情况与顺铂（DDP）相似：“低剂量双峰、高剂量单峰异食癖现象”。有趣的是，DAS处理可刺激外周回肠和延髓，并在急性期增加5-HT、SP和前速激肽原-A的释放以及这两个部位5-HT和NK受体的表达。此外，5-HT和NK受体拮抗剂可有效减轻DAS诱导的高岭土摄取，并显著降低急性期这两个部位DAS诱导的5-HT和SP水平。在多巴胺受体抑制的情况下未观察到类似反应。本研究创新性地揭示，5-HT和SP介导的呕吐网络在DAS诱导的急性呕吐中起重要作用；值得注意的是，昂丹司琼和阿瑞匹坦可有效拮抗DAS诱导的呕吐。我们的结果提示了一种潜在的治疗策略（基于已批准用于人类的药物）来预防与DAS相关的不良反应。
