Involvement of 5-Serotonin and Substance p Pathways in Dichroa Alkali Salt-Induced Acute Pica in Rats.
Involvement of 5-Serotonin and Substance p Pathways in Dichroa Alkali Salt-Induced Acute Pica in Rats.
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DOI：
10.3389/fphar.2021.588837
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发表时间：
2021
影响因子：
5.6
通讯作者：
Ye Z
中科院分区：
文献类型：
--
作者：
Ma L;Li S;Li J;Zhang G;Hou H;Ye Z
常山碱是我国传统抗疟药常山的有效成分。但是，由于其呕吐副作用，其临床应用受到限制。近年来，DAS引起的呕吐引起了广泛的关注，但其机制尚未阐明。本研究旨在探讨DAS引起的呕吐，并破译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的背景下使用了多种方法的组合，例如免疫印迹分析、HPLC-ECD、ELISA、定量实时PCR、药理学抑制和免疫组织化学测定。我们证明DAS通过激活5-HT和SP信号通路参与常山所致呕吐。DAS可诱导大鼠异食癖模型的高岭土摄入量呈剂量依赖性。此外，DAS引起类似顺铂（DDP）的特征：“低剂量双峰，高剂量单峰异食癖现象”。有趣的是，DAS刺激周围回肠和中央延髓，并增加5-HT，SP和前速激肽-A的释放和5-HT 3和NK 1受体的表达在急性期的两个问题。此外，5-HT 3和NK 1受体拮抗剂有效地减轻DAS诱导的高岭土摄入，并显着降低DAS诱导的急性期5-HT和SP水平。在多巴胺受体抑制的情况下没有观察到类似的反应。本研究创新性地揭示了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以有效地拮抗DAS诱导的呕吐。我们的研究结果提示了一种潜在的治疗策略（基于批准用于人类的药物），以防止DAS相关的不良反应。
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 p (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-HT3 and NK1 receptors in the two issues in acute phase. Additionally, the 5-HT3 and NK1 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.
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影响因子：
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作者：
Darmani, Nissar A.;Crim, Jennifer L.;Ramirez, Juan
通讯作者：
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影响因子：
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作者：
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通讯作者：
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作者：
Mehendale, SR;Aung, HH;Yuan, CS
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通讯作者：
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P 物质增强大鼠三叉神经节神经元 5-HT3 受体介导的电流
影响因子：
2.5
作者：
Hu, WP;You, XH;Li, ZW
通讯作者：
Li, ZW