Song Zhimin, Li Meijing, Zhou Ziwei, Guo Xiaomeng, Wang Qi, Zhang Zekuan, Wang Keshu, Zheng Qixiang, Gou Wenjing, Wu Sha, Zhao Hui, Gong Muxin
School of Traditional Chinese Medicine, Capital Medical University, No. 10 of Xitoutiao, Youanmenwai, Fengtai District, Beijing 100069, China.
Beijing Key Laboratory of Traditional Chinese Medicine Collateral Disease Theory Research, Beijing 100069, China.
Pharmaceuticals (Basel). 2025 Mar 18;18(3):426. doi: 10.3390/ph18030426.
Chronic migraine (CM) is a common complex nervous system disease, often accompanied by symptoms of the digestive tract that interact with each other, leading to prolonged and difficult-to-cure migraines. These symptoms are associated with abnormalities in 5-HT and its receptors. Wuzhuyu decoction (WZYD) is a traditional Chinese medicine prescription commonly used in clinics to treat CM; it relieves gastrointestinal symptoms, such as nausea and vomiting; however, its mechanism is still unclear. Investigating the differences in the role of WZYD compared to existing drugs targeting 5-HT receptors in the treatment of CM not only helps elucidate its pathogenesis but also provides possibilities for the development of new therapeutic approaches. An inflammation soup (IS)-induced CM male rat model was established. Based on a preliminary experiment, the target of WZYD in treating CM was determined by network pharmacology, and verified by molecular docking. ELISA, immunofluorescence, western blot, and real-time quantitative polymerase chain reaction (RT-qPCR) were used to evaluate the expression levels of CM-related indicators (5-HT, calcitonin gene-related peptide (CGRP), and c-Fos) to ensure the successful establishment of the CM model and the effectiveness of the drug. On this basis, the protein expression levels of 5-HT1A/3A receptors and their cAMP-response element binding protein (CREB) signaling pathway were detected by western blot and immunohistochemistry. The role of 5-HT1A/3A receptors in the treatment of CM by WZYD was validated using a 5-HT1A receptor antagonist (WAY 100635) and a 5-HT3A receptor agonist (SR 57227). The results showed that WZYD increased the expression of 5-HT in the brain, decreased the expression of CGRP, c-Fos, ionized calcium-binding adapter molecule 1 (Iba1), and relieved CM. At the same time, WZYD also increased the expression of the 5-HT1A receptor and decreased the expression of the 5-HT3A receptor in the brain and colon of CM rats. Subsequently, WZYD further exerted its brain-gut integrated therapeutic effects by regulating the CREB signaling pathway mediated by 5-HT1A/3A receptors in the brain and colon of CM rats. WZYD not only regulates neurotransmitters in the brain and colon at the same time, but also specifically regulates 5-HT1A/3A receptors in the brain and colon, which explains the characteristics and advantages of WZYD from a new perspective. While effectively relieving headache symptoms, it also improves related gastrointestinal symptoms, which is more conducive to the treatment of CM.
慢性偏头痛（CM）是一种常见的复杂神经系统疾病，常伴有相互作用的消化道症状，导致偏头痛迁延难愈。这些症状与5-羟色胺（5-HT）及其受体异常有关。吴茱萸汤（WZYD）是临床常用的治疗CM的中药方剂；它能缓解恶心、呕吐等胃肠道症状；然而，其作用机制尚不清楚。研究WZYD与现有靶向5-HT受体的药物在治疗CM方面作用的差异，不仅有助于阐明其发病机制，也为开发新的治疗方法提供了可能。建立了炎症汤（IS）诱导的CM雄性大鼠模型。基于初步实验，通过网络药理学确定WZYD治疗CM的靶点，并通过分子对接进行验证。采用酶联免疫吸附测定（ELISA）、免疫荧光、蛋白质免疫印迹法（western blot）和实时定量聚合酶链反应（RT-qPCR）评估CM相关指标（5-HT、降钙素基因相关肽（CGRP）和c-Fos）的表达水平，以确保成功建立CM模型和药物的有效性。在此基础上，通过western blot和免疫组织化学检测5-HT1A/3A受体及其环磷酸腺苷反应元件结合蛋白（CREB）信号通路的蛋白表达水平。使用5-HT1A受体拮抗剂（WAY 100635）和5-HT3A受体激动剂（SR 57227）验证5-HT1A/3A受体在WZYD治疗CM中的作用。结果表明，WZYD增加了脑中5-HT的表达，降低了CGRP、c-Fos、离子钙结合衔接分子1（Iba1）的表达，并缓解了CM。同时，WZYD还增加了CM大鼠脑和结肠中5-HT1A受体的表达，降低了5-HT3A受体的表达。随后，WZYD通过调节CM大鼠脑和结肠中由5-HT1A/3A受体介导的CREB信号通路，进一步发挥其脑肠综合治疗作用。WZYD不仅同时调节脑和结肠中的神经递质，还特异性调节脑和结肠中的5-HT1A/3A受体，从新的角度解释了WZYD的特点和优势。在有效缓解头痛症状的同时，还改善了相关胃肠道症状，更有利于CM的治疗。
