Zhu Zhiyao, Wu Sha, Wang Yuxuan, Wang Jiayi, Zhang Yujia
School of Traditional Chinese Medicine, Capital Medical University, Beijing, China.
Beijing Key Lab of Traditional Chinese Medicine Collateral Disease Theory Research, Capital Medical University, Beijing, China.
Front Pharmacol. 2022 Mar 24;13:805984. doi: 10.3389/fphar.2022.805984. eCollection 2022.
Migraine is a common neurological disorder that manifests as recurrent attacks of unilateral and throbbing headache. "Chuanxiong" (Apiaceae; Chuanxiong rhizoma) and rotundus L. (Cyperaceae; Cyperi rhizoma) (CRCR), is a classic prescription for treating migraine. This study aimed to reveal the potential mechanisms of CRCR extract against migraine using integrated analysis of metabolomics and network pharmacology. Behavioral changes in the nitroglycerin rat migraine model were determined from von Frey withdrawal response. Untargeted serum metabolomics was used to identify the differentially expressed metabolites and metabolic pathways. The differentially expressed metabolites were analyzed to obtain the corresponding targets by a compound-reaction-enzyme-gene network. Network pharmacology was used to construct a compound-target-pathway network. The common targets of metabolomics and network pharmacology were further analyzed. Metabolomics analysis identified 96 differentially expressed metabolites and 77 corresponding targets. Network pharmacology analysis identified 201 potential targets for CRCR against migraine. By intersecting 77 targets with 201 targets, monoamine oxidase A (MAO-A), monoamine oxidase B (MAO-B), and catechol--methyltransferase (COMT) were identified as the common targets, and MAO-A, MAO-B, and COMT were involved in the tyrosine metabolism pathway. Further experiments demonstrated that the contents of MAO-A and COMT were significantly increased in serum and brainstem tissue of the migraine rats. CRCR extract significantly decreased the contents of MAO-A and COMT, while no significant difference was found in MAO-B. Metabolomics analysis indicated that the contents of 3,4-dihydroxyphenylacetate (DOPAC) and 3-(4-hydroxyphenyl)pyruvate (HPP) were significantly increased in the migraine rats, and CRCR extract caused significant decreases in DOPAC and HPP. Interestingly, DOPAC and HPP were two differentially expressed metabolites involved in the tyrosine metabolism pathway. Correlation analysis showed that DOPAC and HPP were highly positively correlated with MAO-A and COMT. Taken together, two key differentially expressed metabolites (DOPAC and HPP), two key targets (MAO-A and COMT), and one relevant metabolic pathway (tyrosine metabolism) showed great importance in the treatment of migraine. This research could provide a new understanding of the potential mechanism of CRCR against migraine. More attentions should be paid into the tyrosine metabolism pathway in future studies.
偏头痛是一种常见的神经系统疾病，表现为单侧搏动性头痛反复发作。“川芎”（伞形科；川芎根茎）和香附（莎草科；香附根茎）（CRCR）是治疗偏头痛的经典方剂。本研究旨在通过代谢组学和网络药理学的综合分析揭示CRCR提取物抗偏头痛的潜在机制。通过von Frey撤针反应测定硝酸甘油大鼠偏头痛模型的行为变化。采用非靶向血清代谢组学方法鉴定差异表达的代谢物和代谢途径。通过化合物-反应-酶-基因网络分析差异表达的代谢物以获得相应靶点。利用网络药理学构建化合物-靶点-途径网络。进一步分析代谢组学和网络药理学的共同靶点。代谢组学分析鉴定出96种差异表达的代谢物和77个相应靶点。网络药理学分析确定了CRCR抗偏头痛的201个潜在靶点。通过将77个靶点与201个靶点进行交叉分析，确定单胺氧化酶A（MAO-A）、单胺氧化酶B（MAO-B）和儿茶酚-O-甲基转移酶（COMT）为共同靶点，且MAO-A、MAO-B和COMT参与酪氨酸代谢途径。进一步实验表明，偏头痛大鼠血清和脑干组织中MAO-A和COMT的含量显著增加。CRCR提取物显著降低了MAO-A和COMT的含量，而MAO-B未发现显著差异。代谢组学分析表明，偏头痛大鼠中3,4-二羟基苯乙酸（DOPAC）和3-（4-羟基苯基）丙酮酸（HPP）的含量显著增加，CRCR提取物使DOPAC和HPP显著降低。有趣的是，DOPAC和HPP是参与酪氨酸代谢途径的两种差异表达代谢物。相关性分析表明，DOPAC和HPP与MAO-A和COMT高度正相关。综上所述，两种关键的差异表达代谢物（DOPAC和HPP）、两个关键靶点（MAO-A和COMT）和一条相关代谢途径（酪氨酸代谢）在偏头痛治疗中具有重要意义。本研究可为CRCR抗偏头痛的潜在机制提供新的认识。未来研究应更多关注酪氨酸代谢途径。
