Untargeted and Targeted Metabolomics Reveal the Regulatory Mechanisms of the Chuanxiong–Baizhi Herb Pair in Treating Migraine

RATIONALE: Migraine is a debilitating neurological disorder characterized by headaches, autonomic changes, and heightened sensitivity to stimuli. Traditional Chinese medicine, particularly the Chuanxiong-Baizhi (CX-BZ) herb pair, has shown clinical efficacy in migraine management, but its underlying mechanisms remain unclear. METHODS: A migraine model was established by subcutaneous NTG injection. Sixty Sprague-Dawley rats were randomly divided into control, model, positive, and low-, medium-, and high-dose CX-BZ groups. Behavioral tests were used to assess writhing behavior and thermal pain thresholds. Histopathological examination and enzyme-linked immunosorbent assays were performed to evaluate neuronal damage and inflammatory cytokines. Metabolic alterations were analyzed using untargeted metabolomics based on UHPLC-Orbitrap-MS, followed by targeted metabolomics validation with UPLC-QQQ-MS. RESULTS: CX-BZ pretreatment significantly reduced migraine-like behaviors, including writhing frequency, and increased pain thresholds in NTG-induced rats. It also lowered calcitonin gene-related peptide (CGRP) and tumor necrosis factor-α (TNF-α) levels in serum and the medulla. Metabolomic profiling identified distinct metabolic alterations between the model and CX-BZ-treated groups, mainly involving amino acid metabolism and the tricarboxylic acid (TCA) cycle. Targeted metabolomics confirmed the regulation of key metabolites within these pathways. CONCLUSIONS: CX-BZ exerts preventive effects against migraine by modulating inflammatory responses and restoring metabolic homeostasis, particularly through the regulation of amino acid metabolism and the TCA cycle. These findings provide new insights into the multi-target protective mechanisms of CX-BZ in migraine prevention.