Intranasal Da Chuanxiong formula alleviates vestibular migraine-like phenotypes via modulation of DRD2/TRPV1-associated signaling

ETHNOPHARMACOLOGICAL RELEVANCE: Da Chuanxiong Formula (DCXF), composed of Ligusticum chuanxiong and Gastrodia elata, is a classical traditional Chinese medicine prescription historically used for headache disorders. However, its role in vestibular migraine (VM) remains unclear. AIM OF THE STUDY: This study investigated the therapeutic effects of DCXF on VM-related phenotypes in an nitroglycerin (NTG)-induced VM-like rat model, evaluated whether intranasal administration could enhance its efficacy, and further explored the underlying molecular mechanisms. MATERIALS AND METHODS: Real-world clinical prescription mining based on an electronic medical record database was performed to support formula selection. An NTG-induced VM-like rat model was established, and the effects of oral and intranasal DCXF were assessed using behavioral tests, histopathology, Evans blue extravasation, ELISA, immunofluorescence, qRT-PCR, and Western blotting. Network pharmacology and HPLC-based cerebrospinal fluid analysis were further used to predict candidate targets and characterize major cerebrospinal fluid (CSF)-exposed constituents. RESULTS: Clinical prescription mining supported the selection of DCXF for VM treatment. In the NTG-induced VM-like rat model, DCXF significantly alleviated nociceptive hypersensitivity, spontaneous nocifensive/agitation-related behaviors, and behavioral abnormalities relevant to vestibular/postural dysfunction, while attenuating vascular leakage, histopathological injury, and CGRP pathway activation. At the same dose, intranasal administration consistently showed better therapeutic effects than oral administration. Network pharmacology and experimental validation indicated that the protective effects of DCXF in the VM-like model were associated with suppression of CGRP-related signaling and modulation of DRD2/TRPV1-related pathways. HPLC analysis identified gastrodin, (Z)-ligustilide, and senkyunolide I as major CSF-exposed constituents, with higher exposure after intranasal administration. CONCLUSION: DCXF exerted protective effects in the NTG-induced VM-like rat model, and intranasal administration showed better therapeutic effects than oral administration at the same dose, providing preclinical support for the potential application of DCXF in VM.