Circadian Rhythm Cascade SIRT1/PGC-1α/BMAL1 Pathway Regulates Nitroglycerin-Induced Chronic Migraine

Previous findings have suggested that inflammation activation in the trigeminal nervous system and circadian rhythms disruption contributed to the chronic migraine (CM). Linking the two critical processes, the involvement of signaling cascade SIRT1/PGC-1α/BMAL1 in CM is suggested. Our objective is to elucidate the important signaling cascade implicated in the CM pathogenesis, hence enhancing the comprehension of the mechanisms underlying CM development. NTG-induced migraine model was established. Thresholds of thermal and mechanical stimulation were examined in sensory sensitivity test, and western blot (WB) of CGRP and c-Fos evaluated CM severity. Co-immunoprecipitation (CoIP) assessed SIRT1 and PGC-1α interaction, while chromatin immunoprecipitation quantitative PCR (ChIP-qPCR) examined their binding rates to the BMAL1 promoter. Additionally, cell transfection and SRT1720 administration were performed to further investigate the regulatory role of the pathway. In the NTG-induced migraine model, inflammation activation and the aberrant expression of circadian rhythm-related genes and hormones were detected. The downregulation of SIRT1 and PGC-1α activity, along with the interactions within the pathway, provided evidence of this pathway plays a role in regulating migraine. The overexpression of SIRT1 through virus injection and SRT1720 administration both demonstrated the effect of alleviating the key link of CM mechanisms, including central sensitization and inflammatory activation in the trigeminal nucleus and circadian rhythms disruption. Moreover, the anti-inflammatory effect was further demonstrated to be mediated by BMAL1 by using shRNA.