The Role of the AMY1 Receptor Signaling Cascade in the Protective Effect of Sulforaphane Against Nitroglycerin-Induced Migraine in Mice

Abstract

Migraine is a prevalent neurological disorder that is more commonly observed in women than in men. The activation of trigeminal vascular pathways and the release of calcitonin gene-related peptide (CGRP) are central to its pathogenesis. Notably, amylin and CGRP share the amylin-1 (AMY1) receptor, which is expressed in key structures implicated in migraine mechanisms. Recent research has highlighted the AMY1 receptor as a promising therapeutic target for migraine treatment. Sulforaphane, a natural compound recognized for its neuroprotective and anti-inflammatory effects, has gained interest for its potential benefits in this context. This study evaluated the protective effects of sulforaphane against nitroglycerin induced migraine in female mice, comparing its efficacy to the standard migraine medication, topiramate. Migraine was induced using nitroglycerin (10 mg/kg, i.p., administered every other day), and treatments included sulforaphane (5 mg/kg/day, i.p.) or topiramate (30 mg/kg/day, i.p.) for a duration of 9 days. Sulforaphane demonstrated significant improvements in behavioral symptoms such as photophobia, head grooming, and both mechanical and thermal allodynia. These behavioral changes were accompanied by reductions in serum levels of nitric oxide, CGRP, and pro-inflammatory cytokines. Histological analysis revealed that sulforaphane ameliorated nitroglycerin induced damage in the trigeminal ganglia and trigeminal nucleus caudalis. Additionally, sulforaphane reduced AMY1 receptor expression in the medulla and inhibited its downstream signaling components, including phosphorylated ERK1/2, P38, and c-Fos. Sulforaphane further enhanced the Nrf2/HO-1 pathway while suppressing the NF-κB/NLRP3/caspase-1 signaling cascade. The findings suggest that sulforaphane may offer a novel therapeutic approach for managing migraines by modulating AMY1 receptor-related signaling pathways.