Effect of BAY‐117082, a NLRP3 inflammasome inhibitor, in a mouse model of nitroglycerin (NTG)‐induced migraine

Abstract

Migraine is a common brain disorder characterized by recurrent episodes of headache. It is a complex and multifactorial disease with a higher prevalence in females than in males. Several risk factors have been associated to migraine disease as genetic factors, sex and age. The pathophysiology of migraine is still unclear; however, it has been proven that NOD‐like receptor protein 3 (NLRP3) inflammasome pathway overactivation as well as p‐ERK/p‐CREB axis contribute to migraine pathogenesis. Therefore, the aim of this study was to investigate the effect of BAY‐117082, a NLRP3 inflammasome inhibitor and p‐ERK/p‐CREB modulator, in an in vivo model of nitroglycerin (NTG)‐induced migraine.Migraine model was induced by NTG intraperitoneal administration at dose of 10 mg/kg diluted in 0.9% saline. Mice were treated intraperitoneally with BAY‐117082 at doses of 1 mg/kg, 5 mg/kg, and 10 mg/kg, 5 minutes after NTG injection. Mice were sacrificed 4 h following NTG injection; the whole brain with the rostral spinal cord was removed to perform several analysis.Our results demonstrated that, following behavioral tests for pain and photophobia, BAY‐117082 treatment at doses of 5 mg/kg and 10 mg/kg reduced pain attacks induced by NTG more than BAY‐117082 at the dose of 1 mg/kg. Moreover, the treatment with BAY‐117082 at doses of 5 mg/kg and 10 mg/kg significantly reduced histological damage in the trigeminal nerve nucleus and significantly decreased inflammosome activation by reduction of NLRP3, ASC, IL‐1β and TNF‐α expression. Additionally, the treatment with BAY‐117082 at doses of 5 mg/kg and 10 mg/kg significantly modulated p‐ERK/p‐CREB axis activation through the reduction of p‐ERK, p‐AKT, p‐CREB and p‐PI3K expression.Therefore, the obtained results offer new insight into the role of NLRP3 inflammasome pathway and p‐ERK/p‐CREB axis in migraine pathogenesis, suggesting that BAY‐117082 could be considered a novel therapeutic strategy to treat migraine.