Sex differences in response to NLRP3 inflammasome blockage in a mouse migraine model: A genetic and pharmacological study

Migraine is a common disorder that affects more than a billion of people worldwide, with an incidence in women three times higher than in men. The medical need for new therapeutic treatments is only partially satisfied by innovative approaches, and a significant percentage of migraineurs are still not satisfied with their therapy. Several lines of evidence links migraine to the activation of the NLRP3-IL-1β pathway. The aim of this research was to test whether NLRP3 blockers may represent innovative therapeutics for migraine. A well-established murine migraine model triggered by nitroglycerine (GTN) was used, together with NLRP3 knockout ( Nlrp3 (-/-) ) mice and the NLRP3 inhibitor MCC950. Both genetic and pharmacological blockade of NLRP3 were effective in reducing and preventing the onset of the periorbital mechanical allodynia (PMA) evoked by GTN in female mice, but not in males. The chronic administration of MCC950 was sufficient to induce PMA on its on, suggesting that the chronic treatment with a NLRP3 blocker may induce medication overuse headache as a side effect. Western blot analysis showed the activation of the NLRP3 pathway in the hippocampus of female mice treated with GTN, but not in their trigeminal ganglion, trigeminal nucleus caudalis and cortex. No activation of the NLRP3 pathway was detected in male mice. Collectively, this study strengthens the view that NLRP3 inhibitors may represent innovative migraine treatments. However, at the same time, it underlines for the first time some limitations that may affect NLRP3 inhibitors, namely sexual dimorphism in drug responsiveness and issues related to their chronic use. • GTN activates NLRP3 in the hippocampus of female mice but not in males. • NLRP3 blockade counteracts GTN-induced migraine-like pain in female mice. • NLRP3 blockade is ineffective in male mice. • Chronic NLRP3 inhibition may induce migraine-like pain and medication-overuse headache. • NLRP3 inhibitors emerge as a promising migraine therapy specifically for women.