Perampanel inhibits calcitonin gene-related peptide release from rat brainstem in vitro

Background:Perampanel is a novel antiepileptic drug acting via non-competitive antagonism on glutamatergicAMPA receptors, and the subsequent inhibition of ion calcium influx. Since it was recently postulated that theantagonists of glutamate receptors might play a role in the treatment of migraine, in this study we investigated theputative anti-migraine activity of perampanel in an in vitro animal model involving the static incubation of ratbrainstem explants and the subsequent measurement of immune-reactive calcitonin gene-related peptide releasedinto the incubation medium.\r\nMethods:Acute rat brainstem explants were incubated in plain medium or in medium containing gradedconcentrations of perampanel. The release into the medium was assessed by radioimmunoassay either underbaseline conditions or after stimulation by such secretagogues as high K+concentrations, veratridine or capsaicin.\r\nResults:We found that: 1) under baseline conditions perampanel, given in the range 0.01–100μM, inhibited in aconcentration-dependent manner calcitonin gene-related peptide’s release compared to controls; the decreasewas statistically significant as from 10μM; 2) a significant and consistent increase in calcitonin gene-relatedpeptide’s secretion was induced by all depolarizing stimuli after 1 h of incubation; 3) under these conditions,calcitonin gene-related peptide’s release stimulated by 56 mM KCl was significantly reduced by perampanel from0.1μM onward, whereas secretion stimulated by veratridine was significantly reduced as from 1μM; 4) on thecontrary, perampanel had no effect on capsaicin-induced calcitonin gene-related peptide’s release up to 100μM.\r\nConclusions:Here we provided preliminary in vitro evidencesuggesting that perampanel might control paintransmission under conditions of activated trigeminal system, in a preclinical model mimicking thepathophysiology of human migraine.