NXN-188, a selective nNOS inhibitor and a 5-HT1B/1D receptor agonist, inhibits CGRP release in preclinical migraine models

Abstract

Background: NXN-188 is a combined neuronal nitric oxide synthase (nNOS) inhibitor and 5-hydroxytryptamine 1B/1D (5-HT1B/1D) receptor agonist. Using preclinical models, we evaluated whether these two unique therapeutic principles have a synergistic effect in attenuating stimulated calcitonin gene-related peptide (CGRP) release, a marker of trigeminal activation. Methods: We examined the effect of NXN-188 on: (1) KCl-, capsaicin- and resiniferatoxin (RTX)-induced immunoreactive CGRP (iCGRP) release from isolated preparation of rat dura mater, trigeminal ganglion (TG) and trigeminal nucleus caudalis (TNC); and (2) capsaicin- and electrical stimulation (ES)-induced middle meningeal artery (MMA) dilation in a rat closed-cranial window. Results: NXN-188 inhibited: (1) KCl-stimulated iCGRP release from dura mater (% decrease mean±SEM, lowest effective concentration) (35±6%, 30 μ), TG (24±11 %, 10 μ) and TNC (40±8%, 10 μ); (2) capsaicin- and RTX-induced iCGRP release from dura mater; and (3) capsaicin- and ES-induced increase in dural artery diameter (32±5%, 3mg kg1 intravenous (i.v.) and 36±1%, 10 mg kg1 i.v.). Conclusions: NXN-188 inhibits CGRP release from migraine-relevant cephalic tissues. Its effect is most likely mediated via a combination of nNOS-inhibition and 5-HT 1B/1D receptor agonism in dura mater while the mechanisms of action for inhibition of CGRP release from TG and TNC have to be investigated further. © International Headache Society 2012 Reprints and permissions.