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

• Published in: Cephalalgia 2013-01, Vol.33 (2), p.87-100
• Main Authors: Bhatt, Deepak K, Gupta, Saurabh, Jansen-Olesen, Inger, Andrews, John S, Olesen, Jes
• Format: Article
• Language: English
• Subjects: Animals; Disease Models, Animal; Humans; Male; Migraine Disorders - drug therapy; Migraine Disorders - metabolism; Nitric Oxide Synthase Type I - antagonists & inhibitors; Nitric Oxide Synthase Type I - metabolism; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT1B - metabolism; Receptor, Serotonin, 5-HT1D - metabolism; Receptors, Calcitonin Gene-Related Peptide - antagonists & inhibitors; Receptors, Calcitonin Gene-Related Peptide - metabolism; Serotonin 5-HT1 Receptor Agonists - administration & dosage; Signal Transduction - drug effects; Treatment Outcome
• ISSN: 0333-1024; 1468-2982
• DOI: 10.1177/0333102412466967

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 µM), TG (24 ± 11 %, 10 µM) and TNC (40 ± 8%, 10 µM); (2) capsaicin- and RTX-induced iCGRP release from dura mater; and (3) capsaicin- and ES-induced increase in dural artery diameter (32 ± 5%, 3 mg kg−1 intravenous (i.v.) and 36 ± 1%, 10 mg kg−1 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-HT1B/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.