NXN-188, a selective nNOS inhibitor and a 5-HT1B/1D receptor agonist, inhibits CGRP release in preclinical migraine models
- Authors:
- DOI:
- 10.1177/0333102412466967
- Abstract:
- BackgroundNXN-188 is a combined neuronal nitric oxide synthase (nNOS) inhibitor and 5-hydroxytryptamine 1B/1D (5-HT(1B/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.MethodsWe 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.ResultsNXN-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.).ConclusionsNXN-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.
- Type:
- Journal article
- Language:
- English
- Published in:
- Cephalalgia, 2013, Vol 33, Issue 2, p. 87-100
- Keywords:
- Journal Article; Research Support, Non-U.S. Gov't
- Main Research Area:
- Medical science
- Publication Status:
- Published
- Review type:
- Peer Review
- Submission year:
- 2013
- Scientific Level:
- Scientific
- ID:
- 234150249
