We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
NXN-188, a selective nNOS inhibitor and a 5-HT1B/1D receptor agonist, inhibits CGRP release in preclinical migraine models.
- Authors
Bhatt, Deepak K; Gupta, Saurabh; Jansen-Olesen, Inger; Andrews, John S; Olesen, Jes
- 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 mM), 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%, 3mg 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.
- Subjects
NITRIC-oxide synthases; NEURONS; PEPTIDES; CALCITONIN; CAPSAICIN
- Publication
Cephalalgia, 2013, Vol 33, Issue 2, p87
- ISSN
0333-1024
- Publication type
Article
- DOI
10.1177/0333102412466967