title: 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 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.
authors.affiliation: Department of Neurology, Glostrup Hospital, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
authors.forename: Deepak K
authors.initials: DK
authors.lastname: Bhatt
authors.forename: Saurabh
authors.initials: S
authors.lastname: Gupta
authors.forename: Inger
authors.initials: I
authors.lastname: Jansen-Olesen
authors.forename: John S
authors.initials: JS
authors.lastname: Andrews
authors.forename: Jes
authors.initials: J
authors.lastname: Olesen
mesh_terms: D000818:Animals; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D004195:Disease Models, Animal; D006801:Humans; D008297:Male; D008881:Migraine Disorders / Q000188:drug therapy* / Q000378:metabolism*; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044302:Receptor, Serotonin, 5-HT1B / Q000378:metabolism; D044346:Receptor, Serotonin, 5-HT1D / Q000378:metabolism; D018015:Receptors, Calcitonin Gene-Related Peptide / Q000378:metabolism; D058825:Serotonin 5-HT1 Receptor Agonists / Q000008:administration & dosage*; D015398:Signal Transduction / Q000187:drug effects; D016896:Treatment Outcome
chemical_list: D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D044302:Receptor, Serotonin, 5-HT1B; D044346:Receptor, Serotonin, 5-HT1D; D018015:Receptors, Calcitonin Gene-Related Peptide; D058825:Serotonin 5-HT1 Receptor Agonists; D052248:Nitric Oxide Synthase Type I