title: Drugs targeting nitric oxide synthase for migraine treatment.
abstract: BACKGROUND
  Ample evidence that nitric oxide (NO) is a causative molecule in migraine has encouraged research to develop drugs that target the NO-cGMP cascade for migraine treatment. NO synthase (NOS) inhibition is an innovative therapeutic principle.
  
  
  METHODS
  This paper reviews the rationale underlying NOS inhibition in migraine treatment. It also provides a review on the efficacy and safety data for NOS inhibitors (nonselective NOS inhibitor L-N(G)-methyl-arginine hydrochloride [L-NMMA], selective inducible NOS [iNOS] inhibitors GW273629 and GW274150, combined neuronal NOS [nNOS] inhibitor and 5-HT1B/1D receptor agonist NXN-188) in acute or preventive migraine treatment.
  
  
  CONCLUSIONS
  The data highlighted herein, from four placebo-controlled trials and 1 open-labeled clinical trial using 4 different NOS inhibitors on a total of 705 patients, provide convincing efficacy data only for the nonselective NOS inhibitor L-NMMA. Unfortunately, this NOS inhibitor raises cardiovascular safety concerns and has an unfavorable pharmacokinetic profile. As experimental studies predicted, iNOS inhibitors are ineffective in migraine. Still, upcoming selective nNOS inhibitors are a hope for migraine treatment, with the nNOS isoform being most clearly involved in trigeminovascular transmission and central sensitization. Future studies should help to clarify whether NOS inhibition is equally fruitful in acute and preventive treatment. It should also clarify if nNOS inhibition holds promise as a therapeutic tool for the treatment of chronic migraine and other forms of headache.
authors.affiliation: Headache and Pain Unit, IRCCS San Raffaele Pisana , Rome , Italy piero.barbanti@sanraffaele.it.
authors.forename: Piero
authors.initials: P
authors.lastname: Barbanti
authors.forename: Gabriella
authors.initials: G
authors.lastname: Egeo
authors.forename: Cinzia
authors.initials: C
authors.lastname: Aurilia
authors.forename: Luisa
authors.initials: L
authors.lastname: Fofi
authors.forename: David
authors.initials: D
authors.lastname: Della-Morte
mesh_terms: D000818:Animals; D006152:Cyclic GMP / Q000378:metabolism; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D008881:Migraine Disorders / Q000188:drug therapy* / Q000503:physiopathology; D058990:Molecular Targeted Therapy; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D006152:Cyclic GMP
keywords: headache; migraine; nitric oxide; nitric oxide synthases inhibitors; treatment