title: Altered kynurenine pathway metabolites in serum of chronic migraine patients.
abstract: BACKGROUND
  Activation of glutamate (Glu) receptors plays a key role in the pathophysiology of migraine. Both NMDA and metabotropic Glu receptors are activated or inhibited by metabolites of the kynurenine pathway, such as kynureninic acid (KYNA), quinolinic acid (QUINA), and xanthurenic acid (XA). In spite of the extensive research carried out on KYNA and other kynurenine metabolites in experimental models of migraine, no studies have ever been carried out in humans. Here, we measured all metabolites of the kynurenine pathway in the serum of patients affected by chronic migraine (CM) and age- and gender-matched healthy controls.
  
  
  METHODS
  We assessed serum levels of tryptophan (Trp), L-kynurenine (KYN), KYNA, anthranilic acid (ANA), 3-hydroxyanthranilic acid (3-HANA), 3-hydroxykynirenine (3-HK), XA, QUINA, and 5-hydroxyindolacetic acid (5-HIAA) in 119 patients affected by CM (ICHD-3beta criteria) and 84 age-matched healthy subjects. Patients with psychiatric co-morbidities, systemic inflammatory, endocrine or neurological disorders, and mental retardation were excluded. Serum levels of all metabolites were assayed using liquid chromatography/tandem mass spectrometry (LC-MS/MS).
  
  
  RESULTS
  LC-MS/MS analysis of kynurenine metabolites showed significant reductions in the levels of KYN (-32 %), KYNA (-25 %), 3-HK (-49 %), 3-HANA (-63 %), 5-HIAA (-36 %) and QUINA (-80 %) in the serum of the CM patients, as compared to healthy controls. Conversely, levels of Trp, ANA and XA were significantly increased in CM patients (+5 %, +339 % and +28 %, respectively).
  
  
  CONCLUSIONS
  These findings suggest that in migraine KYN is unidirectionally metabolized into ANA at expenses of KYNA and 3-HK. The reduction in the levels of KYNA, which behaves as a competitive antagonist of the glycine site of NMDA receptors, is consistent with the hypothesis that NMDA receptors are overactive in migraine. The increase in XA, a putative activator of Glu2 receptors, may represent a compensatory event aimed at reinforcing endogenous analgesic mechanisms. The large increase in the levels of ANA encourages research aimed at establishing whether ANA has any role in the regulation of nociceptive transmission.
authors.affiliation: Department of Psychiatry, Harvard Medical School, Boston, MA, USA. martina.curto@uniroma1.it.|Department of Molecular Medicine, Sant'Andrea Medical Center, Sapienza University, Via di Grottarossa 1035-1039, Rome, 00189, Italy. martina.curto@uniroma1.it.
authors.forename: Martina
authors.initials: M
authors.lastname: Curto
authors.affiliation: Advanced Molecular Diagnostics, IDI-IRCSS, Rome, Italy.
authors.forename: Luana
authors.initials: L
authors.lastname: Lionetto
authors.affiliation: Department of Molecular Medicine, Sant'Andrea Medical Center, Sapienza University, Via di Grottarossa 1035-1039, Rome, 00189, Italy.|Regional referral headache center, Sant'Andrea Hospital, Rome, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Negro
authors.affiliation: Advanced Molecular Diagnostics, IDI-IRCSS, Rome, Italy.
authors.forename: Matilde
authors.initials: M
authors.lastname: Capi
authors.affiliation: IRCCS Neuromed, Pozzilli, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Fazio
authors.affiliation: Headache Center and Geriatrics Clinic, Department of Medicine and Science of Aging, "G. D'Annunzio" University, Chieti, Italy.
authors.forename: Maria Adele
authors.initials: MA
authors.lastname: Giamberardino
authors.affiliation: Advanced Molecular Diagnostics, IDI-IRCSS, Rome, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Simmaco
authors.affiliation: IRCCS Neuromed, Pozzilli, Italy.|Department of Physiology and Pharmacology, Sapienza University, Rome, Italy.
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Nicoletti
authors.affiliation: Department of Molecular Medicine, Sant'Andrea Medical Center, Sapienza University, Via di Grottarossa 1035-1039, Rome, 00189, Italy.|Regional referral headache center, Sant'Andrea Hospital, Rome, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Martelletti
mesh_terms: D000328:Adult; D005260:Female; D006801:Humans; D006897:Hydroxyindoleacetic Acid / Q000097:blood; D007736:Kynurenic Acid / Q000097:blood; D007737:Kynurenine / Q000097:blood / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D008881:Migraine Disorders / Q000097:blood / Q000378:metabolism*; D017378:Quinolinic Acid / Q000097:blood; D053719:Tandem Mass Spectrometry; D014364:Tryptophan / Q000097:blood; D014977:Xanthurenates / Q000097:blood; D062367:ortho-Aminobenzoates / Q000097:blood
chemical_list: D014977:Xanthurenates; D062367:ortho-Aminobenzoates; C031385:anthranilic acid; D007737:Kynurenine; D006897:Hydroxyindoleacetic Acid; C028330:xanthurenic acid; D014364:Tryptophan; D017378:Quinolinic Acid; D007736:Kynurenic Acid
keywords: Chronic migraine; Glutamate; Kynurenine; Metabotropic Glu receptors; NMDA receptors; Pain