Altered kynurenine pathway metabolites in serum of chronic migraine patients

The Journal of Headache and Pain

Research Article

Maurizio Simmaco¹  Luana Lionetto¹  Matilde Capi¹  Andrea Negro²  Paolo Martelletti²  Martina Curto³  Maria Adele Giamberardino⁴  Francesco Fazio⁵  Ferdinando Nicoletti⁶ 

[1] Advanced Molecular Diagnostics, IDI-IRCSS, Rome, Italy;Department of Molecular Medicine, Sant’Andrea Medical Center, Sapienza University, Via di Grottarossa 1035-1039, 00189, Rome, Italy;Regional referral headache center, Sant’Andrea Hospital, Rome, Italy;Department of Psychiatry, Harvard Medical School, Boston, MA, USA;Department of Molecular Medicine, Sant’Andrea Medical Center, Sapienza University, Via di Grottarossa 1035-1039, 00189, Rome, Italy;Headache Center and Geriatrics Clinic, Department of Medicine and Science of Aging, “G. D’Annunzio” University, Chieti, Italy;IRCCS Neuromed, Pozzilli, Italy;IRCCS Neuromed, Pozzilli, Italy;Department of Physiology and Pharmacology, Sapienza University, Rome, Italy;

关键词: Chronic migraine;    Glutamate;    Kynurenine;    Metabotropic Glu receptors;    NMDA receptors;    Pain;   

DOI  :  10.1186/s10194-016-0638-5

 received in 2016-01-16, accepted in 2016-04-12,  发布年份 2016

来源: Springer

【 摘 要 】

BackgroundActivation 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.MethodsWe 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).ResultsLC-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).ConclusionsThese 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.

【 授权许可】

CC BY   
© Curto et al. 2016