Abstract
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.
Highlights
Activation of glutamate (Glu) receptors plays a key role in the pathophysiology of migraine
The significant increase in xanthurenic acid (XA) levels found in chronic migraine (CM) patients is difficult to explain because the enzyme Kynurenine Aminotrasferase (KAT), which transaminates 3-HK into XA converts KYN into kynureninic acid (KYNA), the levels of which were reduced in CM patients
The reduction in KYNA levels we have seen in the serum of CM patients is consistent with the hypothesis that NMDA receptors are overactive in migraine
Summary
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). Curto et al The Journal of Headache and Pain (2016) 17:47 sensitization of the trigeminovascular system; (ii) central sensitization of the caudal trigeminal nucleus and other central nervous system (CNS) structures of the pain neuraxis; (iii) activation of brainstem migraine generators; and, (iv) cortical spreading depression, underlying aura phenomenon of migraine with aura [8] All these processes are mediated by allostatic changes in mechanisms of activity-dependent synaptic plasticity, such as long-term potentiation (LTP) and long-term depression (LTD). Recent evidence suggests that XA behaves as an endogenous activator of type-2 metabotropic Glu receptors (mGlu receptors) [20], whereas cinnabarinic acid is a weak orthosteric agonist of mGlu receptors [21]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
