Altered kynurenine pathway metabolites in serum of chronic migraine patients

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.

A Combination of Tanacetum parthenium, Griffonia simplicifolia and Magnesium (Aurastop) as Symptomatic Acute Treatment for Migraine Aura: A Retrospective Cohort Study

“…As a further step, 5-HTP (from Griffonia simpliciofila supplement) entered kynurenine pathway as kinurenic acid that was able to act as an endogenous NMDA receptor antagonist, blocking glutamatergic activity. In migraine patients, kynurenine pathway perturbation was related to an aberrant unidirectional metabolization of kinurenic acid in antralic acid P. Zavarise, G. D. Volta 7/9 OALib Journal (promoting itself free radical production), with a consequent loss of the inhibitory action on glutamatergic acid and its excitatory activity [16] [29]. Thus, low plasmatic levels of kinurenic acid could be considered as an effective proxy of NMDA receptor activity [29].…”

“…In migraine patients, kynurenine pathway perturbation was related to an aberrant unidirectional metabolization of kinurenic acid in antralic acid P. Zavarise, G. D. Volta 7/9 OALib Journal (promoting itself free radical production), with a consequent loss of the inhibitory action on glutamatergic acid and its excitatory activity [16] [29]. Thus, low plasmatic levels of kinurenic acid could be considered as an effective proxy of NMDA receptor activity [29]. Finally, magnesium deficiency has been related to CSD [30], as well as to free radical formation and NMDA modulation of glutamatergic activity [31] [32].…”

Topical dura mater application of CFA induces enhanced expression of c-fos and glutamate in rat trigeminal nucleus caudalis: attenuated by KYNA derivate (SZR72)

“…Recent studies have demonstrated lower levels of kynurenic acid (KYNA) in serum of patients suffering from chronic migraine compared to controls [12, 13]. KYNA could be a new therapeutic line in migraine chronification, but KYNA can poorly cross the blood–brain barrier (BBB), while newer KYNA analogues have better BBB penetration characteristics [14, 15].…”

Combination of Tanacethum Partenium, 5-Hydrossitriptophan (5-http) and Magnesium in the Prophylaxis of Episodic Migraine without Aura (AURASTOP®) An Observational Study

“…Low plasma levels of KYNA may be considered a reliable marker of NMDA receptor activation. Cerebral levels of KYNA can be increased by the assumption of its precursor 5-HTP [13] . Based on the mechanisms described above, the combination of 3 components, tanacetum parthenium, 5-HTP, and magnesium is expected to synergistically influence the biologic pathways involved in migraine pathogenesis, and, therefore, to have a therapeutic potential in migraine prevention.…”