Clinical relevance of depressed kynurenine pathway in episodic migraine patients: potential prognostic markers in the peripheral plasma during the interictal period

Abstract

Background Altered glutamatergic neurotransmission and neuropeptide levels play a central role in migraine pathomechanism. Previously, we confirmed that kynurenic acid, an endogenous glutamatergic antagonist, was able to decrease the expression of pituitary adenylate cyclase-activating polypeptide 1–38, a neuropeptide with known migraine-inducing properties. Hence, our aim was to reveal the role of the peripheral kynurenine pathway (KP) in episodic migraineurs. We focused on the complete tryptophan (Trp) catabolism, which comprises the serotonin and melatonin routes in addition to kynurenine metabolites. We investigated the relationship between metabolic alterations and clinical characteristics of migraine patients. Methods Female migraine patients aged between 25 and 50 years (n = 50) and healthy control subjects (n = 34) participated in this study. Blood samples were collected from the cubital veins of subjects (during both the interictal/ictal periods in migraineurs, n = 47/12, respectively). 12 metabolites of Trp pathway were determined by neurochemical measurements (UHPLC-MS/MS). Results Plasma concentrations of the most Trp metabolites were remarkably decreased in the interictal period of migraineurs compared to healthy control subjects, especially in the migraine without aura (MWoA) subgroup: Trp (p < 0.025), L-kynurenine (p < 0.001), kynurenic acid (p < 0.016), anthranilic acid (p < 0.007), picolinic acid (p < 0.03), 5-hydroxy-indoleaceticacid (p < 0.025) and melatonin (p < 0.023). Several metabolites showed a tendency to elevate during the ictal phase, but this was significant only in the cases of anthranilic acid, 5-hydroxy-indoleaceticacid and melatonin in MWoA patients. In the same subgroup, higher interictal kynurenic acid levels were identified in patients whose headache was severe and not related to their menstruation cycle. Negative linear correlation was detected between the interictal levels of xanthurenic acid/melatonin and attack frequency. Positive associations were found between the ictal 3-hydroxykynurenine levels and the beginning of attacks, just as between ictal picolinic acid levels and last attack before ictal sampling. Conclusions Our results suggest that there is a widespread metabolic imbalance in migraineurs, which manifests in a completely depressed peripheral Trp catabolism during the interictal period. It might act as trigger for the migraine attack, contributing to glutamate excess induced neurotoxicity and generalised hyperexcitability. This data can draw attention to the clinical relevance of KP in migraine.

Kynurenine Pathway Metabolites as Potential Clinical Biomarkers in Coronary Artery Disease

“…The biologically active metabolites of KP might be used as measurable biomarkers for different pathological conditions. In the field of neurology, decreased Trp metabolites were reported in patients with migraine without aura in the interictal period ( 53 ), and KP metabolites were suggested to be promising biomarkers for amyotrophic lateral sclerosis ( 54 ). In hemodialysis patients, increased KYN/Trp ratio was found to be associated with atherosclerotic changes, such as decreased ankle-brachial pressure index and increased carotid artery intima-medial thickness ( 55 ).…”

The Organ of Vision and the Stomatognathic System—Review of Association Studies and Evidence-Based Discussion

“…It may act as a trigger for migraine attacks, contributing to excess glutamate, induced neurotoxicity, and generalized hyperactivity. This may draw attention to the clinical significance of the kynurenine pathway in migraine [ 91 ]. According to studies, KYNA and its derivatives may act as modulators at different levels of the migraine pathomechanism.…”

Indoleamine 2,3-Dioxygenase Cannot Inhibit Chlamydia trachomatis Growth in HL-60 Human Neutrophil Granulocytes

“…The applied bioanalytical method optimization and its applicability for human body fluids (cerebrospinal fluid, serum, and plasma) were described in our previous publications ( 17 , 18 ). The UHPLC separation of TRP and its metabolites was performed on an ACQUITY I-Class UPLC™ liquid chromatography system (Waters, Manchester, UK) consisting of Binary Solvent Manager, Sample Manager-FL, and Column Manager.…”