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

DOI: https://doi.org/10.1186/s10194- 021- 01239- 1

Abstract-Summary Altered glutamatergic neurotransmission and neuropeptide levels play a central role in migraine pathomechanism.

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.

Female migraine patients aged between 25 and 50 years (n = 50) and healthy con-

trol 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).

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 xanth-

urenic acid/melatonin and attack frequency.

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.

Extended: Our systematic and detailed analysis revealed associations between Trp metabolism and clinical features of migraine, which may lead to new therapeu- tic options in the future.

Introduction Human studies about the function of the KP in headache diseases are scarce: Curto and co-workers were the first who measured the metabolites of the KP in the serum of patients diagnosed with chronic migraine and cluster headache [294, 295].

A systematic and detailed examination, which contains the (1) determination of not only the KP, but also main peripheral Trp metabolites with particular regard to the influence of (2) interictal/ictal periods and (3) clinical features of episodic migraine patients is needed which can help us understand the role of kynurenine

2.2 Biology

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metabolites and develop new, potential strategies in the diagnosis and therapy of migraine.

Our aims were: to determine the concentrations of main metabolites of Trp path- way (5-HT, MELA and KP) in the peripheral plasma of episodic migraine patients compared to healthy control subjects.

Materials and Methods Peripheral blood samples were collected from the cubital vein of patients during the interictal (attack free) and ictal (attack) periods, and from healthy controls on one occasion.

During headache attacks, patients were asked not to take their usual painkillers

or specific migraine attack medication until blood samples were taken.

The method was applied for quantification of these metabolites in cerebrospinal fluid and serum samples of patients with multiple sclerosis and now for plasma samples of migraineurs.

The effect of clinical parameters (disease duration, attack frequency, VAS, pres- ence of allodynia, involvement of menstruation cycle, applied therapies and age) on the metabolic changes was investigated only in the MWoA subgroup using linear regression models and two independent samples analyses.

We asked whether participants could be accurately classified as migraine patient or healthy participant in our sample based on all measured interictal metabolite levels, and which metabolites are (most) important in making this distinction.

Results We detected significantly lower plasma concentrations of Trp metabolites (Trp, KYN, ANA, XA and PICA) in the interictal phase of migraineurs (n = 38) com- pared to the healthy control group (n = 34).

Decreased interictal plasma concentrations of Trp metabolites were measured in both subgroups of migraineurs (except of 5-HT), but significant alterations were detected in the Trp, KYN, KYNA, ANA, XA, PICA and MELA levels in the MWoA group compared to healthy controls (n = 34).

Two independent samples comparison showed that concentrations of ANA (34.45 ± 15.95 vs. 51.18 ± 33.64, p < 0.040), 5-HIAA (36.14 ± 9.26 vs. 41.95 ± 8.83, p < 0.030) and MELA (0.15 ± 0.07 vs. 0.19 ± 0.08, p < 0.37) increased signifi- cantly during the ictal period compared to the attack free phase in MWoA patients.

Discussion Most of the investigated molecules are considered protective factors (Trp, KYN, KYNA, ANA, PICA, MELA) and their elevated levels in the periphery might be a consequence of the migraine attack, possibly aimed to restore the balance of energy homeostasis and protect the organism against harmful effects.

Higher 5-HIAA levels seem to be a triggering or aggravating factor of headache, which may originate from interictally increased 5-HT levels (paired with an unknown trigger the metabolism of 5-HT can shift toward the 5-HIAA resulted in the formation of attack, while the concentration of plasma 5-HT decrease).

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2 Mechanisms

We showed that concentrations of pituitary adenylate cyclase-activating poly- peptide 1–38 (PACAP1–38) and calcitonin gene-related peptide (CGRP) decreased in the peripheral plasma during the interictal period in migraineurs, while their lev- els increased during attacks [296].

It is hypothesised that decreasing expression of TRP metabolites can generate an increase in not only glutamate levels but also PACAP1–38 and CGRP concentra- tions, which can contribute to the formation of migraine attacks.

Conclusion It seems that chronically low peripheral levels of TRP metabolites can initiate molecular disturbances underlying migraine pathomechanism, which may partici- pate in triggering events (e.g. glutamate excess, oxidative stress, altered immune functions and neuroinflammation) that can induce hyperexcitability and culminate in headache attacks.

The attack itself can be considered as a response to the unbalanced peripheral energy metabolism and the consequent increase in levels of kynurenine, 5-HT and MELA metabolites may serve as protective factor.

Our systematic and detailed analysis revealed associations between Trp metabo- lism and clinical features of migraine, which may lead to new therapeutic options in the future.

Acknowledgement A machine generated summary based on the work of Tuka, Bernadett; Nyári, Aliz; Cseh, Edina Katalin; Körtési, Tamás; Veréb, Dániel; Tömösi, Ferenc; Kecskeméti, Gábor; Janáky, Tamás; Tajti, János; Vécsei, László. 2021  in The Journal of Headache and Pain.

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