Altered serum levels of kynurenine metabolites in patients affected by cluster headache.

Martina Curto,Maurizio Simmaco,Ferdinando Nicoletti,Francesca Perugino,Paolo Martelletti,Luana Lionetto,Maria Adele Giamberardino,Matilde Capi,Andrea Negro,Francesco Fazio

doi:10.1186/s10194-016-0620-2

Abstract

BackgroundThe reported efficacy of memantine in the treatment of patients with cluster headache (CH) suggests that NMDA receptors are involved in mechanisms of nociceptive sensitization within the trigeminal system associated with CH. NMDA receptors are activated or inhibited by neuroactive compounds generated by tryptophan metabolism through the kynurenine pathway. In the accompanying manuscript, we have found that serum levels of all kynurenine metabolites are altered in patients with chronic migraine. Here, we have extended the study to patients affected by episodic or chronic CH as compared to healthy controls.MethodWe assessed serum levels of kynurenine (KYN), kynurenic Acid (KYNA), anthranilic acid (ANA), 3-hydroxy-anthranilic acid (3-HANA), 3-hydroxykynurenine (3-HK), xanthurenic acid (XA), quinolinic acid (QUINA), tryptophan (Trp) and 5-hydroxyindolacetic acid (5-HIAA) by means of a liquid chromatography/tandem mass spectrometry (LC/MS-MS) method in 21 patients affected by CH (15 with episodic and 6 with chronic CH), and 35 age-matched healthy subjects. Patients with psychiatric co-morbidities, systemic inflammatory, endocrine or neurological disorders, and mental retardation were excluded.ResultsLC/MS-MS analysis of kynurenine metabolites showed significant reductions in the levels of KYN (-36 %), KYNA (-34 %), 3-HK (-51 %), 3-HANA (-54 %), XA (-25 %), 5-HIAA (-39 %) and QUINA (-43 %) in the serum of the overall population of patients affected by CH, as compared to healthy controls. Serum levels of Trp and ANA were instead significantly increased in CH patients (+18 % and +54 %, respectively). There was no difference in levels of any metabolite between patients affected by episodic and chronic CH, with the exception of KYN levels, which were higher in patients with chronic CH.ConclusionThe reduced levels of KYNA (an NMDA receptor antagonist) support the hypothesis that NMDA receptors are overactive in CH. A similar reduction in KYNA levels was shown in the accompanying manuscript in patients affected by chronic migraine. The reduced levels of XA, a putative analgesic compound, may contribute to explain the severity of pain attacks in CH. These data, associated with the data reported in the accompanying manuscript, supports a role for the kynurenine pathway in the pathophysiology of chronic headache disorders.

Highlights

The reported efficacy of memantine in the treatment of patients with cluster headache (CH) suggests that NMDA receptors are involved in mechanisms of nociceptive sensitization within the trigeminal system associated with CH
LC/MS-MS analysis of kynurenine metabolites showed significant reductions in the levels of KYN (-36 %), kynurenic Acid (KYNA) (-34 %), 3-HK (-51 %), 3-hydroxyanthranilic acid (3-HANA) (-54 %), xanthurenic acid (XA) (-25 %), 5-hydroxyindolacetic acid (5-HIAA) (-39 %) and quinolinic acid (QUINA) (-43 %) in the serum of the overall population of patients affected by CH, as compared to healthy controls
A similar reduction in KYNA levels was shown in the accompanying manuscript in patients affected by chronic migraine

Summary

Introduction

The reported efficacy of memantine in the treatment of patients with cluster headache (CH) suggests that NMDA receptors are involved in mechanisms of nociceptive sensitization within the trigeminal system associated with CH. Changes in the secretion of hormones regulated by the hypothalamus, such as prolactin, growth hormone and cortisol are found in patients affected by CH [7,8,9], and functional imaging studies showed the activation of hypothalamic gray matter during headache attacks [6, 10]. Glutamate acting at N-methyl-D-aspartate (NMDA) receptors plays a key role in the induction of nociceptive sensitization [12], and this suggests that alterations in NMDA receptor signaling or in the endogenous machinery that activates NMDA receptors may be relevant to the pathophysiology of CH. It is consistent with this hypothesis that memantine, a fast off-rate NMDA-gated ion channel blocker, has shown efficacy in reducing CH attacks in resistant patients, even if clinical studies are still limited [13]

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Discussion

Conclusion