Altered kynurenine pathway metabolites in serum of chronic migraine patients

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

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Background: 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). 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. Methods: We 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). Results: LC-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). Conclusions: These 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.

Original languageEnglish
Article number47
JournalJournal of Headache and Pain
Volume17
Issue number1
DOIs
Publication statusPublished - Dec 1 2016

Fingerprint

Kynurenine
Migraine Disorders
Acids
Quinolinic Acid
Serum
3-Hydroxyanthranilic Acid
N-Methyl-D-Aspartate Receptors
Tryptophan
Metabotropic Glutamate Receptors
Glutamate Receptors
N-Methylaspartate
Tandem Mass Spectrometry
Nervous System Diseases
Research
Liquid Chromatography
Intellectual Disability
Glycine
Psychiatry
Analgesics
Healthy Volunteers

Keywords

  • Chronic migraine
  • Glutamate
  • Kynurenine
  • Metabotropic Glu receptors
  • NMDA receptors
  • Pain

ASJC Scopus subject areas

  • Anesthesiology and Pain Medicine
  • Clinical Neurology

Cite this

Curto, M., Lionetto, L., Negro, A., Capi, M., Fazio, F., Giamberardino, M. A., ... Martelletti, P. (2016). Altered kynurenine pathway metabolites in serum of chronic migraine patients. Journal of Headache and Pain, 17(1), [47]. https://doi.org/10.1186/s10194-016-0638-5

Altered kynurenine pathway metabolites in serum of chronic migraine patients. / Curto, Martina; Lionetto, Luana; Negro, Andrea; Capi, Matilde; Fazio, Francesco; Giamberardino, Maria Adele; Simmaco, Maurizio; Nicoletti, Ferdinando; Martelletti, Paolo.

In: Journal of Headache and Pain, Vol. 17, No. 1, 47, 01.12.2016.

Research output: Contribution to journalArticle

Curto, M, Lionetto, L, Negro, A, Capi, M, Fazio, F, Giamberardino, MA, Simmaco, M, Nicoletti, F & Martelletti, P 2016, 'Altered kynurenine pathway metabolites in serum of chronic migraine patients', Journal of Headache and Pain, vol. 17, no. 1, 47. https://doi.org/10.1186/s10194-016-0638-5
Curto, Martina ; Lionetto, Luana ; Negro, Andrea ; Capi, Matilde ; Fazio, Francesco ; Giamberardino, Maria Adele ; Simmaco, Maurizio ; Nicoletti, Ferdinando ; Martelletti, Paolo. / Altered kynurenine pathway metabolites in serum of chronic migraine patients. In: Journal of Headache and Pain. 2016 ; Vol. 17, No. 1.
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abstract = "Background: 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). 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. Methods: We 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). Results: LC-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). Conclusions: These 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.",
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AU - Lionetto, Luana

AU - Negro, Andrea

AU - Capi, Matilde

AU - Fazio, Francesco

AU - Giamberardino, Maria Adele

AU - Simmaco, Maurizio

AU - Nicoletti, Ferdinando

AU - Martelletti, Paolo

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N2 - Background: 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). 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. Methods: We 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). Results: LC-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). Conclusions: These 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.

AB - Background: 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). 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. Methods: We 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). Results: LC-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). Conclusions: These 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.

KW - Chronic migraine

KW - Glutamate

KW - Kynurenine

KW - Metabotropic Glu receptors

KW - NMDA receptors

KW - Pain

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