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

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

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Background: 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. 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. Method: We 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. Results: LC/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. Conclusion: The 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.

Original languageEnglish (US)
Article number27
JournalJournal of Headache and Pain
Volume17
Issue number1
DOIs
StatePublished - Dec 1 2016
Externally publishedYes

Fingerprint

Kynurenine
Cluster Headache
Serum
Kynurenic Acid
N-Methyl-D-Aspartate Receptors
Manuscripts
Tryptophan
Quinolinic Acid
Headache Disorders
Migraine Disorders
Memantine
Acids
Tandem Mass Spectrometry
Nervous System Diseases
Liquid Chromatography
Intellectual Disability
Psychiatry
Analgesics

Keywords

  • Cluster headache
  • Glutamate
  • Kynurenine
  • NMDA receptors
  • Pain

ASJC Scopus subject areas

  • Clinical Neurology
  • Anesthesiology and Pain Medicine

Cite this

Altered serum levels of kynurenine metabolites in patients affected by cluster headache. / Curto, Martina; Lionetto, Luana; Negro, Andrea; Capi, Matilde; Perugino, Francesca; Fazio, Francesco; Giamberardino, Maria Adele; Simmaco, Maurizio; Nicoletti, Ferdinando; Martelletti, Paolo.

In: Journal of Headache and Pain, Vol. 17, No. 1, 27, 01.12.2016.

Research output: Contribution to journalArticle

Curto, M, Lionetto, L, Negro, A, Capi, M, Perugino, F, Fazio, F, Giamberardino, MA, Simmaco, M, Nicoletti, F & Martelletti, P 2016, 'Altered serum levels of kynurenine metabolites in patients affected by cluster headache', Journal of Headache and Pain, vol. 17, no. 1, 27. https://doi.org/10.1186/s10194-016-0620-2
Curto, Martina ; Lionetto, Luana ; Negro, Andrea ; Capi, Matilde ; Perugino, Francesca ; Fazio, Francesco ; Giamberardino, Maria Adele ; Simmaco, Maurizio ; Nicoletti, Ferdinando ; Martelletti, Paolo. / Altered serum levels of kynurenine metabolites in patients affected by cluster headache. In: Journal of Headache and Pain. 2016 ; Vol. 17, No. 1.
@article{27d07b5d168442e1b22a137814c2c98b,
title = "Altered serum levels of kynurenine metabolites in patients affected by cluster headache",
abstract = "Background: 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. 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. Method: We 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. Results: LC/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. Conclusion: The 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.",
keywords = "Cluster headache, Glutamate, Kynurenine, NMDA receptors, Pain",
author = "Martina Curto and Luana Lionetto and Andrea Negro and Matilde Capi and Francesca Perugino and Francesco Fazio and Giamberardino, {Maria Adele} and Maurizio Simmaco and Ferdinando Nicoletti and Paolo Martelletti",
year = "2016",
month = "12",
day = "1",
doi = "10.1186/s10194-016-0620-2",
language = "English (US)",
volume = "17",
journal = "The journal of headache and pain",
issn = "1129-2369",
publisher = "Springer-Verlag Italia",
number = "1",

}

TY - JOUR

T1 - Altered serum levels of kynurenine metabolites in patients affected by cluster headache

AU - Curto, Martina

AU - Lionetto, Luana

AU - Negro, Andrea

AU - Capi, Matilde

AU - Perugino, Francesca

AU - Fazio, Francesco

AU - Giamberardino, Maria Adele

AU - Simmaco, Maurizio

AU - Nicoletti, Ferdinando

AU - Martelletti, Paolo

PY - 2016/12/1

Y1 - 2016/12/1

N2 - Background: 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. 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. Method: We 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. Results: LC/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. Conclusion: The 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.

AB - Background: 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. 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. Method: We 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. Results: LC/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. Conclusion: The 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.

KW - Cluster headache

KW - Glutamate

KW - Kynurenine

KW - NMDA receptors

KW - Pain

UR - http://www.scopus.com/inward/record.url?scp=84961644899&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84961644899&partnerID=8YFLogxK

U2 - 10.1186/s10194-016-0620-2

DO - 10.1186/s10194-016-0620-2

M3 - Article

C2 - 27000870

AN - SCOPUS:84961644899

VL - 17

JO - The journal of headache and pain

JF - The journal of headache and pain

SN - 1129-2369

IS - 1

M1 - 27

ER -