Xanthurenic Acid Activates mGlu2/3 metabotropic glutamate receptors and is a potential trait marker for schizophrenia

Francesco Fazio, Luana Lionetto, Martina Curto, Luisa Iacovelli, Michele Cavallari, Cristina Zappulla, Martina Ulivieri, Flavia Napoletano, Matilde Capi, Valentina Corigliano, Sergio Scaccianoce, Alessandra Caruso, Jessica Miele, Antonio De Fusco, Luisa Di Menna, Anna Comparelli, Antonella De Carolis, Roberto Gradini, Robert Nisticò, Antonio De BlasiPaolo Girardi, Valeria Bruno, Giuseppe Battaglia, Ferdinando Nicoletti, Maurizio Simmaco

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

The kynurenine pathway of tryptophan metabolism has been implicated in the pathophysiology of psychiatric disorders, including schizophrenia. We report here that the kynurenine metabolite, xanturenic acid (XA), interacts with, and activates mGlu2 and mGlu3 metabotropic glutamate receptors in heterologous expression systems. However, the molecular nature of this interaction is unknown, and our data cannot exclude that XA acts primarily on other targets, such as the vesicular glutamate transporter, in the CNS. Systemic administration of XA in mice produced antipsychotic-like effects in the MK-801-induced model of hyperactivity. This effect required the presence of mGlu2 receptors and was abrogated by the preferential mGlu2/3 receptor antagonist, LY341495. Because the mGlu2 receptor is a potential drug target in the treatment of schizophrenia, we decided to measure serum levels of XA and other kynurenine metabolites in patients affected by schizophrenia. Serum XA levels were largely reduced in a large cohort of patients affected by schizophrenia, and, in patients with first-episode schizophrenia, levels remained low after 12 months of antipsychotic medication. As opposed to other kynurenine metabolites, XA levels were also significantly reduced in first-degree relatives of patients affected by schizophrenia. We suggest that lowered serum XA levels might represent a novel trait marker for schizophrenia.

Original languageEnglish (US)
Article number17799
JournalScientific Reports
Volume5
DOIs
StatePublished - Dec 8 2015
Externally publishedYes

Fingerprint

Schizophrenia
Kynurenine
Acids
Antipsychotic Agents
LY 341495
Vesicular Glutamate Transport Proteins
Serum
Metabotropic Glutamate Receptors
Dizocilpine Maleate
metabotropic glutamate receptor 3
xanthurenic acid
Tryptophan
Psychiatry
Pharmaceutical Preparations

ASJC Scopus subject areas

  • General

Cite this

Xanthurenic Acid Activates mGlu2/3 metabotropic glutamate receptors and is a potential trait marker for schizophrenia. / Fazio, Francesco; Lionetto, Luana; Curto, Martina; Iacovelli, Luisa; Cavallari, Michele; Zappulla, Cristina; Ulivieri, Martina; Napoletano, Flavia; Capi, Matilde; Corigliano, Valentina; Scaccianoce, Sergio; Caruso, Alessandra; Miele, Jessica; De Fusco, Antonio; Di Menna, Luisa; Comparelli, Anna; De Carolis, Antonella; Gradini, Roberto; Nisticò, Robert; De Blasi, Antonio; Girardi, Paolo; Bruno, Valeria; Battaglia, Giuseppe; Nicoletti, Ferdinando; Simmaco, Maurizio.

In: Scientific Reports, Vol. 5, 17799, 08.12.2015.

Research output: Contribution to journalArticle

Fazio, F, Lionetto, L, Curto, M, Iacovelli, L, Cavallari, M, Zappulla, C, Ulivieri, M, Napoletano, F, Capi, M, Corigliano, V, Scaccianoce, S, Caruso, A, Miele, J, De Fusco, A, Di Menna, L, Comparelli, A, De Carolis, A, Gradini, R, Nisticò, R, De Blasi, A, Girardi, P, Bruno, V, Battaglia, G, Nicoletti, F & Simmaco, M 2015, 'Xanthurenic Acid Activates mGlu2/3 metabotropic glutamate receptors and is a potential trait marker for schizophrenia', Scientific Reports, vol. 5, 17799. https://doi.org/10.1038/srep17799
Fazio, Francesco ; Lionetto, Luana ; Curto, Martina ; Iacovelli, Luisa ; Cavallari, Michele ; Zappulla, Cristina ; Ulivieri, Martina ; Napoletano, Flavia ; Capi, Matilde ; Corigliano, Valentina ; Scaccianoce, Sergio ; Caruso, Alessandra ; Miele, Jessica ; De Fusco, Antonio ; Di Menna, Luisa ; Comparelli, Anna ; De Carolis, Antonella ; Gradini, Roberto ; Nisticò, Robert ; De Blasi, Antonio ; Girardi, Paolo ; Bruno, Valeria ; Battaglia, Giuseppe ; Nicoletti, Ferdinando ; Simmaco, Maurizio. / Xanthurenic Acid Activates mGlu2/3 metabotropic glutamate receptors and is a potential trait marker for schizophrenia. In: Scientific Reports. 2015 ; Vol. 5.
@article{bcdcb111da594781913d0014e9ba0432,
title = "Xanthurenic Acid Activates mGlu2/3 metabotropic glutamate receptors and is a potential trait marker for schizophrenia",
abstract = "The kynurenine pathway of tryptophan metabolism has been implicated in the pathophysiology of psychiatric disorders, including schizophrenia. We report here that the kynurenine metabolite, xanturenic acid (XA), interacts with, and activates mGlu2 and mGlu3 metabotropic glutamate receptors in heterologous expression systems. However, the molecular nature of this interaction is unknown, and our data cannot exclude that XA acts primarily on other targets, such as the vesicular glutamate transporter, in the CNS. Systemic administration of XA in mice produced antipsychotic-like effects in the MK-801-induced model of hyperactivity. This effect required the presence of mGlu2 receptors and was abrogated by the preferential mGlu2/3 receptor antagonist, LY341495. Because the mGlu2 receptor is a potential drug target in the treatment of schizophrenia, we decided to measure serum levels of XA and other kynurenine metabolites in patients affected by schizophrenia. Serum XA levels were largely reduced in a large cohort of patients affected by schizophrenia, and, in patients with first-episode schizophrenia, levels remained low after 12 months of antipsychotic medication. As opposed to other kynurenine metabolites, XA levels were also significantly reduced in first-degree relatives of patients affected by schizophrenia. We suggest that lowered serum XA levels might represent a novel trait marker for schizophrenia.",
author = "Francesco Fazio and Luana Lionetto and Martina Curto and Luisa Iacovelli and Michele Cavallari and Cristina Zappulla and Martina Ulivieri and Flavia Napoletano and Matilde Capi and Valentina Corigliano and Sergio Scaccianoce and Alessandra Caruso and Jessica Miele and {De Fusco}, Antonio and {Di Menna}, Luisa and Anna Comparelli and {De Carolis}, Antonella and Roberto Gradini and Robert Nistic{\`o} and {De Blasi}, Antonio and Paolo Girardi and Valeria Bruno and Giuseppe Battaglia and Ferdinando Nicoletti and Maurizio Simmaco",
year = "2015",
month = "12",
day = "8",
doi = "10.1038/srep17799",
language = "English (US)",
volume = "5",
journal = "Scientific Reports",
issn = "2045-2322",
publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - Xanthurenic Acid Activates mGlu2/3 metabotropic glutamate receptors and is a potential trait marker for schizophrenia

AU - Fazio, Francesco

AU - Lionetto, Luana

AU - Curto, Martina

AU - Iacovelli, Luisa

AU - Cavallari, Michele

AU - Zappulla, Cristina

AU - Ulivieri, Martina

AU - Napoletano, Flavia

AU - Capi, Matilde

AU - Corigliano, Valentina

AU - Scaccianoce, Sergio

AU - Caruso, Alessandra

AU - Miele, Jessica

AU - De Fusco, Antonio

AU - Di Menna, Luisa

AU - Comparelli, Anna

AU - De Carolis, Antonella

AU - Gradini, Roberto

AU - Nisticò, Robert

AU - De Blasi, Antonio

AU - Girardi, Paolo

AU - Bruno, Valeria

AU - Battaglia, Giuseppe

AU - Nicoletti, Ferdinando

AU - Simmaco, Maurizio

PY - 2015/12/8

Y1 - 2015/12/8

N2 - The kynurenine pathway of tryptophan metabolism has been implicated in the pathophysiology of psychiatric disorders, including schizophrenia. We report here that the kynurenine metabolite, xanturenic acid (XA), interacts with, and activates mGlu2 and mGlu3 metabotropic glutamate receptors in heterologous expression systems. However, the molecular nature of this interaction is unknown, and our data cannot exclude that XA acts primarily on other targets, such as the vesicular glutamate transporter, in the CNS. Systemic administration of XA in mice produced antipsychotic-like effects in the MK-801-induced model of hyperactivity. This effect required the presence of mGlu2 receptors and was abrogated by the preferential mGlu2/3 receptor antagonist, LY341495. Because the mGlu2 receptor is a potential drug target in the treatment of schizophrenia, we decided to measure serum levels of XA and other kynurenine metabolites in patients affected by schizophrenia. Serum XA levels were largely reduced in a large cohort of patients affected by schizophrenia, and, in patients with first-episode schizophrenia, levels remained low after 12 months of antipsychotic medication. As opposed to other kynurenine metabolites, XA levels were also significantly reduced in first-degree relatives of patients affected by schizophrenia. We suggest that lowered serum XA levels might represent a novel trait marker for schizophrenia.

AB - The kynurenine pathway of tryptophan metabolism has been implicated in the pathophysiology of psychiatric disorders, including schizophrenia. We report here that the kynurenine metabolite, xanturenic acid (XA), interacts with, and activates mGlu2 and mGlu3 metabotropic glutamate receptors in heterologous expression systems. However, the molecular nature of this interaction is unknown, and our data cannot exclude that XA acts primarily on other targets, such as the vesicular glutamate transporter, in the CNS. Systemic administration of XA in mice produced antipsychotic-like effects in the MK-801-induced model of hyperactivity. This effect required the presence of mGlu2 receptors and was abrogated by the preferential mGlu2/3 receptor antagonist, LY341495. Because the mGlu2 receptor is a potential drug target in the treatment of schizophrenia, we decided to measure serum levels of XA and other kynurenine metabolites in patients affected by schizophrenia. Serum XA levels were largely reduced in a large cohort of patients affected by schizophrenia, and, in patients with first-episode schizophrenia, levels remained low after 12 months of antipsychotic medication. As opposed to other kynurenine metabolites, XA levels were also significantly reduced in first-degree relatives of patients affected by schizophrenia. We suggest that lowered serum XA levels might represent a novel trait marker for schizophrenia.

UR - http://www.scopus.com/inward/record.url?scp=84949604514&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84949604514&partnerID=8YFLogxK

U2 - 10.1038/srep17799

DO - 10.1038/srep17799

M3 - Article

C2 - 26643205

AN - SCOPUS:84949604514

VL - 5

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

M1 - 17799

ER -