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Xanthurenic Acid Activates mGlu2/3 Metabotropic Glutamate Receptors and is a Potential Trait Marker for Schizophrenia

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 heterol...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4672300/
https://www.ncbi.nlm.nih.gov/pubmed/26643205
http://dx.doi.org/10.1038/srep17799
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author 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
author_facet 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
author_sort Fazio, Francesco
collection PubMed
description 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.
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spelling pubmed-46723002015-12-11 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 Sci Rep Article 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. Nature Publishing Group 2015-12-08 /pmc/articles/PMC4672300/ /pubmed/26643205 http://dx.doi.org/10.1038/srep17799 Text en Copyright © 2015, Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
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
title Xanthurenic Acid Activates mGlu2/3 Metabotropic Glutamate Receptors and is a Potential Trait Marker for Schizophrenia
title_full Xanthurenic Acid Activates mGlu2/3 Metabotropic Glutamate Receptors and is a Potential Trait Marker for Schizophrenia
title_fullStr Xanthurenic Acid Activates mGlu2/3 Metabotropic Glutamate Receptors and is a Potential Trait Marker for Schizophrenia
title_full_unstemmed Xanthurenic Acid Activates mGlu2/3 Metabotropic Glutamate Receptors and is a Potential Trait Marker for Schizophrenia
title_short Xanthurenic Acid Activates mGlu2/3 Metabotropic Glutamate Receptors and is a Potential Trait Marker for Schizophrenia
title_sort xanthurenic acid activates mglu2/3 metabotropic glutamate receptors and is a potential trait marker for schizophrenia
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4672300/
https://www.ncbi.nlm.nih.gov/pubmed/26643205
http://dx.doi.org/10.1038/srep17799
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