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.

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 Sebastiana Maria; Miele, Jessica; De Fusco, Antonio; Di Menna, Luisa; Comparelli, Anna; DE CAROLIS, Antonella; Gradini, Roberto; Nistico', ROBERT GIOVANNI; DE BLASI, Antonio; Girardi, Paolo; Bruno, Valeria Maria Gloria; Battaglia, Giuseppe; Nicoletti, Ferdinando; Simmaco, Maurizio. - In: SCIENTIFIC REPORTS. - ISSN 2045-2322. - ELETTRONICO. - 5:(2015), p. 17799. [10.1038/srep17799]

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

FAZIO, FRANCESCO;CURTO, MARTINA;IACOVELLI, LUISA;CAVALLARI, MICHELE;ZAPPULLA, CRISTINA;ULIVIERI, MARTINA;NAPOLETANO, FLAVIA;CAPI, MATILDE;CORIGLIANO, Valentina;SCACCIANOCE, Sergio;CARUSO, Alessandra Sebastiana Maria;MIELE, JESSICA;DE CAROLIS, ANTONELLA;GRADINI, Roberto;NISTICO', ROBERT GIOVANNI;DE BLASI, ANTONIO;GIRARDI, Paolo;BRUNO, Valeria Maria Gloria;BATTAGLIA, Giuseppe;NICOLETTI, Ferdinando;SIMMACO, Maurizio
2015

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.
2015
KYNURENINE-PATHWAY-METABOLISM; PREFRONTAL CORTEX; QUINOLINIC ACID; SYNAPTIC-TRANSMISSION; TRYPTOPHAN METABOLISM; MOLECULAR-MECHANISM; VGLUT INHIBITORS; RAT HIPPOCAMPUS; AGONIST; BRAIN
01 Pubblicazione su rivista::01a Articolo in rivista
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 Sebastiana Maria; Miele, Jessica; De Fusco, Antonio; Di Menna, Luisa; Comparelli, Anna; DE CAROLIS, Antonella; Gradini, Roberto; Nistico', ROBERT GIOVANNI; DE BLASI, Antonio; Girardi, Paolo; Bruno, Valeria Maria Gloria; Battaglia, Giuseppe; Nicoletti, Ferdinando; Simmaco, Maurizio. - In: SCIENTIFIC REPORTS. - ISSN 2045-2322. - ELETTRONICO. - 5:(2015), p. 17799. [10.1038/srep17799]
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Note: Fazio et al., 2015 Sci Rep
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/845214
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