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
N1 - Funding Information:
This research project received no specific grant from any funding agency in the public, commercial, or not-profit sectors. We thank Sapienza University of Rome, I.R.C.C.S. Neuromed, and Advanced Molecular Diagnostics Unit of Sant’Andrea Hospital of Rome for their support. Dr. Fazio, Dr. Zappulla, Dr. De Fusco and Dr. Di Menna were supported by internal resources of I.R.C.C.S. Neuromed, Pozzilli (IS). Dr. Battaglia was full-time research fellow of I.R.C.C.S. Neuromed, Pozzilli. Prof. Bruno, Prof. Gradini, and Prof. De Blasi were associate professors at Sapienza University of Rome. In the past three years, Prof. Girardi has received unrestricted educational grants support from Eli Lilly Italia S.p.A., Janssen-Cilag S.p.A., and Springer Healthcare, and has participated in Advisory Boards for Eli Lilly Italia S.p.A., Otsuka, Pfizer, Schering, and Springer Healthcare and received honoraria from Eli Lilly Italia S.p.A. and Springer Healthcare. Dr. Lionetto was a full-time employee of the Advanced Molecular Diagnostics Unit of Sant’Andrea Hospital of Rome. Dr. Comparelli and Dr. De Carolis were full-time employees of the Psychiatry and Neurology Units, respectively. Dr. Curto and Dr. Corigliano were supported by the Psychiatry Residency Program scholarship. Dr. Cavallari, Dr. Capi and Dr. Napoletano were supported by internal resources of NESMOS Department, Sapienza University of Rome. Dr. Iacovelli, Dr. Scaccianoce, and Dr. Caruso were full-time research fellows at Physiology and Pharmacology Department, Sapienza University of Rome. Dr. Ulivieri and Dr. Miele were supported by internal resources of Physiology and Pharmacology Department, Sapienza University of Rome.
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.
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U2 - 10.1038/srep17799
DO - 10.1038/srep17799
M3 - Article
C2 - 26643205
AN - SCOPUS:84949604514
SN - 2045-2322
VL - 5
JO - Scientific reports
JF - Scientific reports
M1 - 17799
ER -