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.
authors.affiliation: I.R.C.C.S. Neuromed, Pozzilli, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Fazio
authors.affiliation: Advanced Molecular Diagnostics Unit, Sant'Andrea Hospital, Rome, Italy.
authors.forename: Luana
authors.initials: L
authors.lastname: Lionetto
authors.affiliation: School of Medicine and Psychology NESMOS Department, Sant'Andrea Hospital, Sapienza University, Rome, Italy.
authors.forename: Martina
authors.initials: M
authors.lastname: Curto
authors.affiliation: Department of Physiology and Pharmacology, Sapienza University, Rome, Italy.
authors.forename: Luisa
authors.initials: L
authors.lastname: Iacovelli
authors.affiliation: School of Medicine and Psychology NESMOS Department, Sant'Andrea Hospital, Sapienza University, Rome, Italy.|Center for Neurological Imaging, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, U.S.A.
authors.forename: Michele
authors.initials: M
authors.lastname: Cavallari
authors.affiliation: I.R.C.C.S. Neuromed, Pozzilli, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Zappulla
authors.affiliation: Department of Physiology and Pharmacology, Sapienza University, Rome, Italy.
authors.forename: Martina
authors.initials: M
authors.lastname: Ulivieri
authors.affiliation: School of Medicine and Psychology NESMOS Department, Sant'Andrea Hospital, Sapienza University, Rome, Italy.
authors.forename: Flavia
authors.initials: F
authors.lastname: Napoletano
authors.affiliation: School of Medicine and Psychology NESMOS Department, Sant'Andrea Hospital, Sapienza University, Rome, Italy.
authors.forename: Matilde
authors.initials: M
authors.lastname: Capi
authors.affiliation: School of Medicine and Psychology NESMOS Department, Sant'Andrea Hospital, Sapienza University, Rome, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Corigliano
authors.affiliation: Department of Physiology and Pharmacology, Sapienza University, Rome, Italy.
authors.forename: Sergio
authors.initials: S
authors.lastname: Scaccianoce
authors.affiliation: Department of Physiology and Pharmacology, Sapienza University, Rome, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Caruso
authors.affiliation: Department of Physiology and Pharmacology, Sapienza University, Rome, Italy.
authors.forename: Jessica
authors.initials: J
authors.lastname: Miele
authors.affiliation: I.R.C.C.S. Neuromed, Pozzilli, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: De Fusco
authors.affiliation: I.R.C.C.S. Neuromed, Pozzilli, Italy.
authors.forename: Luisa
authors.initials: L
authors.lastname: Di Menna
authors.affiliation: School of Medicine and Psychology NESMOS Department, Sant'Andrea Hospital, Sapienza University, Rome, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Comparelli
authors.affiliation: School of Medicine and Psychology NESMOS Department, Sant'Andrea Hospital, Sapienza University, Rome, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: De Carolis
authors.affiliation: I.R.C.C.S. Neuromed, Pozzilli, Italy.|Department of Experimental Medicine, Sapienza University, Rome, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Gradini
authors.affiliation: Department of Physiology and Pharmacology, Sapienza University, Rome, Italy.|I.R.C.C.S. Fondazione Santa Lucia, Rome, Italy.
authors.forename: Robert
authors.initials: R
authors.lastname: Nisticò
authors.affiliation: Department of Molecular Medicine, Sapienza University, Rome, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: De Blasi
authors.affiliation: School of Medicine and Psychology NESMOS Department, Sant'Andrea Hospital, Sapienza University, Rome, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Girardi
authors.affiliation: I.R.C.C.S. Neuromed, Pozzilli, Italy.|Department of Physiology and Pharmacology, Sapienza University, Rome, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Bruno
authors.affiliation: I.R.C.C.S. Neuromed, Pozzilli, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Battaglia
authors.affiliation: I.R.C.C.S. Neuromed, Pozzilli, Italy.|Department of Physiology and Pharmacology, Sapienza University, Rome, Italy.
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Nicoletti
authors.affiliation: Advanced Molecular Diagnostics Unit, Sant'Andrea Hospital, Rome, Italy.|School of Medicine and Psychology NESMOS Department, Sant'Andrea Hospital, Sapienza University, Rome, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Simmaco
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D015415:Biomarkers; D001921:Brain / Q000378:metabolism; D016022:Case-Control Studies; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D007737:Kynurenine / Q000378:metabolism; D008297:Male; D055432:Metabolomics / Q000379:methods; D051379:Mice; D008875:Middle Aged; D011485:Protein Binding; D019655:Quantitative Trait, Heritable; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists*; D012559:Schizophrenia / Q000097:blood / Q000175:diagnosis* / Q000378:metabolism*; D015398:Signal Transduction; D013570:Synaptic Membranes / Q000378:metabolism; D014977:Xanthurenates / Q000097:blood / Q000378:metabolism*; D055815:Young Adult
chemical_list: D015415:Biomarkers; D018094:Receptors, Metabotropic Glutamate; D014977:Xanthurenates; C108822:metabotropic glutamate receptor 2; C102718:metabotropic glutamate receptor 3; D007737:Kynurenine; C028330:xanthurenic acid