title: Evaluation of kynurenine pathway metabolism in Toxoplasma gondii-infected mice: implications for schizophrenia.
abstract: Toxoplasma gondii, an intracellular protozoan parasite, is a major cause of opportunistic infectious disease affecting the brain and has been linked to an increased incidence of schizophrenia. In murine hosts, infection with T. gondii stimulates tryptophan degradation along the kynurenine pathway (KP), which contains several neuroactive metabolites, including 3-hydroxykynurenine (3-HK), quinolinic acid (QUIN) and kynurenic acid (KYNA). As these endogenous compounds may provide a mechanistic connection between T. gondii and the pathophysiology of schizophrenia, we measured KP metabolites in both the brain and periphery of T. gondii-treated C57BL/6 mice 8 and 28 days post-infection. Infected mice showed early decreases in the levels of tryptophan in the brain and serum, but not in the liver. These reductions were associated with elevated levels of kynurenine, KYNA, 3-HK and QUIN in the brain. In quantitative terms, the most significant increases in these KP metabolites were observed in the brain at 28 days post-infection. Notably, the anti-parasitic drugs pyrimethamine and sulfadiazine, a standard treatment of toxoplasmosis, significantly reduced 3-HK and KYNA levels in the brain of infected mice when applied between 28 and 56 days post-infection. In summary, T. gondii infection, probably by activating microglia and astrocytes, enhances the production of KP metabolites in the brain. However, during the first two months after infection, the KP changes in these mice do not reliably duplicate abnormalities seen in the brain of individuals with schizophrenia.
authors.affiliation: Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD 21228, USA. Electronic address: fnotarangelo@mprc.umaryland.edu.
authors.forename: F M
authors.initials: FM
authors.lastname: Notarangelo
authors.affiliation: Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: E H
authors.initials: EH
authors.lastname: Wilson
authors.affiliation: Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD 21228, USA.
authors.forename: K J
authors.initials: KJ
authors.lastname: Horning
authors.affiliation: Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD 21228, USA.
authors.forename: M A R
authors.initials: MA
authors.lastname: Thomas
authors.affiliation: Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: T H
authors.initials: TH
authors.lastname: Harris
authors.affiliation: Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Q
authors.initials: Q
authors.lastname: Fang
authors.affiliation: Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: C A
authors.initials: CA
authors.lastname: Hunter
authors.affiliation: Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD 21228, USA.
authors.forename: R
authors.initials: R
authors.lastname: Schwarcz
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000008:administration & dosage; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000382:microbiology; D004195:Disease Models, Animal; D004338:Drug Combinations; D005260:Female; D007736:Kynurenic Acid / Q000378:metabolism; D007737:Kynurenine / Q000031:analogs & derivatives / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009457:Neuroglia / Q000187:drug effects / Q000473:pathology; D011739:Pyrimethamine / Q000008:administration & dosage; D017378:Quinolinic Acid / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013411:Sulfadiazine / Q000008:administration & dosage; D013997:Time Factors; D014123:Toxoplasmosis / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D014364:Tryptophan / Q000378:metabolism
chemical_list: D000890:Anti-Infective Agents; D004338:Drug Combinations; D012333:RNA, Messenger; D013411:Sulfadiazine; C005045:3-hydroxykynurenine; D007737:Kynurenine; D014364:Tryptophan; D017378:Quinolinic Acid; D007736:Kynurenic Acid; D011739:Pyrimethamine
keywords: 3-HK; 3-Hydroxykynurenine; 3-hydroxykynurenine; Astrocytes; IDO; KYNA; Kynurenic acid; Microglia; QUIN; Quinolinic acid; T. gondii; Toxoplasma gondii; indoleamine 2,3-dioxygenase; quinolinic acid