Schizophr Res. 2013 Dec 14. pii: S0920-9964(13)00607-5. doi: 10.1016/j.schres.2013.11.011. [Epub ahead of print]

Evaluation of kynurenine pathway metabolism in Toxoplasma gondii-infected mice: Implications for schizophrenia

Notarangelo FM1, Wilson EH2, Horning KJ3, Thomas MA3, Harris TH2, Fang Q2, Hunter CA2, Schwarcz R3.

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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 28days 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 28days 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 56days 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.

Copyright © 2013 Elsevier B.V. All rights reserved.

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

PMID:

 

24345671

 

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