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 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 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.

<em>Toxoplasma gondii</em> Infection

“…In addition, increased levels of kynurenine lead to increased levels of its active metabolite quinolinic acid, a potent N-methyl-d-aspartate receptor agonist, which may increase the risk for aggressive behavior in humans. 50 While this hypothesis is partially supported by reported elevations of kynurenine and quinolinic acid levels in mice with chronic T. gondii infection, 52 we did not find differences in circulating levels of proinflammatory cytokines (ie, IL-6) as a function of T. gondii seropositivity. It is possible that the proinflammatory processes that keep T. gondii in a latent state are confined to the brain and are not reflected in the periphery.…”

Shared Immune and Repair Markers During ExperimentalToxoplasmaChronic Brain Infection and Schizophrenia

“…The kynurenine pathway constitutes a promising target for novel antipsychotic drugs. However, a recent study revealed that kynurenine pathway alterations in acutely T gondii-infected mice might not fully reflect changes observed in the brain of schizophrenia patients, 10 suggesting that other mechanisms may contribute to schizophrenia pathogenesis in individuals infected with T gondii.…”

“…T gondii infection and schizophrenia both involve increased production of L-kynurenine and its metabolites affecting glutamate receptor signaling and neuro-excitotoxicity. [8][9][10] T gondii infection and schizophrenia also both manifest significant neuroinflammation [11][12][13][14][15][16][17] and disregulation of neurotransmitters, particularly dopamine and serotonin. [18][19][20][21] Additionally, several reports have documented the ability of T gondii to alter rodent neural connectivity 22 and fear behavior, 23,24 and influence human behavior (reviewed in ref.…”

Toxoplasma gondii infection in the context of the risk of schizophrenia development

“…It is worth noting that the antiparasitic drugs pyrimethamine and sulfadiazine, the standard treatment for toxoplasmosis, substantially lower 3-HK and KYNA levels in the brains of infected mice when applied from 28 to 56 days after infection. The results of the study indicate that T. gondii infection, probably through the activation of the microglia and astrocytes, increases the production of KP metabolites in the brain, which may be linked to the occurrence of symptoms typical of schizophrenia (15).…”