Impaired kynurenine pathway metabolism in the prefrontal cortex of individuals with schizophrenia

Abstract

The levels of kynurenic acid (KYNA), an astrocyte-derived metabolite of the branched kynurenine pathway (KP) of tryptophan degradation and antagonist of α7 nicotinic acetylcholine and N-methyl-D-aspartate receptors, are elevated in the prefrontal cortex (PFC) of individuals with schizophrenia (SZ). Because endogenous KYNA modulates extracellular glutamate and acetylcholine levels in the PFC, these increases may be pathophysiologically significant. Using brain tissue from SZ patients and matched controls, we now measured the activity of several KP enzymes (kynurenine 3-monooxygenase [KMO], kynureninase, 3-hydroxyanthranilic acid dioxygenase [3-HAO], quinolinic acid phosphoribosyltransferase [QPRT], and kynurenine aminotransferase II [KAT II]) in the PFC, ie, Brodmann areas (BA) 9 and 10. Compared with controls, the activities of KMO (in BA 9 and 10) and 3-HAO (in BA 9) were significantly reduced in SZ, though there were no significant differences between patients and controls in kynureninase, QPRT, and KAT II. In the same samples, we also confirmed the increase in the tissue levels of KYNA in SZ. As examined in rats treated chronically with the antipsychotic drug risperidone, the observed biochemical changes were not secondary to medication. A persistent reduction in KMO activity may have a particular bearing on pathology because it may signify a shift of KP metabolism toward enhanced KYNA synthesis. The present results further support the hypothesis that the normalization of cortical KP metabolism may constitute an effective new treatment strategy in SZ.

Fig. 1.

The kynurenine pathway of tryptophan degradation, indicating the enzymes measured in the present study. Large open arrows: differences between schizophrenia and control tissues, as described in the text.

Fig. 2.

Individual case representation of kynurenic acid levels in BA 9 and BA 10 in controls (squares) and schizophrenia patients (triangles). Horizontal lines indicate mean values. *P < .05 (ANCOVA post hoc test).

Fig. 3.

(A) Individual case representation of kynurenine 3-monooxygenase (KMO) activity in BA 9 and BA 10 in controls (squares) and schizophrenia (SZ) patients (triangles). Horizontal lines indicate mean values. *P < .05 (ANCOVA post hoc test). (B and C) Kinetic characteristics of KMO activity in BA 9 and BA 10, respectively. [S], kynurenine concentration.

Fig. 4.

Individual case representation of 3-hydroxyanthranilic acid dioxygenase activity in BA 9 and BA 10 in controls (squares) and schizophrenia patients (triangles). Horizontal lines indicate mean values. *P < .05 vs controls (ANCOVA post hoc test). ns, not significant.

Fig. 5.

Individual case representation of kynureninase (A), quinolinic acid phosphoribosyltransferase (B), and kynurenine aminotransferase II (C) activity in BA 9 and BA 10 in controls (squares) and schizophrenia (SZ) patients (triangles). Horizontal lines indicate mean values. None of the enzymes showed differences between controls and SZ patients (all P > .05; ANCOVA post hoc tests). ns, not significant.

Fig. 6.

Chronic (28 d) treatment with risperidone (RISP; 3 mg/kg/d, intraperitoneally) does not alter the tissue levels of kynurenic acid and the activities of kynurenine 3-monooxygenase and 3-hydroxyanthranilic acid dioxygenase in the rat frontal cortex (all P > .1; student t test). Data are mean ± standard error of the mean (SEM) (n = eight animals per group).