Increased cortical kynurenate content in schizophrenia

Background: Metabolites of the kynurenine pathway of tryptophan degradation may play a role in the pathogenesis of several human brain diseases. One o f the key metabolites in this pathway, kynurenine, is either transaminated to form the glutamate receptor antagonist, kynurenate, or hydroxylated to 3 -hydroxykynurenine, which in turn is further degraded to the excitotoxic N- methyl-D-aspartate receptor agonist quinolinate. Because a hypoglutamatergi c tone may be involved in the pathophysiology of schizophrenia, it is conce ivable that alterations in kynurenine pathway metabolism may play a role in the disease. Methods: The tissue levels of kynurenine, kynurenate, and 3-hydroxykynureni ne were measured in brain tissue specimens obtained from the Maryland Brain Collection. All three metabolites A-ere determined in the same samples fro m three cortical brain regions (Brodmann areas 9, 10, and 19), obtained fro m 30 schizophrenic and 31 matched control subjects. Results: Kynurenate levels were significantly increased in schizophrenic ca ses in Brodmann area 9 (2.9 +/- 2.2 vs. 1.9 +/- 1.3 pmol/mg protein, p < .0 5), but not in Brodmann areas 10 and 19. Kynurenine levels were elevated in schizophrenic cases in Brodmann areas 9 (35.2 <plus/minus> 28.0 vs. 22.4 /- 14.3 pmol/mg protein; p < .05) and 19 (40.3 <plus/minus> 23.4 vs. 30.9 /- 10.8; p < .05). No significant differences in 3-hydroxykynurenine conten t were observed between the two groups. In both groups, significant (p < .0 5) correlations were found in all three brain areas between kynurenine and kynurenate, but not between kynurenine and 3-hydroxykynurenine (p > .05). I n rats, chronic (6-months) treatment with haloperidol did not cause an incr ease in kynurenate levels in the frontal cortex, indicating that the elevat ion observed in schizophrenia is not due to antipsychotic medication. Conclusions: The data demonstrate an impairment of brain kynurenine pathway metabolism in schizophrenia, resulting in elevated kynurenate levels and s uggesting a possible concomitant reduction in glutamate receptor function. Biol Psychiatry 2001;50:521-530 (C) 2001 Society of Biological Psychiatry.