Increased cortical kynurenate content in schizophrenia

Robert Schwarcz, Arash Rassoulpour, Hui Qiu Wu, Deborah Medoff, Carol A. Tamminga, Rosalinda C. Roberts

Research output: Contribution to journalArticle

415 Citations (Scopus)

Abstract

Background: Metabolites of the kynurenine pathway of tryptophan degradation may play a role in the pathogenesis of several human brain diseases. One of 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 hypoglutamatergic tone may be involved in the pathophysiology of schizophrenia, it is conceivable that alterations in kynurenine pathway metabolism may play a role in the disease. Methods: The tissue levels of kynurenine, kynurenate, and 3-hydroxykynurenine were measured in brain tissue specimens obtained from the Maryland Brain Collection. All three metabolites were determined in the same samples from three cortical brain regions (Brodmann areas 9, 10, and 19), obtained from 30 schizophrenic and 31 matched control subjects. Results: Kynurenate levels were significantly increased in schizophrenic cases in Brodmann area 9 (2.9 ± 2.2 vs. 1.9 ± 1.3 pmol/mg protein, p < .05), but not in Brodmann areas 10 and 19. Kynurenine levels were elevated in schizophrenic cases in Brodmann areas 9 (35.2 ± 28.0 vs. 22.4 ± 14.3 pmol/mg protein; p < .05) and 19 (40.3 ± 23.4 vs. 30.9 ± 10.8; p < .05). No significant differences in 3-hydroxykynurenine content were observed between the two groups. In both groups, significant (p < .05) correlations were found in all three brain areas between kynurenine and kynurenate, but not between kynurenine and 3-hydroxykynurenine (p > .05). In rats, chronic (6-months) treatment with haloperidol did not cause an increase in kynurenate levels in the frontal cortex, indicating that the elevation 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 suggesting a possible concomitant reduction in glutamate receptor function.

Original languageEnglish (US)
Pages (from-to)521-530
Number of pages10
JournalBiological Psychiatry
Volume50
Issue number7
DOIs
StatePublished - Oct 1 2001

Fingerprint

Kynurenic Acid
Kynurenine
Schizophrenia
Brain
Quinolinic Acid
Excitatory Amino Acid Antagonists
Glutamate Receptors
Brain Diseases
Frontal Lobe
Haloperidol
N-Methyl-D-Aspartate Receptors
Tryptophan
Antipsychotic Agents
Proteins

Keywords

  • 3-hydroxykynurenine
  • Glutamate
  • Glycine
  • Kynurenate
  • NMDA
  • Schizophrenia

ASJC Scopus subject areas

  • Biological Psychiatry

Cite this

Schwarcz, R., Rassoulpour, A., Wu, H. Q., Medoff, D., Tamminga, C. A., & Roberts, R. C. (2001). Increased cortical kynurenate content in schizophrenia. Biological Psychiatry, 50(7), 521-530. https://doi.org/10.1016/S0006-3223(01)01078-2

Increased cortical kynurenate content in schizophrenia. / Schwarcz, Robert; Rassoulpour, Arash; Wu, Hui Qiu; Medoff, Deborah; Tamminga, Carol A.; Roberts, Rosalinda C.

In: Biological Psychiatry, Vol. 50, No. 7, 01.10.2001, p. 521-530.

Research output: Contribution to journalArticle

Schwarcz, R, Rassoulpour, A, Wu, HQ, Medoff, D, Tamminga, CA & Roberts, RC 2001, 'Increased cortical kynurenate content in schizophrenia', Biological Psychiatry, vol. 50, no. 7, pp. 521-530. https://doi.org/10.1016/S0006-3223(01)01078-2
Schwarcz, Robert ; Rassoulpour, Arash ; Wu, Hui Qiu ; Medoff, Deborah ; Tamminga, Carol A. ; Roberts, Rosalinda C. / Increased cortical kynurenate content in schizophrenia. In: Biological Psychiatry. 2001 ; Vol. 50, No. 7. pp. 521-530.
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abstract = "Background: Metabolites of the kynurenine pathway of tryptophan degradation may play a role in the pathogenesis of several human brain diseases. One of 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 hypoglutamatergic tone may be involved in the pathophysiology of schizophrenia, it is conceivable that alterations in kynurenine pathway metabolism may play a role in the disease. Methods: The tissue levels of kynurenine, kynurenate, and 3-hydroxykynurenine were measured in brain tissue specimens obtained from the Maryland Brain Collection. All three metabolites were determined in the same samples from three cortical brain regions (Brodmann areas 9, 10, and 19), obtained from 30 schizophrenic and 31 matched control subjects. Results: Kynurenate levels were significantly increased in schizophrenic cases in Brodmann area 9 (2.9 ± 2.2 vs. 1.9 ± 1.3 pmol/mg protein, p < .05), but not in Brodmann areas 10 and 19. Kynurenine levels were elevated in schizophrenic cases in Brodmann areas 9 (35.2 ± 28.0 vs. 22.4 ± 14.3 pmol/mg protein; p < .05) and 19 (40.3 ± 23.4 vs. 30.9 ± 10.8; p < .05). No significant differences in 3-hydroxykynurenine content were observed between the two groups. In both groups, significant (p < .05) correlations were found in all three brain areas between kynurenine and kynurenate, but not between kynurenine and 3-hydroxykynurenine (p > .05). In rats, chronic (6-months) treatment with haloperidol did not cause an increase in kynurenate levels in the frontal cortex, indicating that the elevation 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 suggesting a possible concomitant reduction in glutamate receptor function.",
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N2 - Background: Metabolites of the kynurenine pathway of tryptophan degradation may play a role in the pathogenesis of several human brain diseases. One of 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 hypoglutamatergic tone may be involved in the pathophysiology of schizophrenia, it is conceivable that alterations in kynurenine pathway metabolism may play a role in the disease. Methods: The tissue levels of kynurenine, kynurenate, and 3-hydroxykynurenine were measured in brain tissue specimens obtained from the Maryland Brain Collection. All three metabolites were determined in the same samples from three cortical brain regions (Brodmann areas 9, 10, and 19), obtained from 30 schizophrenic and 31 matched control subjects. Results: Kynurenate levels were significantly increased in schizophrenic cases in Brodmann area 9 (2.9 ± 2.2 vs. 1.9 ± 1.3 pmol/mg protein, p < .05), but not in Brodmann areas 10 and 19. Kynurenine levels were elevated in schizophrenic cases in Brodmann areas 9 (35.2 ± 28.0 vs. 22.4 ± 14.3 pmol/mg protein; p < .05) and 19 (40.3 ± 23.4 vs. 30.9 ± 10.8; p < .05). No significant differences in 3-hydroxykynurenine content were observed between the two groups. In both groups, significant (p < .05) correlations were found in all three brain areas between kynurenine and kynurenate, but not between kynurenine and 3-hydroxykynurenine (p > .05). In rats, chronic (6-months) treatment with haloperidol did not cause an increase in kynurenate levels in the frontal cortex, indicating that the elevation 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 suggesting a possible concomitant reduction in glutamate receptor function.

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KW - Glutamate

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