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. 2024 Feb 27;10(1):27.
doi: 10.1038/s41537-024-00447-3.

Changes in kynurenine metabolites in the gray and white matter of the dorsolateral prefrontal cortex of individuals affected by schizophrenia

Nico Antenucci #  1   2 , Giovanna D'Errico #  3 , Francesco Fazio  3   4 , Ferdinando Nicoletti  1   3 , Valeria Bruno  5   6 , Giuseppe Battaglia  1   3
Affiliations

Changes in kynurenine metabolites in the gray and white matter of the dorsolateral prefrontal cortex of individuals affected by schizophrenia

Nico Antenucci et al. Schizophrenia (Heidelb). .

Abstract

Alterations in the kynurenine pathway of tryptophan metabolism have been implicated in the pathophysiology of schizophrenia. Here, we performed an in-depth analysis of all metabolites of the kynurenine pathway, i.e., tryptophan (TRY), kynurenic acid (KYNA), L-kynurenine (KYN), 3-hydroxykynurenine (3-HK), anthranylic acid (ANA), 3-hydroxyanthranylic acid (3-HANA), xanthurenic acid (XA) and quinolinic acid (QUINA), in postmortem samples of the dorsolateral prefrontal cortex (DLPFC, Brodmann area 46, 9) of individuals affected by schizophrenia and non-schizophrenic controls. The analysis was carried out in the gray and white matter. Levels of KYN, 3-HK, ANA, and 3-HANA were significantly increased in both the gray and white matter of the DLPFC of individuals affected by schizophrenia, whereas levels of TRY, KYNA, and QUINA were increased exclusively in the white matter and remained unchanged in the gray matter. These increases in kynurenine metabolites did not correlate with age, sex, duration of the disease, and duration and type of antipsychotic medication. These findings suggest that the two major branches of the kynurenine pathway, i.e., the transamination of KYN into KYNA, and hydroxylation of KYN into 3-HK are activated in the white matter of individuals affected by schizophrenia, perhaps as a result of neuroinflammation, and support the evidence that abnormalities of the white matter are consistenly associated with schizophrenia.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1. The kynurenine pathway.
Metabolites and enzymes involved are shown.
Fig. 2
Fig. 2. Cumulative endogenous levels of kynurenine pathway metabolites in both gray and white matter of DLPFC in control subjects (n = 24) and patients affected by schizophrenia (n = 21).
*p < 0.05 (Student’s t test) vs. control subjects. Grubbs’s test was performed once and one sample for each group was excluded as an outlier, when the case.
Fig. 3
Fig. 3. Endogenous levels of kynurenine pathway metabolites in gray and white matter of males and females in the DLPFC of control subjects and patients affected by schizophrenia.
*p < 0.05 (Student’s t test) vs. control subjects. The control group is composed of 20 males and 4 females whereas the group of patients affected by schizophrenia is composed of 14 males and 7 females. Grubbs’s test was performed once and one sample for each group was excluded as an outlier, when the case.
Fig. 4
Fig. 4. The KYNA:QUINA and TRY:KYN ratios are modified in the DLPFC of individuals affected by schizophrenia.
The KYNA:QUINA ratio was increased by 55% and the TRY:KYN ratio was reduced by 36% in the gray matter of the SCZ group. The KYNA:QUINA ratio was increased by 34% and the TRY:KYN ratio was reduced by 33% in the white matter of the SCZ group.
Fig. 5
Fig. 5. Lack of correlation between levels of TRY and kynurenine metabolites and the duration of disease.
Correlation analysis between kynurenine metabolite levels in the gray and white matter and duration of antipsychotic medication.
Fig. 6
Fig. 6. Lack of correlation between levels of kynurenine metabolites and the type of antipsychotic medication.
Correlation analysis between kynurenine metabolite levels in the gray and white matter and duration of typical and atypical antipsychotic drugs.
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