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

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.

Elevated serum kynurenic acid in individuals with first-episode psychosis and insufficient response to antipsychotics

“…For example, the significantly shorter duration of illness before treatment initiation in the current study and the greater number of antipsychotic-naïve individuals could explain KP hyperactivity, compared to previous findings in FEP patients 51 . Given the considerable clinical heterogeneity among patients with FEP, it is argued that a range of clinical aspects and state-dependent symptom manifestations or psychological stress might be responsible for the observed KP metabolite disturbances during FEP or even at later stages of schizophrenia and bipolar disorder 38 , 77 , 78 . Consequently, additional research is required to fully elucidate the causes of KP dysregulation in psychotic disorders, and clarify whether this constitutes a pathological reaction or a physiological mechanism to essentially compensate the effects of enhanced inflammatory responses 79 .…”

“…Extensive experimental research has demonstrated that KP is physiologically regulated by enhanced immune responses, while KP metabolite fluctuations have been observed in major psychiatric disorders including schizophrenia, bipolar disorder, and major depressive disorder 32 – 34 . Higher levels of kynurenine (KYN) and KYNA metabolites have been detected in both blood and CSF from patients with schizophrenia 27 , 28 , 35 – 37 , as well as in white matter of dorsolateral prefrontal cortex postmortem samples 38 . The above observations provide evidence that the dysregulation of KP could potentially contribute to the development of psychotic symptomatology via molecular mechanisms negatively affecting glutamatergic neurotransmission 30 , 39 .…”