Dysregulation of kynurenine metabolism is related to proinflammatory cytokines, attention, and prefrontal cortex volume in schizophrenia

Abstract

The kynurenine pathway (KP) of tryptophan (TRP) catabolism links immune system activation with neurotransmitter signaling. The KP metabolite kynurenic acid (KYNA) is increased in the brains of people with schizophrenia. We tested the extent to which: (1) brain KP enzyme mRNAs, (2) brain KP metabolites, and (3) plasma KP metabolites differed on the basis of elevated cytokines in schizophrenia vs. control groups and the extent to which plasma KP metabolites were associated with cognition and brain volume in patients displaying elevated peripheral cytokines. KP enzyme mRNAs and metabolites were assayed in two independent postmortem brain samples from a total of 71 patients with schizophrenia and 72 controls. Plasma KP metabolites, cognition, and brain volumes were measured in an independent cohort of 96 patients with schizophrenia and 81 healthy controls. Groups were stratified based on elevated vs. normal proinflammatory cytokine mRNA levels. In the prefrontal cortex (PFC), kynurenine (KYN)/TRP ratio, KYNA levels, and mRNA for enzymes, tryptophan dioxygenase (TDO) and kynurenine aminotransferases (KATI/II), were significantly increased in the high cytokine schizophrenia subgroup. KAT mRNAs significantly correlated with mRNA for glial fibrillary acidic protein in patients. In plasma, the high cytokine schizophrenia subgroup displayed an elevated KYN/TRP ratio, which correlated inversely with attention and dorsolateral prefrontal cortex (DLPFC) volume. This study provides further evidence for the role of inflammation in a subgroup of patients with schizophrenia and suggests a molecular mechanism through which inflammation could lead to schizophrenia. Proinflammatory cytokines may elicit conversion of TRP to KYN in the periphery and increase the N-methyl-D-aspartate receptor antagonist KYNA via increased KAT mRNA and possibly more enzyme synthesis activity in brain astrocytes, leading to DLPFC volume loss, and attention impairment in schizophrenia.

Kynurenic Acid Levels are Increased in the CSF of Alzheimer’s Disease Patients

“…This finding suggests that KYNA concentration in CSF does not depend on its systemic levels. TRP catabolism is activated by pro-inflammatory cytokines [54]. It has been shown that…”

“…This finding suggests that KYNA concentration in CSF does not depend on its systemic levels. TRP catabolism is activated by pro-inflammatory cytokines [54]. It has been shown that neural synthesis of KYNA takes place predominantly in astrocytes [55], being secreted in response to astrogliosis and inflammatory actions, both features of AD.…”

<p>Increased Plasma Kynurenic Acid Levels are Associated with Impaired Attention/Vigilance and Social Cognition in Patients with Schizophrenia</p>

“…Consistent with some previous studies, the KYN/TRP ratio was also increased in the plasma of individuals with SCZ in our study, and an elevated KYN/ TRP ratio is associated with immune activation in individuals with SCZ. 40,41 In the brain, immune activation can activate astrocytes, where KYN can be transaminated to KYNA through KYN aminotransferases (KATs). 42,43 Thus, we speculate that elevated plasma KYNA levels and KYN/TRP ratio may indicate higher KYNA levels in the brain.…”

Does kynurenic acid act on nicotinic receptors? An assessment of the evidence

“…Schizophrenia, for example, has been linked closely with kynurenic acid concentrations in the CNS (Stone and Darlington ; Cho et al ; Plitman et al ; Erhardt et al 2017; Ogyu et al ; Laumet et al ; Dantzer et al ; Kindler et al ). In schizophrenia, the concentration of kynurenate in the brain is elevated above normal and nucleotide polymorphisms of kynurenine pathway enzymes have been identified (Wonodi and Schwarcz ; Holtze et al ; Stone and Darlington ; Erhardt et al ; Hahn et al ).…”