Tryptophan, kynurenine, and kynurenine metabolites: Relationship to lifetime aggression and inflammatory markers in human subjects

Abstract

Inflammatory proteins are thought to be causally involved in the generation of aggression, possibly due to direct effects of cytokines in the central nervous system and/or by generation of inflammatory metabolites along the tryptophan-kynurenine (TRP/KYN) pathway, including KYN and its active metabolites kynurenic acid (KA), quinolinic acid (QA), and picolinic acid (PA). We examined plasma levels of TRP, KYN, KA, QA, and PA in 172 medication-free, medically healthy, human subjects to determine if plasma levels of these substances are altered as a function of trait aggression, and if they correlate with current plasma levels of inflammatory markers. Plasma levels of C-reactive protein (CRP), interleukin-6 (IL-6), and soluble interleukin-1 receptor-II (sIL-1RII) protein were also available in these subjects. We found normal levels of TRP but reduced plasma levels of KYN (by 48%), QA (by 6%), and a QA/KA (by 5%) ratio in subjects with Intermittent Explosive Disorder (IED) compared to healthy controls and psychiatric controls. Moreover, the metabolites were not associated with any of the inflammatory markers studied. These data do not support the hypothesis that elevated levels of KYN metabolites would be present in plasma of subjects with IED, and associated with plasma inflammation. However, our data do point to a dysregulation of the KYN pathway metabolites in these subjects. Further work will be necessary to replicate these findings and to understand their role in inflammation and aggression in these subjects.

Keywords: Aggression; CRP; IL-6; Kynurenine pathway; Plasma; sIL-1RII.

Fig. 1

Correlation between Composite Inflammatory Markers and LHA Aggression (r = 0.48, p < 0.001; partial r = 0.37, p < 0.001 including relevant covariates; see text).

Fig. 2

Marginal Means (+SEM), after including all relevant covariates (see text), for Log plasma levels of Tryptophan (TRP), Kynurenine (KYN), Kynurinic Acid (KA), Quinolinic Acid (QA), and Picolinic Acid (PA) in Healthy Control (HC), Psychiatric Control (PC) and IED subjects. * = p < 0.05 compared with HC Subjects.

Fig. 3

Marginal Means (+SEM), after including all relevant covariates (see text), for ratios among Kynuernine Pathway Metabolites: KYN/TRP Ratio, KYN/KA Ratio, and QAN/KA Ratio in Healthy Control (HC), Psychiatric Control (PC) and IED subjects. * = p < 0.05 compared with HC Subjects.