Kynurenine pathway metabolites and suicidality

Abstract

Suicide is a major global problem, claiming more than 800,000 lives annually. The neurobiological changes that underlie suicidal ideation and behavior are not fully understood. Suicidal patients have been shown to display elevated levels of inflammation both in the central nervous system and the peripheral blood. A growing body of evidence suggests that inflammation is associated with a dysregulation of the kynurenine pathway in suicidal patients, resulting in an imbalance of neuroactive metabolites. Specifically, an increase in the levels of the NMDA receptor agonist quinolinic acid and a simultaneous decrease in neuroprotective metabolites have been observed in suicidal patients, and may contribute to the development of suicidality via changes in glutamate neurotransmission and neuroinflammation. The cause of the dysregulation of kynurenine metabolites in suicidality is not known, but is likely due to differential activity of the involved enzymes in patients. As knowledge in these areas is rapidly growing, targeting the kynurenine pathway enzymes may provide novel therapeutic approaches for managing suicidal behavior.

Tryptophan and Kynurenine Metabolites: Are They Related to Depression?

“…The main findings of this study differed from some previous reports of decreased concentrations of circulating TRY and increased levels of KYN in the body fluids of depressed subjects [4,22], in that we found increased TRY and decreased KYN, with a 3.0-fold greater ratio of TRY/KYN than in healthy controls (Table 1; Fig. 1).…”

“…Similar findings have been reported previously [32]. Moreover, we found no relation between KYN-related metabolites and a lifetime history of suicidal behavior, unlike previous findings regarding recent suicide attempts [4,22]. Plasma concentrations of other KYN-related analytes (AA, XA, and 5-HIAA) did not differ between depressed subjects and controls (Table 1), in accord with previous reports [32,33].…”

“…Notably, serum concentrations of such metabolites were significantly increased (QA), decreased (KA and picolinic acid), or showed no differences (3-hydroxyanthranilic acid) in subjects who had recently attempted suicide when compared to nonsuicidal but depressed controls [4,5,23].…”

Phytochemical treatments target kynurenine pathway induced oxidative stress

“…Quinolinic acid and kynurenic acid form an important balance in maintaining levels of oxidative stress [24]. Quinolinic acid's neurotoxicity occurs through three methods: increased glutamate signalling, acting as an Nmethyl-D-aspartic acid receptor agonist, or lipid peroxidation [19]. Picolinic acid, which is produced from 2-amino-4-carboxymuconic-6-semialdehyde in the presence of picolinic carboxylase instead of spontaneously transforming into quinolinic acid, acts as an endogenous neuroprotective agent by chelating iron, necessary for quinolinic acid to function, or zinc to antagonize quinolinic acid [19,25].…”

The kynurenine pathway: Towards metabolic equilibrium

“…Equally, activation of the kynurenine pathway by glucocorticoids is an important factor for many stress-related disorders (O'Farrell and Harkin, 2015). The possibility that kynurenine pathway metabolism could be implicated as a neurobiological factor underpinning suicidality has also received attention (Bryleva and Brundin, 2016). Finally, it is important to bear in mind that some kynurenines participate in redox reactions, and this may have repercussions for critical biological functions that malfunction in relevant pathologies (Gonzalez Esquivel et al, 2016).…”