Role of Kynurenine Pathway in Oxidative Stress during Neurodegenerative Disorders

Abstract

Neurodegenerative disorders are chronic and life-threatening conditions negatively affecting the quality of patients' lives. They often have a genetic background, but oxidative stress and mitochondrial damage seem to be at least partly responsible for their development. Recent reports indicate that the activation of the kynurenine pathway (KP), caused by an activation of proinflammatory factors accompanying neurodegenerative processes, leads to the accumulation of its neuroactive and pro-oxidative metabolites. This leads to an increase in the oxidative stress level, which increases mitochondrial damage, and disrupts the cellular energy metabolism. This significantly reduces viability and impairs the proper functioning of central nervous system cells and may aggravate symptoms of many psychiatric and neurodegenerative disorders. This suggests that the modulation of KP activity could be effective in alleviating these symptoms. Numerous reports indicate that tryptophan supplementation, inhibition of KP enzymes, and administration or analogs of KP metabolites show promising results in the management of neurodegenerative disorders in animal models. This review gathers and systematizes the knowledge concerning the role of metabolites and enzymes of the KP in the development of oxidative damage within brain cells during neurodegenerative disorders and potential strategies that could reduce the severity of this process.

Keywords: 3-hydroxykynurenine; excitotoxicity; kynurenine; kynurenine pathway; neurodegenerative disorders; oxidative stress; quinolinic acid; reactive oxygen species; tryptophan.

Figure 1

The main pathways of tryptophan (TRP) metabolism.

Figure 2

The course of the kynurenine pathway in various populations of the central nervous system cells. 3-HAA: 3-hydroxyanthranilic acid, 3-HAO: 3-hydroxyanthranilic acid 3,4-dioxygenase, 3-HKYN: 3-hydorxykynurenine, AA: anthranilic acid, AMO: aminocarboxymuconatesemialdehyde decarboxylase, IDO: indoleamine 2,3-dioxygenase, KAT: kynurenine aminotransferase, KMO: kynurenine 3-monooxygenase, KYN: kynurenine, KYNA: kynurenic acid, KYNU: kynureninase, LAT-1: large neutral amino acid transporter 1, NAD+: oxidized form of nicotinamide adenine dinucleotide, OATs: organic anion transporters, PA: picolinic acid, QA: quinolinic acid, TDO: tryptophan 2,3-dioxygenase, TRP: tryptophan, XA: xanthurenic acid.

Figure 3

The involvement of 3-hydroxykynurenine, 3-hydroxyanthranilic acid, and quinolinic acid in the development of oxidative damages in the central nervous system cells. 3-HAA: 3-hydroxyanthranilic acid 3,4-dioxygenase, 3-HKYN: 3-hydroxykynurenine, acetyl-CoA: acetyl coenzyme A; Ca²⁺: calcium, NAD⁺: oxidized form of nicotinamide adenine dinucleotide, NADH: reduced form of nicotinamide adenine dinucleotide, NMDA: N-methyl-D-aspartate, nNOS: neuronal nitric oxide synthases, NO: nitric oxide, O₂^•−: superoxide, OONO⁻: peroxynitrite, QA: quinolinic acid, ROS: reactive oxygen species, TCA cycle: tricarboxylic acid cycle, Ψm: the mitochondrial membrane potential.