Kynurenines with Neuroactive and Redox Properties: Relevance to Aging and Brain Diseases

Abstract

The kynurenine pathway (KP) is the main route of tryptophan degradation whose final product is NAD+. The metabolism of tryptophan can be altered in ageing and with neurodegenerative process, leading to decreased biosynthesis of nicotinamide. This fact is very relevant considering that tryptophan is the major source of body stores of the nicotinamide-containing NAD+ coenzymes, which is involved in almost all the bioenergetic and biosynthetic metabolism. Recently, it has been proposed that endogenous tryptophan and its metabolites can interact and/or produce reactive oxygen species in tissues and cells. This subject is of great importance due to the fact that oxidative stress, alterations in KP metabolites, energetic deficit, cell death, and inflammatory events may converge each other to enter into a feedback cycle where each one depends on the other to exert synergistic actions among them. It is worth mentioning that all these factors have been described in aging and in neurodegenerative processes; however, has so far no one established any direct link between alterations in KP and these factors. In this review, we describe each kynurenine remarking their redox properties, their effects in experimental models, their alterations in the aging process.

Tryptophan-kynurenine pathway is dysregulated in inflammation and immune activation

“…Following its synthesis by IDO, Kyn can be further metabolized by various enzymes (Figure 1)(1, 32–34). Kynureninase produces anthranilic acid (AA) from Kyn(35, 36).…”

“…The ability of IDO to deprive cells of an essential amino acid and to promote the formation of bioactive Kynurenines underscores its biological role in many human diseases, including cancer(58–61), chronic infectious diseases(11, 51), allergy, autoimmune diseases(29, 51, 54, 62–64), neurodegeneration, psychiatric disorders(34, 65–67), and other immunosuppressive disorders(9, 10, 40). …”

“…Humans express one kynureninase enzyme that is encoded by the L-Kyn hydrolase gene located on chromosome 2(36). In rats, the enzyme is predominantly located in the cytoplasm(34, 95), and it displays higher affinity and maximal velocity towards L-3-OHkyn than L-Kyn(34, 36). …”

“…This enzyme is crucial in the biosynthesis of nicotinamide nucleotides(34–36) and also gives rise to other pathophysiologically important compounds, such as picolinic acid, an enhancer of nitric oxide synthase expression(36, 96). Recent evidence suggested that the stimulation of kynureninase activity may also represent a relevant response in inflammation.…”

“…Additionally, the anthranilate has elicited more pronounced effects on active than on resting rate of respiration. These contradictory effects found for AA may be due to its capability as a substrate to produce hydroxyl radicals to the 3-HAA metabolite(34). …”