L-kynurenine (L-KYN) is an endogenous metabolite, that has been used as a neuroprotective strategy in experimental models. The protective effects of L-KYN have been attributed mainly to kynurenic acid (KYNA). However, considering that L-KYN is prone to oxidation, this redox property may play a substantial role in its protective effects. The aim of this work was to characterize the potential impact of the redox properties of L-KYN, in both synthetic and biological systems. First, we determined whether L-KYN scavenges reactive oxygen species (ROS) and prevents DNA and protein oxidative degradation in synthetic systems. The effect of L-KYN and KYNA (0.1–100 µM) on redox markers (ROS production, lipoperoxidation and cellular function) was compared in rat brain homogenates when exposed to FeSO₄ (10 µM). Then, the effect of L-KYN administration (75 mg/kg/day for 5 days) on the GSH content and the enzymatic activity of glutathione reductase (GR) and glutathione peroxidase (GPx) was determined in rat brain tissue. Finally, brain homogenates from rats pretreated with L-KYN were exposed to pro-oxidants and oxidative markers were evaluated. The results show that L-KYN is an efficient scavenger of ^●OH and ONOO⁻, but not O₂^●– or H₂O₂ and that it prevents DNA and protein oxidative degradation in synthetic systems. L-KYN diminishes the oxidative effect induced by FeSO₄ on brain homogenates at lower concentrations (1 µM) when compared to KYNA (100 µM). Furthermore, the sub-chronic administration of L-KYN increased the GSH content and the activity of both GR and GPx, and also prevented the oxidative damage induced by the ex vivo exposure to pro-oxidants. Altogether, these findings strongly suggest that L-KYN can be considered as a potential endogenous antioxidant.

Aging is a physiological decline process. The number of older adults is growing around the world; therefore, the incidence of cognitive impairment, dementia, and other diseases related to aging increases. The main cellular factors that converge in the aging process are mitochondrial dysfunction, antioxidant impairment, inflammation, and immune response decline, among others. In this context, these cellular changes have an influence on the kynurenine pathway (KP), the main route of tryptophan (Trp) catabolism. KP metabolites have been involved in the aging process and neurodegenerative diseases. Although there are changes in the metabolite levels with age, at this time, there is no study that has evaluated cognitive decline as a consequence of Trp catabolism fluctuation in aging. The aim of this study was to evaluate the relation between the changes in Trp catabolism and cognitive impairment associated with age through KP metabolites level alterations in women over 50 years of age. Seventy‐seven nondemented women over 50 years old were examined with a standardized cognitive screening evaluation in Spanish language (Neuropsi), Beck anxiety inventory (BAI), and the geriatric depression scale (GDS). Also, serum levels of Trp, kynurenine (Kyn), kynurenic acid (KYNA), and 3‐hydroykynurenine (3‐HK) and the glutathione ratio (GSH/GSSG) were measured. Results showed a negative correlation between age and Trp levels and a positive correlation between age and KYNA/Trp and 3‐HK/Trp ratios. The level of cognitive impairment showed a significant positive association with age and with kynurenine pathway activation and a significant negative correlation with Trp levels. The GSH/GSSG ratio correlated positively with Trp levels and negatively with Kyn/Trp and 3‐HK/Trp ratios. The depression score correlated negatively with Trp and positively with the 3‐HK/Trp ratio. We concluded that KP activation increases with age and it is strongly associated with the level of cognition performance in nondemented women over 50 years of age.

The tryptophan (Trp) metabolite kynurenic acid (KYNA) is an α7-nicotinic and N-methyl-d-aspartate receptor antagonist. Elevated brain KYNA levels are commonly seen in psychiatric disorders and neurodegenerative diseases and may be related to cognitive impairments. Recently, we showed that N-acetylcysteine (NAC) inhibits kynurenine aminotransferase II (KAT II), KYNA’s key biosynthetic enzyme, and reduces KYNA neosynthesis in rats in vivo. In this study, we examined if repeated systemic administration of NAC influences brain KYNA and cognitive performance in mice. Animals received NAC (100 mg/kg, i.p.) daily for 7 days. Redox markers, KYNA levels, and KAT II activity were determined in the brain. We also assessed the effect of repeated NAC treatment on Trp catabolism using brain tissue slices ex vivo. Finally, learning and memory was evaluated with and without an acute challenge with KYNA’s bioprecursor L-kynurenine (Kyn; 100 mg/kg). Subchronic NAC administration protected against an acute pro-oxidant challenge, decreased KYNA levels, and lowered KAT II activity and improved memory both under basal conditions and after acute Kyn treatment. In tissue slices from these mice, KYNA neosynthesis from Trp or Kyn was reduced. Together, our data indicate that prolonged treatment with NAC may enhance memory at least in part by reducing brain KYNA levels.

Endurance and resistance exercises, alone or in combination, induce metabolic changes that affect tryptophan (Trp) catabolism. The kynurenine pathway (KP) is the main route of Trp degradation, and it is modulated by the inflammatory and redox environments. Previous studies have shown that KP metabolites work as myokines that mediate the positive systemic effects related to exercise. However, it is poorly understood how different exercise modalities and intensities impact the KP. The aim of this study was to characterize the effect of two different exercise modalities, military diving and swimming, on the KP and the redox environment. A total of 34 healthy men from the Mexican Navy were included in the study, 20 divers and 14 swimmers, who started and stayed in military training consistently during the six months of the study; 12 Mexican men without fitness training were used as the control group. Physical fitness was determined at the beginning and after 6 months of training; criteria included body composition; serum levels of Trp, kynurenine (KYN), kynurenic acid (KYNA) and 3-hydroxykynurenine (3-HK); the glutathione ratio (GSH/GSSG); and malondialdehyde (MDA).. Results showed a significant loss of body fat in both the diver and swimmer groups. Compared with the control group, divers showed a decrease in Trp and 3-HK levels, but no changes were observed in the KYN/Trp, KYNA/Trp or 3-HK/Trp ratios, while swimmers showed a decrease in KYN levels and an increase in the KYNA and 3-HK levels. Additionally, divers showed a decrease in the GSH/GSSG ratio and an increase in MDA levels, in contrast to the swimmers, who showed a decrease in MDA levels and an increase in GSH/GSSG levels. Our findings suggest a differential shift in the KP and redox environment induced by diving and swimming. Swimming promotes an antioxidant environment and a peripheral overactivation of the KP.

Kynureninase (KYNU) is a kynurenine pathway (KP) enzyme that produces metabolites with immunomodulatory properties. In recent years, overactivation of KP has been associated with poor prognosis of several types of cancer, in particular by promoting the invasion, metastasis, and chemoresistance of cancer cells. However, the role of KYNU in gliomas remains to be explored. In this study, we used the available data from TCGA, CGGA and GTEx projects to analyze KYNU expression in gliomas and healthy tissue, as well as the potential contribution of KYNU in the tumor immune infiltrate. In addition, immune-related genes were screened with KYNU expression. KYNU expression correlated with the increased malignancy of astrocytic tumors. Survival analysis in primary astrocytomas showed that KYNU expression correlated with poor prognosis. Additionally, KYNU expression correlated positively with several genes related to an immunosuppressive microenvironment and with the characteristic immune tumor infiltrate. These findings indicate that KYNU could be a potential therapeutic target for modulating the tumor microenvironment and enhancing an effective antitumor immune response.

Lead (Pb²⁺) exposure during early life induces cognitive impairment, which was recently associated with an increase in brain kynurenic acid (KYNA), an antagonist of NMDA and alpha-7 nicotinic receptors. It has been described that N-acetylcysteine (NAC) favors an antioxidant environment and inhibits kynurenine aminotransferase II activity (KAT II, the main enzyme of KYNA production), leading to brain KYNA levels decrease and cognitive improvement. This study aimed to investigate whether the NAC modulation of the brain KYNA levels in mice ameliorated Pb²⁺-induced cognitive impairment. The dams were divided into four groups: Control, Pb²⁺, NAC, and Pb²⁺+NAC, which were given drinking water or 500 ppm lead acetate in the drinking water ad libitum, from 0 to 23 postnatal days (PNDs). The NAC and Pb²⁺+NAC groups were simultaneously fed NAC (350 mg/day) in their chow from 0 to 23 PNDs. At PND 60, the effect of the treatment with Pb²⁺ and in combination with NAC on learning and memory performance was evaluated. Immediately after behavioral evaluation, brain tissues were collected to assess the redox environment; KYNA and glutamate levels; and KAT II activity. The NAC treatment prevented the long-term memory deficit exhibited in the Pb²⁺ group. As expected, Pb²⁺ group showed redox environment alterations, fluctuations in glutamate levels, and an increase in KYNA levels, which were partially avoided by NAC co-administration. These results confirmed that the excessive KYNA levels induced by Pb²⁺ were involved in the onset of cognitive impairment and could be successfully prevented by NAC treatment. NAC could be a tool for testing in scenarios in which KYNA levels are associated with the induction of cognitive impairment.