Relevance of Alternative Routes of Kynurenic Acid Production in the Brain.

The catabolism of tryptophan has gained great importance in recent years due to the fact that the metabolites produced during this process, with neuroactive and redox properties, are involved in physiological and pathological events. One of these metabolites is kynurenic acid (KYNA), which is considered as a neuromodulator since it can interact with NMDA, nicotinic, and GPR35 receptors among others, modulating the release of neurotransmitters as glutamate, dopamine, and acetylcholine. Kynureninate production is attributed to kynurenine aminotransferases. However, in some physiological and pathological conditions, its high production cannot be explained just with kynurenine aminotransferases. This review focuses on the alternative mechanism whereby KYNA can be produced, either from D-amino acids or by means of other enzymes as D-amino acid oxidase or by the participation of free radicals. It is important to mention that an increase in KYNA levels in processes as brain development, aging, neurodegenerative diseases, and psychiatric disorders, which share common factors as oxidative stress, inflammation, immune response activation, and participation of gut microbiota that can also be related with the alternative routes of KYNA production, has been observed.

Mitochondrial dysfunction related to cell damage induced by 3-hydroxykynurenine and 3-hydroxyanthranilic acid: Non-dependent-effect of early reactive oxygen species production.

The kynurenines 3-hydroxyanthranilic acid (3-HANA) and its precursor 3-hydroxykynurenine (3-HK) are metabolites derived from tryptophan degradation. 3-HK, has been related to diverse neurodegenerative diseases including Huntington's, Alzheimer's and Parkinson's diseases that share mitochondrial metabolic dysregulation. Nevertheless, the direct effect of these kynurenines on mitochondrial function has not been investigated despite it could be regulated by their redox properties that are controversial. A body of literature has suggested a ROS mediated cell death induced by 3-HK and 3-HANA. On the other hand, some works have supported that both kynurenines have antioxidant effects. Therefore, the aim of this study was to investigate 3-HK and 3-HANA effects on mitochondrial and cellular function in rat cultured cortical astrocytes (rCCA) and in animals intrastriatally injected with these kynurenines as well as to determinate the ROS role on these effects. First, we evaluated 3-HK and 3-HANA effect on cellular function, ROS production and mitochondrial membrane potential in vivo and in vitro in rCCA. Our results show that both kynurenines decreased MTT reduction in a concentration-dependent manner together with mitochondrial membrane potential. These observations were accompanied with increased cell death in rCCA and in circling behavior and morphological changes of injected animals. Interestingly, we found that ROS production was not increased in both in vitro and in vivo experiments, and accordingly lipid peroxidation (LP) was neither increased in striatal tissue of animals injected with both kynurenines. The lack of effect on these oxidative markers is in agreement with the ·OH and ONOO(-) scavenging capacity of both kynurenines detected by chemical combinatorial assays. Altogether, these data indicate that both kynurenines exert toxic effects through mechanisms that include impairment of cellular energy metabolism which are not related to early ROS production.

On the antioxidant properties of kynurenic acid: free radical scavenging activity and inhibition of oxidative stress.

Kynurenic acid (KYNA) is an endogenous metabolite of the kynurenine pathway for tryptophan degradation and an antagonist of both N-methyl-D-aspartate (NMDA) and alpha-7 nicotinic acetylcholine (α7nACh) receptors. KYNA has also been shown to scavenge hydroxyl radicals (OH) under controlled conditions of free radical production. In this work we evaluated the ability of KYNA to scavenge superoxide anion (O(2)(-)) and peroxynitrite (ONOO(-)). The scavenging ability of KYNA (expressed as IC(50) values) was as follows: OH=O(2)(-)>ONOO(-). In parallel, the antiperoxidative and scavenging capacities of KYNA (0-150 µM) were tested in cerebellum and forebrain homogenates exposed to 5 µM FeSO(4) and 2.5 mM 3-nitropropionic acid (3-NPA). Both FeSO(4) and 3-NPA increased lipid peroxidation (LP) and ROS formation in a significant manner in these preparations, whereas KYNA significantly reduced these markers. Reactive oxygen species (ROS) formation were determined in the presence of FeSO(4) and/or KYNA (0-100 µM), both at intra and extracellular levels. An increase in ROS formation was induced by FeSO(4) in forebrain and cerebellum in a time-dependent manner, and KYNA reduced this effect in a concentration-dependent manner. To further know whether the effect of KYNA on oxidative stress is independent of NMDA and nicotinic receptors, we also tested KYNA (0-100 µM) in a biological preparation free of these receptors - defolliculated Xenopus laevis oocytes - incubated with FeSO(4) for 1 h. A 3-fold increase in LP and a 2-fold increase in ROS formation were seen after exposure to FeSO(4), whereas KYNA attenuated these effects in a concentration-dependent manner. In addition, the in vivo formation of OH evoked by an acute infusion of FeSO(4) (100 µM) in the rat striatum was estimated by microdialysis and challenged by a topic infusion of KYNA (1 µM). FeSO(4) increased the striatal OH production, while KYNA mitigated this effect. Altogether, these data strongly suggest that KYNA, in addition to be a well-known antagonist acting on nicotinic and NMDA receptors, can be considered as a potential endogenous antioxidant.