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

Abstract

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.