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 (alpha 7nACh) receptors. KYNA has also been shown to scavenge hydroxyl radicals (center dot OH) under controlled conditions of free radical production. In this work we evaluated the ability of KYNA to scavenge superoxide anion (O-2 center dot(-)) and peroxynitrite (ONOO-). The scavenging ability of KYNA (expressed as IC50 values) was as follows: center dot OH = O-2 center dot(-) > ONOO-. In parallel, the antiperoxidative and scavenging capacities of KYNA (0-150 mu M) were tested in cerebellum and forebrain homogenates exposed to 5 mu M FeSO4 and 2.5 mM 3-nitropropionic acid (3-NPA). Both FeSO4 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 FeSO4 and/or KYNA (0-100 mu M), both at intra and extracellular levels. An increase in ROS formation was induced by FeSO4 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 mu M) in a biological preparation free of these receptors - defolliculated Xenopus laevis oocytes - incubated with FeSO4 for 1 h. A 3-fold increase in LP and a 2-fold increase in ROS formation were seen after exposure to FeSO4, whereas KYNA attenuated these effects in a concentration-dependent manner. In addition, the in vivo formation of center dot OH evoked by an acute infusion of FeSO4 (100 mu M) in the rat striatum was estimated by microdialysis and challenged by a topic infusion of KYNA (1 mu M). FeSO4 increased the striatal center dot 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. (C) 2011 Elsevier Inc. All rights reserved.