5-Hydroxyanthranilic acid, a tryptophan metabolite, generates oxidative stress and neuronal death via p38 activation in cultured cerebellar granule neurones

Abstract

The essential amino acid tryptophan is primarily metabolised through the kynurenine pathway, some components of which may be neurotoxic. We have now examined the potential toxicity of several kynurenine metabolites in relation to the generation of oxidative stress and activation of cell death signalling pathways in cultured cerebellar granule neurons. 3-Hydroxykynurenine (3HK), 3-hydroxyanthranilic acid (3HAA) and 5-hydroxyanthranilic acid (5HAA) induced cell death which increased with exposure time and compound concentration. The neurotoxic effects of 3HK, 3HAA and 5HAA were prevented by catalase, but not by superoxide dismutase. In addition, Western blot analysis demonstrated p38 activation due to 3HK or 5HAA treatment, although caspase-3 activation was not evident in either case. The results indicate that kynurenine metabolites can be neurotoxic via a caspase-3 independent mechanism, and that the minor metabolite 5HAA is as potent a toxin as the better documented compounds 3HK and 3HAA.