5-Hydroxyanthranilic acid, a tryptophan metabolite, generates oxidative stress and neuronal death via p38 activation in cultured cerebellar granule neurones.
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.
Smith
Andrew J
AJ
Division of Neuroscience and Biomedical Systems, Institute of Biomedical and Life Sciences, University of Glasgow, West Medical Building, Glasgow, G12-8QQ, Scotland, UK.
Smith
Robert A
RA
Stone
Trevor W
TW
D015095:3-Hydroxyanthranilic Acid; D000450:Aldosterone / Q000031:analogs & derivatives; D000818:Animals; D000831:Animals, Newborn; D053148:Caspase 3 / Q000378:metabolism; D002374:Catalase / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology*; D003513:Cycloheximide / Q000494:pharmacology; D005452:Fluoresceins / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D007737:Kynurenine / Q000031:analogs & derivatives; D016501:Neurites / Q000187:drug effects; D009474:Neurons / Q000166:cytology / Q000187:drug effects*; D018384:Oxidative Stress / Q000187:drug effects*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D051381:Rats; D013997:Time Factors; D062367:ortho-Aminobenzoates / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D005452:Fluoresceins; D011500:Protein Synthesis Inhibitors; D062367:ortho-Aminobenzoates; C048926:3-hydroxy-delta(5)-aldosterone; D015095:3-Hydroxyanthranilic Acid; C005045:3-hydroxykynurenine; D007737:Kynurenine; D000450:Aldosterone; D003513:Cycloheximide; D002374:Catalase; D048051:p38 Mitogen-Activated Protein Kinases; D053148:Caspase 3; C018506:diacetylfluorescein