Similarities and differences in the neuronal death processes activated by 3OH-kynurenine and quinolinic acid.
3OH-Kynurenine and quinolinic acid are tryptophan metabolites able to cause, at relatively elevated concentrations, neuronal death in vitro and in vivo. In primary cultures of mixed cortical cells, the minimal concentration of these compounds leading to a significant degree of neurotoxicity decreased from 100 to 1 microM, when the exposure time was prolonged from 24 to 72 h. NMDA receptor antagonists and inhibitors of nitric oxide synthase or poly(ADP-ribose) polymerase reduced quinolinic acid, but not 3OH-kynurenine toxicity. In contrast, scavengers of free radicals, caspase inhibitors and cyclosporin preferentially reduced 3OH-kynurenine neurotoxicity. These observations suggest that quinolinic acid causes necrosis, whereas 3OH-kynurenine-exposed neurons primarily die in apoptosis. In line with this possibility, we found that ATP levels decreased more rapidly in quinolinate- than in 3OH-kynurenine-exposed cultures and that poly(ADP-ribose) polymer, the product of poly(ADP-ribose) polymerase activity, was more abundant in the nuclei of quinolinic acid than in those of 3OH-kynurenine-exposed neurons. Because minor changes in the physiological concentrations of 3OH-kynurenine and quinolinic acid may cause neuronal death, our data suggest that these metabolites play a key role in the pathogenesis of several neurological disorders.
Chiarugi
A
A
Department of Preclinical and Clinical Pharmacology, University of Florence, Florence, Italy.
Meli
E
E
Moroni
F
F
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology; D005960:Glucosides / Q000633:toxicity*; D007150:Immunohistochemistry; D007737:Kynurenine / Q000031:analogs & derivatives* / Q000633:toxicity*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D051379:Mice; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D052248:Nitric Oxide Synthase Type I; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D017378:Quinolinic Acid / Q000633:toxicity*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors
D015415:Biomarkers; D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D005960:Glucosides; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D016194:Receptors, N-Methyl-D-Aspartate; C029366:hydroxykynurenine glucoside; D007737:Kynurenine; D000255:Adenosine Triphosphate; D007770:L-Lactate Dehydrogenase; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496321:Nos1 protein, mouse; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D017378:Quinolinic Acid