Quinolinate neurotoxicity in cortical cell culture.
The central neurotoxicity of the endogenous tryptophan metabolite, quinolinate, has been postulated to participate in the pathogenesis of the neuronal cell loss associated with several neurological disease states. In the present study, quinolinate neurotoxicity was quantitatively studied in dissociated cell cultures prepared from the fetal mouse neocortex. Sufficient exposure of cortical cultures to quinolinate was associated with considerable neuronal cell loss, but no glial cell loss; this neurotoxicity could be blocked by 2-amino-5-phosphonovalerate and kynurenate, drugs known to block N-methyl-D-aspartate receptors. The quinolinate dose-toxicity relationship showed that the potency of quinolinate as a neurotoxin is relatively low, especially with brief (20 min) exposure times, where an ED50 of 2 mM was observed. However, with longer exposure times of 24 and 96 h, quinolinate is more potent: the latter exposure was characterized by an ED50 of 250-400 microM. Ion substitution experiments suggested that quinolinate neurotoxicity can be separated into two distinct components on the basis of differences in time course and ionic dependence: an acute, sodium-dependent "excitotoxic" component, marked by early cell swelling; and a late, calcium-dependent component, marked by delayed cell degeneration. Acute neuronal swelling was seen only with exposure to quinolinate concentrations in excess of 1 mM, so under actual pathophysiological conditions, quinolinate neurotoxicity might be nearly completely related to the calcium-dependent component, with little or no "excitotoxic" contribution.
D015763:2-Amino-5-phosphonovalerate / Q000031:analogs & derivatives*; D000596:Amino Acids / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000494:pharmacology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D007736:Kynurenic Acid / Q000494:pharmacology; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D051379:Mice; D009457:Neuroglia / Q000166:cytology / Q000187:drug effects; D011725:Pyridines / Q000633:toxicity*; D017378:Quinolinic Acid; D011805:Quinolinic Acids / Q000633:toxicity*
D000596:Amino Acids; D011725:Pyridines; D011805:Quinolinic Acids; D015763:2-Amino-5-phosphonovalerate; D007770:L-Lactate Dehydrogenase; D017378:Quinolinic Acid; D007736:Kynurenic Acid; C031231:2-amino-7-phosphonoheptanoic acid; D002118:Calcium