The neurotoxic actions of quinolinic acid in the central nervous system.
Excitotoxins such as kainic acid, ibotenic acid, and quinolinic acid are a group of molecules structurally related to glutamate or aspartate. They are capable of exciting neurons and producing axon sparing neuronal degeneration. Quinolinic acid (QUIN), an endogenous metabolite of the amino acid, tryptophan, has been detected in brain and its concentration increases with age. The content of QUIN in the brain and the activity of the enzymes involved in its synthesis and metabolism show a regional distribution. The neuroexcitatory action of QUIN is antagonized by magnesium (Mg2+) and the aminophosphonates, proposed N-methyl-D-aspartate (NMDA) receptor antagonists, suggesting that QUIN acts at the Mg2+ -sensitive NMDA receptor. Like its excitatory effects, QUIN's neurotoxic actions in the striatum are antagonized by the aminophosphonates. This suggests that QUIN neurotoxicity involves the NMDA receptor and (or) another receptor sensitive to the aminophosphonates. The neuroexcitatory and neurotoxic effects of QUIN are antagonized by kynurenic acid (KYN), another metabolite of tryptophan. QUIN toxicity is dependent on excitatory amino acid afferents and shows a regional variation in the brain. Local injection of QUIN into the nucleus basalis magnocellularis (NBM) results in a dose-dependent reduction in cortical cholinergic markers including the evoked release of acetylcholine. A significant reduction in cortical cholinergic function is maintained over a 3-month period. Coinjection of an equimolar ratio of QUIN and KYN into the NBM results in complete protection against QUIN-induced neurodegeneration and decreases in cortical cholinergic markers. In contrast, focal injections of QUIN into the frontoparietal cortex do not alter cortical cholinergic function.(ABSTRACT TRUNCATED AT 250 WORDS)
D000818:Animals; D001711:Biotransformation; D001921:Brain / Q000187:drug effects* / Q000201:enzymology; D002540:Cerebral Cortex / Q000201:enzymology; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D003342:Corpus Striatum / Q000201:enzymology; D006801:Humans; D007736:Kynurenic Acid / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects; D010430:Pentosyltransferases / Q000378:metabolism; D011188:Potassium / Q000494:pharmacology; D011725:Pyridines / Q000633:toxicity*; D017378:Quinolinic Acid; D011805:Quinolinic Acids / Q000378:metabolism / Q000633:toxicity*; D014018:Tissue Distribution; D000098553:Nicotinate-Nucleotide Diphosphorylase (Carboxylating)
D011725:Pyridines; D011805:Quinolinic Acids; D002795:Choline O-Acetyltransferase; D010430:Pentosyltransferases; D000098553:Nicotinate-Nucleotide Diphosphorylase (Carboxylating); D017378:Quinolinic Acid; D007736:Kynurenic Acid; D011188:Potassium