Neurotoxicity of quinolinic acid and its derivatives in hypoxic rat hippocampal slices.
The excitotoxicity of quinolinic acid (2,3-pyridinedicarboxylic acid), a potent endogenous N-methyl-D-aspartate (NMDA)-type agonist, was characterized in the hypoxic hippocampal slice preparation. A series of other pyridinedicarboxylic acids was also tested in this preparation in order to obtain information about the structural requirements for the interaction between the NMDA receptor and its agonists. Of the 7 pyridinedicarboxylic acids tested, only quinolinic acid and its anhydride exerted their excitotoxicity by enhancing hypoxic neuronal damage in rat hippocampal slices at a relatively low concentration (100 microM). Much higher concentration (1 mM) of 3,4-pyridinedicarboxylic acid was required to exhibit any enhancement of hypoxic neuronal damage. The rest of the derivatives were innocuous. The effect of quinolinic acid was blocked by DL-2-amino-5-phosphonovaleric acid, by elevated magnesium levels in the incubation medium or by perfusion with a medium depleted of calcium. Aglycemic damage was also enhanced by quinolinic acid. It appears from the present study that two adjacent carboxylic groups on the pyridine ring, preferably at positions 2 and 3, are a prerequisite for an interaction between the NMDA receptor and its agonist. However, other factors may have great influence on that interaction as was evident from the total impotency of 6-methyl-quinolinic acid. The hypoxic hippocampal slice preparation and its neuronal function is an inexpensive model system, sensitized to the neurotoxins, and thus, allows the easy screening and evaluation of potential ligands of the glutamate receptor and its subtypes.
Schurr
A
A
Department of Anesthesiology, University of Louisville School of Medicine, KY 40292.
West
C A
CA
Rigor
B M
BM
D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology*; D000860:Hypoxia; D066298:In Vitro Techniques; D008274:Magnesium / Q000494:pharmacology; D008297:Male; D015394:Molecular Structure; D016202:N-Methylaspartate / Q000494:pharmacology; D009498:Neurotoxins / Q000633:toxicity*; D010848:Picolinic Acids / Q000494:pharmacology; D017378:Quinolinic Acid; D011805:Quinolinic Acids / Q000633:toxicity*; D051381:Rats; D011919:Rats, Inbred Strains; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D009498:Neurotoxins; D010848:Picolinic Acids; D011805:Quinolinic Acids; D016194:Receptors, N-Methyl-D-Aspartate; D016202:N-Methylaspartate; D015763:2-Amino-5-phosphonovalerate; D017378:Quinolinic Acid; D008274:Magnesium; D002118:Calcium; C004860:dipicolinic acid