Action of picolinic acid and structurally related pyridine carboxylic acids on quinolinic acid-induced cortical cholinergic damage.
Picolinic acid, a pyridine monocarboxylic acid derived from tryptophan metabolism by the kynurenine pathway, was shown to block cortical cholinergic neurotoxicity induced by quinolinic acid (QUIN), a pyridine dicarboxylic acid yielded by the same pathway. This study examined the specificity of the anti-toxic effect of picolinic acid by comparing its effect with several structurally related mono- and dicarboxylic acids, and by evaluating its potential to influence cholinergic neurotoxicity produced by kainic, ibotenic and quisqualic acid. Picolinic acid or related agents were injected alone or in combination with a fixed dose of QUIN into the right nucleus basalis magnocellularis (nbM) of rats anesthetized with halothane. Cholinergic neurotoxicity was assessed 7 days post injection by measuring choline acetyltransferase (ChAT) activity in the frontoparietal cortex on the injected and uninjected side. In picolinate experiments, the staining of nbM neurons by acetylcholinesterase (AChE) histochemistry was also examined. Focal injections of QUIN depleted cortical ChAT activity and staining of AChE in the nbM. Co-injection of picolinic acid with QUIN attenuated the decline in these two cholinergic neuron markers. Isonicotinate (4-pyridine monocarboxylate), but not nicotinate (3-pyridine monocarboxylate), significantly attenuated QUIN's effect on cortical ChAT activity. Among several dicarboxylic acids examined, only dipicolinate (2,6-pyridine dicarboxylate) showed activity. It produced a modest QUIN-like effect, but in co-injection experiments it attenuated the QUIN-induced decrease in cortical ChAT. When co-injected into the nbM with a neurotoxic dose of kainic, ibotenic or quisqualic acid which produced a neurotoxic response comparable to that of QUIN, picolinic acid attenuated kainic acid-induced neurotoxicity, but not ibotenate or quisqualate neurotoxicity.(ABSTRACT TRUNCATED AT 250 WORDS)
Cockhill
J
J
Department of Pharmacology, Queen's University, Kingston, Ont., Canada.
Jhamandas
K
K
Boegman
R J
RJ
Beninger
R J
RJ
D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D002795:Choline O-Acetyltransferase / Q000378:metabolism*; D007051:Ibotenic Acid / Q000494:pharmacology; D007608:Kainic Acid / Q000494:pharmacology; D007736:Kynurenic Acid / Q000494:pharmacology; D008297:Male; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D009498:Neurotoxins / Q000633:toxicity*; D010848:Picolinic Acids / Q000494:pharmacology*; D017378:Quinolinic Acid / Q000633:toxicity*; D016318:Quisqualic Acid / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
D009498:Neurotoxins; D010848:Picolinic Acids; D007051:Ibotenic Acid; D016318:Quisqualic Acid; D002795:Choline O-Acetyltransferase; D017378:Quinolinic Acid; D007736:Kynurenic Acid; C030614:picolinic acid; D007608:Kainic Acid