Domoic acid-induced neurovisceral toxic syndrome: characterization of an animal model and putative antidotes.
A rodent model of neurovisceral toxic syndrome induced by the neuroexcitant amino acid, domoic acid, is described, along with the activity of a putative antidote, the nonselective excitotoxin antagonist, kynurenic acid. Both an extract of contaminated mussels and pure domoic acid induced a characteristic syndrome including: sluggishness, scratching stereotypy, convulsions and death. Autopsy revealed gastric and duodenal lesions and peritoneal ascites. Kynurenic acid significantly obtunded these behavioral and physiological effects, particularly when given 60-75 min after the toxic insult. Probenecid, a blocker of organic acid transport, and tryptophan, a precursor of endogenous brain kynurenic acid, increased the time frame in which kynurenic acid exerted its protective effects. Kynurenic acid alone, in nontoxin-challenged animals significantly blocked cold-stress gastric lesions, significantly reduced basal gastric acid secretion and was protective to a lesser degree against ethanol-induced gastric mucosal injury. The murine model of domoate toxicity represents an inexpensive, reliable and sensitive biological assay for screening commercial shellfish for excitotoxin contamination. We are currently exploring kynurenic acid and other compounds for possible therapeutic use in both current and any future victims of neuroexcitant amino acid toxicosis.
Glavin
G B
GB
Department of Surgery, Faculty of Medicine, University of Manitoba, Winnipeg, Canada.
Pinsky
C
C
Bose
R
R
D000818:Animals; D000931:Antidotes / Q000627:therapeutic use; D005767:Gastrointestinal Diseases / Q000139:chemically induced* / Q000188:drug therapy; D007608:Kainic Acid / Q000031:analogs & derivatives* / Q000633:toxicity; D007736:Kynurenic Acid / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D009422:Nervous System Diseases / Q000139:chemically induced* / Q000188:drug therapy; D009498:Neurotoxins / Q000494:pharmacology*; D013577:Syndrome
D000931:Antidotes; D009498:Neurotoxins; D007736:Kynurenic Acid; C012301:domoic acid; D007608:Kainic Acid