Domoic acid is a potent neurotoxin to neonatal rats.
ABSTRACT Domoic acid induces a time-dependent neuroexcitotoxic effect in neonatal rats characterized by hyperactivity, stereotypic scratching, convulsions, and death with observable behaviors occurring at exposures 40 times lower by body weight in neonates than reported in adults. Low doses of domoic acid (0.1 mg/kg) induced c-fos in the central nervous system which was inhibited in part by 2-amino-5-phosphonovaleric acid, an NMDA receptor antagonist. Domoic acid caused no evidence of structural alteration in the brain of neonates as assessed by Nissel staining and cupric silver histochemistry. Domoic acid induced reproducible behavioral effects at doses as low as 0.05 mg/kg and induced seizures doses as low as 0.2 mg/kg. Determination of serum domoic acid levels after 60 min exposure indicated that serum levels of domoic acid in the neonates corresponded closely to the serum levels that induce similar symptoms in adult rats and mice. We conclude that neonatal rats are highly sensitive to the neuroexcitatory and lethal effects of domoic acid and that the increased sensitivity results from higher than expected serum levels of domoic acid. These findings are consistent with other findings that reduced serum clearance of domoic acid is a predisposing factor to domoic acid toxicity.
- SourceAvailable from: Michael G Janech[Show abstract] [Hide abstract]
ABSTRACT: Domoic acid (DA), an excitatory amino acid produced by diatoms belonging to the genus Pseudo-nitzschia, is a glutamate analog responsible for the neurologic condition referred to as amnesic shellfish poisoning. To date, the renal effects of DA have been underappreciated, although renal filtration is the primary route of systemic elimination and the kidney expresses ionotropic glutamate receptors. To characterize the renal effects of DA, we administered either a neurotoxic dose of DA or doses below the recognized limit of toxicity to adult Sv128/Black Swiss mice. DA preferentially accumulated in the kidney and elicited marked renal vascular and tubular damage consistent with acute tubular necrosis, apoptosis, and renal tubular cell desquamation, with toxic vacuolization and mitochondrial swelling as hallmarks of the cellular damage. Doses≥0.1 mg/kg DA elevated the renal injury biomarkers kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin, and doses≥0.005 mg/kg induced the early response genes c-fos and junb. Coadministration of DA with the broad spectrum excitatory amino acid antagonist kynurenic acid inhibited induction of c-fos, junb, and neutrophil gelatinase-associated lipocalin. These findings suggest that the kidney may be susceptible to excitotoxic agonists, and renal effects should be considered when examining glutamate receptor activation. Additionally, these results indicate that DA is a potent nephrotoxicant, and potential renal toxicity may require consideration when determining safe levels for human exposure.Journal of the American Society of Nephrology 02/2014; · 9.47 Impact Factor
- Marine Mammal Science 02/2014; · 2.13 Impact Factor