Acute Neurotoxicity of Domoic Acid in the Rat

Abstract

A recent outbreak of human food poisoning, characterized by severe gastrointestinal and neurologic abnormalities, with a fatal outcome in 3 patients, was attributed to the consumption of poisonous mussels containing domoic acid at an abnormally high concentration. The purpose of the present study was to determine if domoic acid, a glutamate analogue extracted from poisonous mussel, was neurotoxic to rats. Groups of female Sprague-Dawley rats were dosed once intraperitoneally with 0, 1, 2, 4, or 7.5 mg domoic acid/kg of body weight and observed for a maximum period of 24 hr. Clinically, control rats and rats in the 1 mg/kg group were unremarkable. Seventy-five percent of the animals in the 2 mg/kg group had equivocal transient behavioral signs. One that was given 2 mg/kg and all rats given in excess of 4 mg/kg of body weight developed unequivocal behavioral and neurologic signs culminating in partial seizures and status epilepticus. Histopathologically, severely affected rats developed selective encephalopathy characterized by neuronal degeneration and vacuolation of the neuropil in the limbic and the olfactory systems, and retinopathy characterized by neuronal hydropic degeneration of the inner nuclear layer and vacuolation of the external plexiform layer. The results of this study suggest that domoic acid is excitotoxic and causes a characteristic syndrome with clinical signs and histopathologic lesions similar to those reported for kainic acid.

Pathology of Domoic Acid Toxicity in California Sea Lions (Zalophus californianus)

“…16,24,32,34 A significant difference in the lesions of the CSLs compared with experimental animal data is the necrosis of the dentate gyrus granule cells. The reason for this difference is not known.…”

“…17 Exogenous excitotoxic brain injury secondary to natural DA exposure has been described in humans 29 and experimentally in rats and macaques. 33,34 In this study, we describe the pathologic findings in 84 California sea lions (Zalophus californianus, CSL) and one Northern fur seal (Callorhinus ursinus, NFS) involved in unusual stranding events. These animals were naturally exposed to DA during the course of three HAB in central and northern California.…”

Histomorphogenesis of Soman-Induced Encephalocardiomyopathy in Sprague-Dawley Rats

“…Soman shares with d~m~ic acid and kainic acid (53,72,73). In addition, domoic acid and kainic acid have been shown to be retinotoxic (33,53,72,73).…”

“…In addition, domoic acid and kainic acid have been shown to be retinotoxic (33,53,72,73). To determine whether or not soman is also retinotoxic, it was decided to extend our histopathologic investigation to the eye.…”

Adverse Outcome Pathway on binding of agonists to ionotropic glutamate receptors in adult brain leading to excitotoxicity that mediates neuronal cell death, contributing to learning and memory impairment

“…111-114. Tryphonas, L. et al (1990), Acute neurotoxicity of domoic acid in the rat, Toxicologic Pathology, Vol. 18, pp.…”