Acute Parenteral Neurotoxicity of Domoic Acid in Cynomolgus Monkeys (M. fascicularis)

Abstract

To study the CNS effects of domoic acid (D.A.), 6 adult Cynomolgus monkeys (M. fascicularis) were dosed intraperitoneally (4 mg/kg) or intravenously (0.025-0.5 mg/kg) with D.A. obtained from cultured mussels contaminated with this neurotoxin. Clinical signs of neurotoxicity were preceded by a short presymptomatic period (2-3 min) and an even shorter prodromal period (0.5-1 min). The symptomatic period proper was characterized by persistent chewing with frothing, varying degrees of gagging, and vomit. Monkeys in the higher dose regimen exhibited additional signs including abnormal head and body positions, rigidity of movements and loss of balance, and tremors. The duration of the symptomatic period was dose dependent. Excitotoxic lesions consisting of vacuolation of the neuropil, astrocytic swelling, and neuronal shrinkage and hyperchromasia were detected in the area postrema, the hypothalamus, the hippocampus, and the inner layers of the retina in monkeys given D.A. at 0.5 mg/kg intravenously and 4 mg/kg intraperitoneally. It was concluded that D.A., administered intravenously, is neuroexcitatory and a powerful emetic at doses of 0.025 to 0.2 mg/kg. At higher doses (0.5 mg/kg intravenously and 4 mg/kg intraperitoneally), D.A. is strongly excitotoxic.

Keywords

Area postrema emetics excitotoxins hippocampus mussels neurotoxins primates shellfish toxic encephalopathy toxic mussels

References

1. Bates SS , Bird CJ , de Freitas ASW , Foxall R , Gilgan M , Hanic LA , Johnson GA , McCulloch AW , Odensc P , Pocklington R , Quilliam MA , Sim PG , Smith JC , Subba Rao DV , Todd ECD , Walter JA , and Wright JCL (1989). The pennate diatom Nitzschia pungens as the primary source of domoic acid, a toxin in shellfish from Eastern Prince Edward Island, Canada. Can. J. Fish Aquat. Sci. 46: 1203–1215.

2. Bird CJ, Boyd RK, Brewer D, Craft CA, de Freitas ASW, Dyer EW, Embree DJ, Falk M, Flack MG, Foxall RA, Gillis C, Greenwell M, Hardstaff WR, Jamieson WD, Laicock MV, Leblanc P, Lewis NI, McCulloch AW, McCulIy GK, Mclnterney-North-cott M, Mclnnes AG, McLachlan JL, Odense P, O'Neil D, Pathak V, Quilliam MA, Ragan MA, Seto PF, Sim PG, Tappen D, Thibault P, Water JA, and Wright JLC (1988). Identification of domoic acid as the toxic agent responsible for the P.E.I. contaminated mussel incident: A summary of work conducted at the Atlantic Research Laboratory of the National Research Council, Halifax, between 13 December 1987 and 11 January 1988. Atlantic Research Laboratory Technical Report No. 56, NRCC No. 29083.

3. Carpenters(1990). The human neuropathology of encephalopathic mussel toxin poisoning. In: Proceedings of the Symposium on Domoic Acid Toxicity (Ottawa, April 10–11, 1989). Canada Diseases Weekly Report Supplement, Vol. 16, No. 1 (in press).

4. Iverson F , Truelove J , Nera E , Tryphonas L , Campbell J , and Lok E (1988). Domoic acid poisoning and mussel associated intoxication. Preliminary investigations into the response of mice and rats to toxic mussel extract. Food Chem. Toxicol. 27: 377–384.

5. Iverson F, Truelove J, Tryphonas L, and Nera EA (1990). The toxicology of domoic acid administered systematically to rodents and primates. In: Proceedings of the Symposium on Domoic Acid Toxicity (Ottawa, April 10–11, 1989). Canada Diseases Weekly Report, Vol. 16, Supplement No. 1 (in press).

6. Olney JW (1978). Neurotoxicity of excitatory amino acids. In: Kainic Acid as Tool in Neurobiology, EG McGeer , JW Olney and PL McGeer (eds). Raven Press, New York, pp. 95–121.

7. Olney JW (1989). Excitatory amino acids and neuropsychiatric disorders. Biol. Psychiat. 26: 505–525.

8. Olney JW , Rhee V , and De Gubareff T (1977). Neurotoxic effects of glutamate on mouse area postrema. Brain Res. 120: 151–157.

9. O'Shaughnessy D and Gerber GJ (1986). Damage induced by systemic kainic acid in rats is dependent upon seizure activity. A behavioral and morphological.study. Neurotoxicology 7: 187–202.

10.

10. Perl TM , Bedard L , Kosatsky T , Hockin JC , Todd ECD , and Remis RS (1989). Encephalopathy following mussel consumption: A new clinical syndrome due to domoic acid. New Engl. J. Med. (in press).

11.

11. Takemoto T (1978). Isolation and structural identification of naturally occurring excitatory amino acids. In: Kainic Acid as a Tool in Neurobiology, EG McGeer , JW Olney and PL McGeer (eds). Raven Press, New York, pp. 1–15.

12.

12. Todd E (1990). Chronology of the 1987 amnesicshell-fish poisoning outbreak. In: Proceedings of the Symposium on Domoic Acid Toxicity (Ottawa, April 10–11, 1989). Canada Diseases Weekly Report, Vol. 16, Supplement No. 1 (in press).

13.

13. Tryphonas L, Truelove J, Iverson F, Todd E, and Nera E (1990). Neuropathology of experimental domoic acid poisoning in non-human primates and rats. In: Proceedings of the Symposium on Domoic Acid Toxicity (Ottawa, April 10–11, 1989). Canada Diseases Weekly Report, Vol. 16, Supplement No. 1 (in press).

14.

14. Tryphonas L , Truelove J , Nera E , and Iverson F (1990). Acute neurotoxicity of domoic acid in the rat. Toxicol. Pathol. 18(1)Pt 1: 1–9.

15.

15. Wright JLC , Boyd RK , deFrcitas ASW , Falk M , Fox-all RA , Jamieson WD , Laycock MV , McCulloch AW , Mclnnes AG , Odense P , Pathak VP , Quilliam MA , Ragan MA , Sim PG , Thibault P , Walter JA , Gilgan M , Richard DJA , and Dewar D (1989). Identification of domoic acid, a neuroexcitatory amino acid, in toxic mussels from eastern Prince Edward Island. Can. J. Chem. 67: 481–490.