Domoic acid-treated cynomolgus monkeys (M. fascicularis): effects of dose on hippocampal neuronal and terminal degeneration.
Domoic acid is a tricarboxylic amino acid (structurally related to kainic acid and glutamic acid) that is found in the environment as a contaminant of some seafood. To determine the nature of any neurological damage caused by domoate, as well as the minimum neurotoxic dose, juvenile and adult monkeys were dosed intravenously with domoate at one of a range of doses from 0.25 to 4 mg/kg. When animals were perfused one week later, histochemical staining using a silver method to reveal degenerating axons and cell bodies showed two distinct types of hippocampal lesions. One lesion, termed 'Type A', was a small focal area of silver grains restricted to CA2 stratum lucidum, the site of greatest kainic acid receptor concentration in the brain. Type A lesions occurred over a dose range of 0.5 to 2.0 mg/kg in juvenile animals and 0.5 to 1.0 mg/kg in adult animals. No mortality occurred in any of the juvenile monkeys, but one juvenile animal that received 4.0 mg/kg sustained a second type of lesion, termed 'Type B', characterized by widespread damage to pyramidal neurons and axon terminals of CA4, CA3, CA2, CA1, and subiculum subfields of the hippocampus. Doses of more than 1.0 mg/kg in the adult monkeys either proved lethal or resulted in Type B lesions. Induction of c-fos protein had occurred in the hippocampal dentate gyrus and CA1 regions of moribund animals perfused within hours of their initial dose.(ABSTRACT TRUNCATED AT 250 WORDS)
Scallet
A C
AC
Division of Neurotoxicology, FDA/National Center for Toxicological Research, Jefferson, AR 72079.
Binienda
Z
Z
Caputo
F A
FA
Hall
S
S
Paule
M G
MG
Rountree
R L
RL
Schmued
L
L
Sobotka
T
T
Slikker
W
W
D000818:Animals; D004305:Dose-Response Relationship, Drug; D005260:Female; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects*; D007608:Kainic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000633:toxicity; D008252:Macaca fascicularis; D008297:Male; D008387:Marine Toxins / Q000008:administration & dosage / Q000633:toxicity*; D009410:Nerve Degeneration / Q000187:drug effects*; D009411:Nerve Endings / Q000187:drug effects; D009474:Neurons / Q000187:drug effects*; D009498:Neurotoxins / Q000008:administration & dosage / Q000633:toxicity*; D016622:Silver Staining
D008387:Marine Toxins; D009498:Neurotoxins; C012301:domoic acid; D007608:Kainic Acid