Sub-lethal exposure to
sarin (GB), a potent
chemical warfare agent, produces long-term neurological deficits in both humans and rodents. However, rodents express much higher levels of
carboxylesterase (CaE) than humans and require a much higher dose of GB in rodents to produce neurotoxicity. In mice, the combination of the
carboxylesterase inhibitor 2-(o-cresyl)-4H-1:3:2-benzodioxaphosphorin-2-
oxide (
CBDP) with the organophosphorus (OP)
nerve agent GB renders mice more sensitive to OP
poisoning. After the reduction in CaE, GB inhibits
acetylcholinesterase at doses similar to those in human toxicity. A dose-response curve for GB was determined in male C57BL/6 mice after 1.5mg/kg
CBDP. A functional observational battery (FOB) for behavior was used to determine the dose needed to elicit seizure activity but maintain a mortality of less than 50%. Neuronal cell death was evaluated at 4, 7, 10 and 14 days post-GB exposure. Multiple brain areas were examined using
cresyl violet: CA1 and the dentate gyrus of the hippocampus, amygdala and piriform cortex. GFAP staining was then measured as an index of cell death in the dentate gyrus of the hippocampus. The dentate gyrus and CA1 exhibited significant neuronal death indicated by both
cresyl violet and GFAP staining. The treated animals also had a significant decrease in tissue and blood
acetylcholinesterase, in addition to decreases in plasma CaE.
CBDP renders mice more sensitive to the effects of GB exposure and mirrors a human symptomatic exposure dose.