A murine model for sarin exposure using the carboxylesterase inhibitor CBDP.
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.
Department of Pharmacology & Toxicology, Wright State University, Dayton, OH, USA.
Teresa L
TL
Garrett
Christine M
CM
Rapp
Robert D
RD
Grubbs
John J
JJ
Schlager
James B
JB
Lucot
D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D043182:Carboxylesterase / Q000378:metabolism; D002619:Chemical Warfare Agents; D002802:Cholinesterases / Q000097:blood; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006624:Hippocampus / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009457:Neuroglia / Q000378:metabolism / Q000473:pathology; D020258:Neurotoxicity Syndromes / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D009943:Organophosphorus Compounds / Q000633:toxicity*; D012524:Sarin / Q000633:toxicity*; D012640:Seizures / Q000209:etiology; D013997:Time Factors
D002619:Chemical Warfare Agents; D005904:Glial Fibrillary Acidic Protein; D009943:Organophosphorus Compounds; C000516:2-(2-cresyl)-4H-1-3-2-benzodioxaphosphorin-2-oxide; D012524:Sarin; D043182:Carboxylesterase; D000110:Acetylcholinesterase; D002802:Cholinesterases