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Delayed midazolam dose effects against soman in male and female plasma carboxylesterase knockout mice
Author(s) -
Kundrick Erica,
MarreroRosado Brenda,
Stone Michael,
Schultz Caroline,
Walker Katie,
LeeStubbs Robyn B.,
de Araujo Furtado Marcio,
Lumley Lucille A.
Publication year - 2020
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1111/nyas.14311
Subject(s) - epileptogenesis , status epilepticus , soman , carboxylesterase , convulsion , medicine , pilocarpine , epilepsy , midazolam , knockout mouse , pharmacology , toxicity , gliosis , anesthesia , endocrinology , acetylcholinesterase , chemistry , hippocampus , pathology , biochemistry , receptor , psychiatry , sedation , enzyme
Abstract Chemical warfare nerve agent exposure leads to status epilepticus that may progress to epileptogenesis and severe brain pathology when benzodiazepine treatment is delayed. We evaluated the dose−response effects of delayed midazolam (MDZ) on toxicity induced by soman (GD) in the plasma carboxylesterase knockout ( Es1 −/− ) mouse, which, similar to humans, lacks plasma carboxylesterase. Initially, we compared the median lethal dose (LD 50 ) of GD exposure in female Es1 −/− mice across estrous with male mice and observed a greater LD 50 during estrus compared with proestrus or with males. Subsequently, male and female GD‐exposed Es1 −/− mice treated with a dose range of MDZ 40 min after seizure onset were evaluated for survivability, seizure activity, and epileptogenesis. GD‐induced neuronal loss and microglial activation were evaluated 2 weeks after exposure. Similar to our previous observations in rats, delayed treatment with MDZ dose‐dependently increased survival and reduced seizure severity in GD‐exposed mice, but was unable to prevent epileptogenesis, neuronal loss, or gliosis. These results suggest that MDZ is beneficial against GD exposure, even when treatment is delayed, but that adjunct therapies to enhance protection need to be identified. The Es1 −/− mouse GD exposure model may be useful to screen for improved medical countermeasures against nerve agent exposure.