Delayed midazolam dose effects against soman in male and female plasma carboxylesterase knockout mice

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 (LD50) of GD exposure in female Es1−/− mice across estrous with male mice and observed a greater LD50 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. In the present work, we expand our previous studies and report on the dose−response effects of delayed midazolam (MDZ) treatment in male and female Es1−/− mice when MDZ is administered at 40 min after the onset of status epilepticus. The extended treatment time point is to model a more realistic therapeutic window for first responders in the event of civilian casualties following chemical warfare nerve agent exposure. Results from this study provide the groundwork for a human‐relevant mouse model to use to identify adjunct therapies that enhance or complement the effectiveness of benzodiazepines against CWNA exposure.