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

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. GDinduced 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.

Novel Genetically Modified Mouse Model to Assess Soman-Induced Toxicity and Medical Countermeasure Efficacy: Human Acetylcholinesterase Knock-in Serum Carboxylesterase Knockout Mice

“…This species difference is eliminated in the Es1-/-mouse that specifically lacks CaE activity in plasma, while maintaining its activity in tissues [16]. As expected, the median lethal dose (LD50) of GD and other OP chemicals is lower in Es1-/-mice compared to wild-type (C57BL/6) mice [13,17,18]. Our laboratory established a GD exposure model in Es1-/-mice in which high doses were required to reliably induce electroencephalographic (EEG) seizure activity and associated neuronal loss and neuroinflammatory response [13].…”

“…Even when seizures seem to stop by the administration of diazepam at 1 or 2 h after GD exposure, the intermittent return of seizures is observed in rats so that the overall duration of seizures in the first 24 h after the toxic insult is similar to that of animals that did not receive any anti-seizure treatment [23]. Midazolam, recently approved for the treatment of acute repetitive seizures, increases survival in GD-exposed rats and Es1-/-mice but does not prevent the development of spontaneous recurrent seizures (SRS) or brain pathology when treatment is delayed [13,18,[24][25][26].…”

Combination of antiseizure medications phenobarbital, ketamine, and midazolam reduces soman‐induced epileptogenesis and brain pathology in rats

“…35 In the weeks after exposure, many rats and mice develop SRS. 24,26,38,39 Since the time spent in seizure correlates with neuronal cell damage, 5 prompt control of seizure activity is critical. Phenobarbital reduced time in the initial seizure when administered as a monotherapy, as a dual therapy (with ketamine or midazolam) or as a triple therapy (with ketamine and midazolam) 40 minutes after soman-induced seizure compared F I G U R E 4 Benefit of combination triple therapy with the antiseizure medications phenobarbital, ketamine, and midazolam against soman (GD)-induced neurodegeneration in rats.…”

Ketamine as adjunct to midazolam treatment following soman-induced status epilepticus reduces seizure severity, epileptogenesis, and brain pathology in plasma carboxylesterase knockout mice

“…We previously characterized the seizurogenic, epileptogenic, neuropathological, and neuroinflammatory responses of male Es1−/− mice exposed to various doses of GD and administered midazolam at 15 min after seizure onset [4]. Additionally, we characterized the midazolam dose-response in Es1−/− mice exposed to a seizure-inducing dose of GD with anticonvulsant administration further delayed to 40 min after seizure onset, which may more closely model first responder intervention in a mass casualty CWNA event [21]. Consistent with prior research in rats, delayed midazolam monotherapy is unable to halt progression of SE and prevent the development of SRS and the neuropathology associated with GD exposure.…”