Abstract
The identification of improved medical countermeasures against exposure to chemical warfare nerve agents (CWNAs), a class of organophosphorus compounds, is dependent on the choice of animal model used in preclinical studies. CWNAs bind to acetylcholinesterase and prevent the catalysis of acetylcholine, causing a plethora of peripheral and central physiologic manifestations, including seizure. Rodents are widely used to elucidate the effects of CWNA-induced seizure, albeit with a caveat: they express carboxylesterase activity in plasma. Carboxylesterase, an enzyme involved in the detoxification of some organophosphorus compounds, plays a scavenging role and decreases CWNA availability, thus exerting a protective effect. Furthermore, species-specific amino acid differences in acetylcholinesterase confound studies that use oximes or other compounds to restore its function after inhibition by CWNA. The creation of a human acetylcholinesterase knock-in/serum carboxylesterase knockout (C57BL/6-Ces1ctm1.1LocAChEtm1.1Loc/J; a.k.a KIKO) mouse may facilitate better modeling of CWNA toxicity in a small rodent species. The current studies characterize the effects of exposure to soman, a highly toxic CWNA, and evaluate the efficacy of anti-seizure drugs in this newly developed KIKO mouse model. Data demonstrate that a combination of midazolam and ketamine reduces seizure duration and severity, eliminates the development of spontaneous recurrent seizures, and protects certain brain regions from neuronal damage in a genetically modified model with human relevance to organophosphorus compound toxicity. This new animal model and the results of this study and future studies using it will enhance medical countermeasures development for both defense and homeland security purposes.
Highlights
IntroductionThe use of rodents as small animal models for toxicological studies is common for reasons that include the high throughput collection of data, relatively lower costs, and most importantly the availability of a wide selection of genetically modified rodents that allow for, among other purposes, a more accurate prediction of response in humans
The present study included two main objectives: (1) the development of a GD exposure paradigm that would elicit in KIKO mice seizures that do not respond to a midazolam treatment while maintaining relatively high survival, and (2) the evaluation of the efficacy of ketamine as an adjunct to delayed midazolam treatment on seizure severity, survival, and neuropathological effects of GD exposure
We show the acute and sub-chronic effects of GD-induced status epilepticus in the KIKO genetically modified mouse model
Summary
The use of rodents as small animal models for toxicological studies is common for reasons that include the high throughput collection of data, relatively lower costs, and most importantly the availability of a wide selection of genetically modified rodents that allow for, among other purposes, a more accurate prediction of response in humans. In the field of toxicology, it is critical to identify more effective treatments against the toxic effects of acute poisoning to organophosphorus (OP) compounds. Chemical warfare nerve agents (CWNAs), a class of OP compounds that are chemically related to pesticides used worldwide, are of particular interest due to their extremely high toxicity, ease of access by nefarious groups and potential for mass casualties. Acute poisoning with CWNAs results in the accumulation of the neurotransmitter acetylcholine due to the inhibition of acetylcholinesterase (AChE), an enzyme responsible for its catalysis in neuronal synapses during the process of neurotransmission
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