It is important to comprehensively characterize the natural history of chemical warfare nerve agent (CWNA) toxicity in animal models that represent the human condition so that the FDA Animal Rule may be used to develop effective medical countermeasures (MCM) against chemicals that cannot be assessed in humans. Currently there are no approved MCM to treat status epilepticus (SE) that is refractory to benzodiazepine therapy when treatment is delayed after CWNA exposure or the long-term functional and neuropathological effects of CWNA exposure. Minipigs, which are similar in anatomy and physiology to humans, are increasingly being used as large animal alternatives to nonhuman primates. The goal is to develop, characterize and qualify the Gottingen minipig as a large animal for MCM development to predict effects in humans. A few studies have been conducted using the minipig to assess lethality and cardiotoxicity of CWNA exposure (e.g. Hulet et al., 2014) and to assess the efficacy of MCM in increasing survival against CWNA (Saxena, 2011, 2015), the potential for the minipig to be used as a large animal model to assess seizure-induced brain pathology after exposure to CWNA and to evaluate MCM has not been assessed. A recent study used the Gottingen minipig as an experimental model to show neuronal loss following multiple blasts including loss of neurons in the hippocampus and neuroinflammatory responses including astrocyte activation and activated microglia (Goodrich et al., 2016).
Our specific aim i s determine if the Gottingen minipig will be a useful model to evaluate neuroprotective effects of MCM against CWNA exposure. We propose to first establish the LD50 for intramuscular exposure to soman and to then evaluate standard MCM of atropine against a lethal challenge dose of soman in minipigs to include delayed treatment with benzodiazepine. Neuropathological effects of soman exposure in minipigs to include neuronal loss and neuroinflammation will be evaluated to determine if this model may be useful as a large animal model for screening FDA-approved anti-epileptic drugs and novel neuroprotectants against soman toxicity. If validated, this model could then be used in future studies to evaluate MCM against CWNA in support of the FDA Animal Rule.
The FDA Animal Rule requires use of two animal models with a response predictive for humans or one well- characterized animal model. There is increased use of the minipig as an animal model to predict human response since the minipig has similar anatomy and physiology to humans. This project will identify whether the minipig model may be useful in evaluating anti-epileptic and novel neuroprotectant drugs for efficacy against exposure to chemical warfare nerve agents.