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Objective Cholinergic-induced status epilepticus (SE) is associated with a loss of synaptic gamma-aminobutyric acid A receptors (GABAA R) and an increase in N-methyl-D-aspartate receptors (NMDAR) and amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPAR) that may contribute to pharmacoresistance when treatment with benzodiazepine antiseizure medication is delayed. The barbiturate phenobarbital enhances inhibitory neurotransmission by binding to a specific site in the GABAA R to increase the open state of the channel, decrease neuronal excitability, and reduce glutamate-induced currents through AMPA/kainate receptors. We hypothesized that phenobarbital as an adjunct to midazolam would augment the amelioration of soman-induced SE and associated neuropathological changes and that further protection would be provided by the addition of an NMDAR antagonist. Methods We investigated the efficacy of combining antiseizure medications to include a benzodiazepine and a barbiturate allosteric GABAA R modulator (midazolam and phenobarbital, respectively) to correct loss of inhibition, and ketamine to reduce excitation caused by increased synaptic localization of NMDAR and AMPAR, which are NMDA-dependent. Rats implanted with transmitters to record electroencephalographic (EEG) activity were exposed to soman and treated with atropine sulfate and HI-6 one min after exposure and with antiseizure medication(s) 40 minutes after seizure onset. Results The triple therapy combination of phenobarbital, midazolam, and ketamine administered at 40 minutes after seizure onset effectively prevented soman-induced epileptogenesis and reduced neurodegeneration. In addition, dual therapy with phenobarbital and midazolam or ketamine was more effective than monotherapy (midazolam or phenobarbital) in reducing cholinergic-induced toxicity. Significance Benzodiazepine efficacy is drastically reduced with time after seizure onset and inversely related to seizure duration. To overcome pharmacoresistance in severe benzodiazepine-refractory cholinergic-induced SE, simultaneous drug combination to include drugs that target both the loss of inhibition (eg, midazolam, phenobarbital) and the increased excitatory response (eg, ketamine) is more effective than benzodiazepine or barbiturate monotherapy.

Chemical warfare nerve agent exposure leads to status epilepticus (SE) that may progress to epileptogenesis and severe brain pathology when benzodiazepine treatment is delayed. We evaluated the dose–response effects of delayed midazolam 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 to males. Subsequently, male and female GD-exposed ES1(−/−) mice treated with a dose range of midazolam 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 midazolam 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 midazolam 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.