Abstracts

Rationale: Organophosphate (OP) nerve agents induce refractory status epilepticus (SE) in animals and humans. Benzodiazepines, the current standard of care initial treatment for SE including that caused by nerve agents, are often ineffective in managing OP-induced SE, especially when the therapy is delayed. Allopregnanolone, a neurosteroid positive modulator of synaptic and extrasynaptic GABA-A receptors, is effective in the treatment of some types of benzodiazepine refractory SE in rodents but does not terminate OP-induced SE. Recognizing that glutamate is a key mediator of OP-induced seizures, we examined whether perampanel, an antagonist of AMPA-type glutamate receptors, could augment the efficacy of allopregnanolone in the treatment of SE induced by the OP nerve agent surrogate DFP. For comparison, we studied levetiracetam, a marketed antiseizure medication available in a parenteral formulation that could be used as a second line agent in the treatment of benzodiazepine-refractory OP intoxication. Both regimens were administered after treatment with the benzodiazepine midazolam, which is expected to be used as initial treatment. Methods: Male SD rats were injected with DFP (4 mg/kg, SC) followed one minute later with atropine (2 mg/kg, IM) and pralidoxime chloride (25 mg/kg, IM), representing the standard antidote regimen for the peripheral effects of OP nerve agents. Forty minutes after the DFP challenge, the animals in SE received midazolam (1.8 mg/kg IM) followed by either (a) allopregnanolone (6 mg/kg, IM) plus perampanel (2 mg/kg, IM) or (b) levetiracetam (1,000 mg/kg, IM). Video EEG recording was carried out for at least 5 h after the DFP challenge. Results: Within a few minutes of DFP injection, animals exhibited convulsive seizures and high amplitude epileptiform discharges. The electrographic seizure activity was resistant to midazolam. Intramuscular administration of allopregnanolone and perampanel along with midazolam led to rapid termination of the behavioral and electrographic SE as assessed by EEG power. In contrast, levetiracetam failed to reduce the EEG power more than midazolam alone. Conclusions: Combined treatment with allopregnanolone and perampanel effectively terminates benzodiazepine refractory OP-induced SE in rats, highlighting the potential of a treatment approach that jointly enhances GABA mediated inhibition and inhibits glutamate mediated excitation via block of AMPA receptors. Although levetiracetam is readily available it is unlikely to be useful as a treatment for OP-induced SE. Funding: NINDS Grant 1U54NS079202