Abstract
OBJECTIVE: A benzodiazepine (diazepam or midazolam) is one of the current standards of care therapies to effectively terminate organophosphorus nerve agent-induced status epilepticus when administered shortly after onset. Preclinical studies showed that benzodiazepines were less effective in stopping status epilepticus when treatment was delayed up to 30 min from the time of organophosphorus exposure, highlighting the need for adjuncts to midazolam in a delayed treatment scenario. In this study, we evaluated the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor antagonist perampanel for efficacy as a second-line antiseizure medication against soman-induced benzodiazepine-refractory status epilepticus. METHODS: Adult male Sprague-Dawley rats were exposed to a seizure-inducing dose of soman and treated with midazolam (3 mg/kg; IP) 40 min after seizure onset, followed by perampanel (4 mg/kg; IP) or vehicle 20 min later. Electroencephalography (EEG) was recorded continuously for 2 weeks for analysis of seizure activity, after which brains were processed for an assessment of neurodegeneration. RESULTS: Compared to midazolam alone, perampanel administered 20 min after midazolam lowered the seizure duration during the first 24 h after soman exposure and reduced the EEG power integral over the 1 and 6 h period following treatment. Rats treated with perampanel as second-line therapy to midazolam had reduced incidence and number of spontaneous recurrent seizures compared to those treated with midazolam alone. The perampanel treatment also reduced neurodegeneration in the fiber tracts, amygdala, and hippocampus. SIGNIFICANCE: The seizure-protective effects of perampanel as second-line therapy to midazolam provide support for perampanel in treating benzodiazepine-refractory status epilepticus induced by exposure to organophosphorus nerve agents. PLAIN LANGUAGE SUMMARY: Treatment of status epilepticus, a life-threatening condition of prolonged seizures, becomes less effective when treatment is delayed. This study used a preclinical rat model of chemical-induced seizure to evaluate the ability of the antiseizure medication perampanel as a second-line therapy to midazolam in the treatment of status epilepticus. We show that perampanel following midazolam treatment improved seizure outcomes and reduced brain damage caused by status epilepticus, compared to midazolam alone.