Abstracts

Rationale: Perampanel, a structurally novel, potent and orally active noncompetitive AMPA receptor antagonist, is currently approved in over 40 countries for the adjunctive treatment of partial-onset seizures with or without secondarily generalized seizures in patients with epilepsy aged ≥12 years (Canada aged ≥18 years). We have previously reported that perampanel could terminate established, diazepam-resistant status epilepticus in the lithium-pilocarpine rat model of status epilepticus.1 In the present study, we examined the effect of perampanel on neuroprotection one week after status epilepticus occurred.Methods: Lithium chloride (3 mEq/kg) was intraperitoneally administered to male Sprague Dawley rats (6-weeks old). This was followed 18–26 hours later by 5 mg/kg scopolamine methyl bromide and 30 mg/kg of pilocarpine. Seizure initiation was defined as continuous seizures with a Racine score2 of 4. Either perampanel (2 or 6 mg/kg) or diazepam (10 mg/kg) was administered intravenously 30 minutes after seizure initiation. Due to the experimental conditions in this study, the diazepam-treated group was set as the control rather than a vehicle-treated group. In addition, a treatment-naïve group of rats who had no seizures initiated was also included. Histopathological samples were taken one week after treatment. The samples were stained with anti-NeuN antibody, and analyzed by software (Aperio Technologies, Vista, CA) that quantified the amount of stain in a scanned slide image by using a pixel count algorithm.Results: For all three treatment groups (diazepam and both doses of perampanel), all rats survived for one week (n=6: treatment-naïve, diazepam, and perampanel 2 mg/kg; n=8: perampanel 6 mg/kg). However, treatment with diazepam failed to terminate seizures in all animals (Figure) and significant neuronal cell loss in the CA1 area was observed. In contrast, the 6 mg/kg dose of perampanel immediately terminated seizures in all rats tested and significantly inhibited CA1 neuronal cell loss compared with diazepam (Figure). At 2 mg/kg, perampanel terminated seizures in half of the rats tested (Figure), and significantly inhibited CA1 neurodegeneration compared with diazepam in both rats whose seizures had been terminated following treatment with perampanel (n=3) and in rats whose seizures had not been terminated by treatment with perampanel (n=3).Conclusions: In the present study, both perampanel and diazepam prevented pilocarpine-induced death in all rats. However, only perampanel was able to terminate established status epilepticus seizures and significantly inhibit CA1 neurodegeneration. Inhibition of neurodegeneration by perampanel in the CA1 area was observed regardless of seizure termination, which may suggest that perampanel has a neuroprotective effect. Funding: This study was funded by Eisai Co., Ltd. References 1. Hanada T, et al. Pharma Res Per. 2014 Oct; 2(5): e00063. 2. Racine RJ, Electroenceph Clin Neurophysiol 1972; 32: 281-294.