title: Effect of perampanel, a novel AMPA antagonist, on benzodiazepine-resistant status epilepticus in a lithium-pilocarpine rat model.
abstract: This study assessed the efficacy of diazepam, and the alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor antagonists perampanel and GYKI52466 in a lithium-pilocarpine status epilepticus (SE) model. SE was induced in rats using lithium chloride, scopolamine methyl bromide, and pilocarpine. Diazepam 10, 20, or 40 mg kg(-1), or perampanel 1, 2.5, 5, or 8 mg kg(-1) were administered intravenously at 10 or 30 min after seizure onset, and GYKI52466 50 mg kg(-1), or combinations of diazepam 2.5-5 mg kg(-1) and perampanel 0.5-1 mg kg(-1), were administered intravenously at 30 min after seizure onset. Diazepam 20 mg kg(-1) terminated seizures (based on electroencephalography and assessment of behavioral seizures) in 2/6 rats at 10 min and 0/6 rats at 30 min (ED50: 10 min, 30 mg kg(-1); 30 min, not determined). Perampanel 8 mg kg(-1) terminated seizures in 6/6 rats at both 10 and 30 min (ED50: 10 min 1.7 mg kg(-1); 30 min, 5.1 mg kg(-1)). GYKI52466 50 mg kg(-1) terminated seizures in 2/4 rats at 30 min. Co-administration of diazepam 5 mg kg(-1) and perampanel 1 mg kg(-1) terminated seizures in 9/9 rats at 30 min. In conclusion, perampanel and GYKI52466 provided efficacy in a lithium-pilocarpine SE model at 30 min after seizure onset, when SE was refractory to diazepam, supporting the therapeutic potential of AMPA receptor antagonists for refractory SE. The perampanel dose required to terminate seizures was reduced by combination with diazepam, suggesting synergy.
authors.affiliation: Global Biopharmacology, Neuroscience & General Medicine Product Creation System, Eisai Co., Ltd Tsukuba, Ibaraki, Japan ; Center for Tsukuba Advanced Research Alliance, Graduate School of Life and Environmental Sciences, University of Tsukuba Tsukuba, Ibaraki, Japan.
authors.forename: Takahisa
authors.initials: T
authors.lastname: Hanada
authors.affiliation: Global Biopharmacology, Neuroscience & General Medicine Product Creation System, Eisai Co., Ltd Tsukuba, Ibaraki, Japan.
authors.forename: Katsutoshi
authors.initials: K
authors.lastname: Ido
authors.affiliation: Global Biopharmacology, Neuroscience & General Medicine Product Creation System, Eisai Co., Ltd Tsukuba, Ibaraki, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kosasa
keywords: AMPA receptor antagonist; benzodiazepine-resistant; diazepam; lithium-pilocarpine; perampanel; status epilepticus