Open AccessEffect of perampanel, a novel AMPA antagonist, on benzodiazepine‐resistant status epilepticus in a lithium‐pilocarpine rat model
Author(s) -
Hanada Takahisa,
Ido Katsutoshi,
Kosasa Takashi
Publication year - 2014
Publication title -
pharmacology research and perspectives
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.975
H-Index - 27
ISSN - 2052-1707
DOI - 10.1002/prp2.63
Subject(s) - perampanel , status epilepticus , diazepam , pharmacology , antagonist , epilepsy , benzodiazepine , anesthesia , pilocarpine , ampa receptor , anticonvulsant , chemistry , medicine , nmda receptor , receptor , adverse effect , psychiatry
This study assessed the efficacy of diazepam, and the alpha‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole‐propionic acid ( AMPA ) receptor antagonists perampanel and GYKI 52466 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 GYKI 52466 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 ( ED 50 : 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 ( ED 50 : 10 min 1.7 mg kg −1 ; 30 min, 5.1 mg kg −1 ). GYKI 52466 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 GYKI 52466 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.