Therapeutic Time Window of Perampanel for the Termination of Diazepam-Resistant Status Epilepticus (SE) in a Lithium-Pilocarpine Rat Model (P3.267)

OBJECTIVE: To explore the therapeutic time window of perampanel for the termination of diazepam-resistant status epilepticus (SE) in a lithium-pilocarpine rat model. BACKGROUND: The AMPA receptor antagonist perampanel is approved in Europe and the USA as adjunctive treatment for partial-onset seizures in patients aged 蠅12 years. Previously, perampanel terminated SE when administered 30 minutes after seizure initiation in a lithium-pilocarpine rat model, whereas diazepam only terminated SE when administered at 10 minutes (Ido & Hanada. Abstract 3.221, AES Annual Meeting 2012). Here, the same model was used to further explore the therapeutic time window of perampanel, and to evaluate another AMPA receptor antagonist, GYKI52466. DESIGN/METHODS: An electroencephalography (EEG) electrode was implanted onto the primary somatosensory cortex of male Sprague-Dawley rats (250-450 g), with a reference electrode on the cerebellum. Lithium chloride 3 mEq/kg was administered intraperitoneally, followed 18-26 h later by scopolamine methyl bromide 5 mg/kg and pilocarpine 30 mg/kg. Perampanel 8 mg/kg or GYKI52466 50 mg/kg were administered intravenously 30 (GYKI52466), 60 (perampanel), or 90 (perampanel) minutes after seizure initiation (when the first EEG spike train occurred). Seizures were ‘terminated’ if SE-type high-frequency EEG spike activity was abolished within 30 minutes. RESULTS: When administered at 60 minutes, perampanel terminated seizures in 6/6 rats. Efficacy was reduced when administered at 90 minutes: 2/6 rats experienced seizure termination; 2/6 had EEG suppression with seizure recurrence; 2/6 did not achieve seizure termination. When administered at 30 minutes, GYKI52466 terminated seizures in 2/4 rats. CONCLUSIONS: These data confirm observations that AMPA receptor antagonists terminate SE in a lithium-pilocarpine model, with a longer therapeutic time window than diazepam. Study Supported by: Eisai Co., Ltd. Disclosure: Dr. Ido has received personal compensation for activities with Eisai Inc. as an employee. Dr. Hanada has received personal compensation for activities with Esai Inc. holds stock and/or stock options in Esai Inc. which sponsored research in which Dr Hanada was involved as an investigator. Dr. Hanada has received research support from Esai Inc.