Abstracts

Rationale: Perampanel, a structurally novel, potent, orally active AMPA receptor antagonist, is currently under development for the treatment of epilepsy. Perampanel has previously been shown to have anti-seizure effects in several animal models (Hanada T, et al. Epilepsia 2011;52:1331-1340). In experimental models of status epilepticus, the ability of agents (including other AMPA receptor antagonists) to terminate seizures typically declines as the duration of status epilepticus increases (e.g. Fritsch B, et al. Epilepsia 2010;51:108-117). In the present study, we explored the ability of perampanel and of diazepam to terminate seizures in the lithium-pilocarpine model of status epilepticus. Methods: Male Sprague Dawley rats weighing 250-450 g were implanted with an electroencephalography (EEG) electrode on the surface of the primary somatosensory cortex (AP: -2.5 mm; L: 3 mm according to coordinates of Paxinos and Watson (1997)). A reference electrode was placed on the cerebellum. After at least 1 week recovery, 3 mEq/kg of lithium chloride was administered to the rats (intraperitoneal), followed 18-26 hours later by 5 mg/kg scopolamine methyl bromide and 30 mg/kg pilocarpine. Seizure initiation was documented when the first spike train was observed on the EEG. Drugs (perampanel or diazepam) were administered intravenously10 minutes or 30 minutes after seizure initiation. Electrographic effects were evaluated for 60 minutes after drug dosing. Seizures were considered ‘terminated' if status epilepticus-type high-frequency EEG spike activity was abolished, with only occasional isolated spikes, and EEGs were spike-free at 60 minutes after drug dosing. Results: Diazepam (20 mg/kg) terminated seizures when administered 10 minutes after seizure initiation in all animals, but failed to terminate seizures in any animals when administered 30 minutes after seizure initiation (Table 1). Perampanel, administered 30 minutes after seizure initiation, terminated seizures in one-third of animals at 5 mg/kg and in all animals at 8 mg/kg (Table 1). At this dose (8 mg/kg), perampanel terminated electrographic status epilepticus seizures within 1-5 minutes, with occasional spikes thereafter, and all animals were spike-free at 60 minutes after dosing. Conclusions: In the present study, both perampanel and diazepam were able to terminate status epilepticus seizures, but the therapeutic time window of perampanel is wider than that of diazepam. Perampanel terminated seizures in animals with established status epilepticus of 30 minutes duration, a point at which it is usually considered to be self-sustaining. Supported by Eisai Co., Ltd.