Abstracts

Rationale: Perampanel (PER), a structurally novel, potent, orally active AMPA receptor antagonist is currently under development for the treatment of epilepsy. Anti-seizure effects have been seen in several preclinical models (Hanada T, et al. Epilepsia 2011;52:1331-1340). Phase III clinical studies demonstrated efficacy in partial-onset seizures when used as add-on to 1-3 other AEDs, but were not able to explore specific combinations in detail. Here, we explored the potential synergistic effects of PER with the second generation AEDs lamotrigine (LAM) and levetiracetam (LEV) in the amygdala-kindled rat. Methods: Male Wistar-Kyoto rats weighing 250-400 g were used for the amygdala kindling study. A tripolar electrode was implanted into the basolateral amygdala (AP: -2.5 mm; L: 4.8 mm; D: 7.5 mm according to coordinates of Paxinos and Watson [1997]), with a reference electrode placed on the contralateral cortex. After at least 1 week recovery, electrical stimulation of the amygdala was initiated (500 μA, 1 msec, monophasic square-wave pulses, 50/sec for 1 sec). Stimulation continued until at least 3 consecutive seizures were recorded with a score of 5 on the Racine seizure severity scale (Racine RJ. Electroencephalograph Clin Neurophysiol 1972;32:281-294). The after discharge threshold (ADT) for each rat was determined, and doses of LAM and LEV which increased the ADT were selected (LAM: 20 mg/kg; LEV: 50 mg/kg). To determine drug effects on kindled seizures, a stimulation intensity of 3 times the ADT was used, and drugs were administered intraperitoneally either alone or in combination. Seizure severity, motor seizure duration (duration of score 4-5 seizures), and EEG seizure duration were measured. Data are presented as % reduction from baseline (pre-drug) values. Results: At a stimulation intensity of 3 times the ADT, PER (0.75 mg/kg), LAM (20 mg/kg) and LEV (50 mg/kg) achieved modest reductions in seizure score, EEG seizure duration, and motor seizure duration (Tables 1 and 2). Co-administration of PER with LAM and PER with LEV achieved reductions from baseline in seizure severity and duration that were more than additive (i.e. greater than the sum of the effects of each agent alone) in all but 1 instance (EEG seizure duration with PER + LEV [Tables 1 and 2]). A higher dose of PER (1.5 mg/kg) achieved pronounced reductions in seizure duration (63-94%), and addition of LAM or LEV had no additional effect on seizures. PER alone at 1.5 mg/kg reduced seizure severity by approximately 50%, and addition of LAM or LEV achieved 70-74% reduction from baseline. Conclusions: Here, we demonstrate that the combination of PER with LAM or LEV reduced seizure severity and duration in the rat amygdala kindling model, at doses that had minimal effects on seizures when administered alone. Supported by Eisai Co., Ltd.