Abstracts

Rationale: Dravet syndrome (DS) represents a severe genetic epilepsy syndrome caused by loss-of-function mutations in the SCN1A gene, encoding Nav1.1 channel. Usually starting in infancy, seizures in DS patients are often precipitated by a fever and can evolve into refractory epilepsy. The Scn1a heterozygous mutant mouse model recapitulates many features of DS, including hyperthermia-induced seizures. Perampanel is a selective noncompetitive antagonist at α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors that demonstrates efficacy in non-clinical models of epilepsy and in human focal onset and primary generalized seizures. The purpose of this study was to determine the efficacy of perampanel in an established DS mouse model and to better understand the mechanisms of DS-related epilepsy. Methods: Scn1a+/− mice (postnatal day 25 -28) received perampanel (1mg/kg and 2 mg/kg) or vehicle through oral gavage at a volume of 10 mL/kg body weight (n=13/group). A rectal temperature probe (RET-4, Physitemp) was fitted at 50 minutes post-treatment and mice were acclimated to probe and test chamber for 10 minutes. At 60 minutes post-treatment, core body temperature was elevated with a heat lamp connected to a feedback temperature controller (TCAT-2AC, Physitemp) by 0.5 °C every 2 minutes until maximum of 42.5 °C was reached. The threshold body temperatures for myoclonic jerks and generalized tonic-clonic seizures (GTCS) were recorded for each mouse. When a GTCS occurred (rearing and falling with forelimb clonus), mice were removed from the test chamber. If no seizure occurred after 3 minutes at 42.5 °C, the experiment was stopped and categorized as seizure-free. Mouse behavior was video recorded and reviewed when seizure behavior and threshold temperature was unclear during the experiment. The experiments were performed blindly with respect to treatment group. Statistical analysis included one way ANOVA and Dunnett’s multiple comparisons post-hoc tests for mean threshold temperature comparisons, and log-rank (Matel-Cox) test for Kaplan-Meier analysis. Results: At 2 mg/kg, perampanel significantly elevated the threshold temperatures for myoclonic jerks (41.2 ± 0.2 °C in the perampanel versus 40.6 ± 0.2 °C in the vehicle group, p < 0.05) and GTCS (41.4 ± 0.2 °C in the perampanel versus 40.6 ± 0.2 °C in vehicle group, p < 0.05), while at 1 mg/kg, perampanel showed only a modest effect on raising the mean threshold temperatures for both seizure types (40.9 ± 0.2 °C for myoclonic jerks and 41.0 ± 0.2 °C for GTCS; p>