Abstracts

Rationale: Adjunctive use of perampanel (PER) has shown a 34.5% reduction in the treatment of drug resistant focal seizures at the maximum licensed therapeutic dose, however half this dose amount (6mg) has subsequently been shown in humans to significantly decrease high frequency gamma activity;  a normal physiological rhythm important for cognitive function. Preclinical in vivo studies have focused on the anti-seizure effects of AMPA receptor blockade but there is a paucity of research both on the effect of this medication on normal physiological brain rhythms, and on potential intersex differences in such responses.

Methods: Gamma (γ; 30-80 Hz) oscillations were recorded from extracellular local field potential recordings in the medial entorhinal cortex of rodent (450 μm) brain slices. These rhythms were evoked in vitro by application of kainic acid (400 nM) into the circulating artificial cerebrospinal fluid. Following which, experiments with the following concentration range; 0.1 μM, 0.3 μM, 1 μM, 3 μM, 10 μM of PER were carried out and their effects on the following γ-oscillation parameters; peak frequency (Hz), maximum amplitude (µV²), and area under the curve (µV²/Hz) were measured.

Results: Normality was assessed using the Shapiro-Wilk test. A two-way between subjects factorial ANOVA comparing the main effects of various concentrations of PER and sex revealed a significant interaction effect when looking at the raw change in peak frequency from baseline to end of treatment (F(5,119)=3.94, p=0.002), with Tukey’s post-hoc test suggesting a possible intersex difference in treatment response at 3 μM (adj. p=0.05).  Follow-up one-way ANOVA in males showed a significant effect of drug concentration on raw change in peak frequency (F(2.62,24.6)=6.42, p=0.003), with Tukey’s post-hoc test showing significant differences between 1 μM (32.81 ± 8.77) and vehicle control (36.67 ± 6.84, adj. p=0.04), 10 μM (26.39 ± 9.46) and vehicle control (36.67 ± 6.84, adj. p=0.02), and 0.1 μM (41.47 ± 9.60) and 10 μM (26.39 ± 9.46, adj. p=0.008). In females, the Kruskal-Wallis test showed that at there was a significant difference of means (H = 30.7, p < 0.001) with Dunn’s multiple comparisons finding the reduction in γ peak frequency to be significantly different across multiple comparisons. A t-test at the 3 μM dose showed significant differences t(22)=2.49, p = 0.02 between males (mean: 36.66, ± 9.63) and females (mean: 27.49, ± 9.70).