Long-term treatment with carbamazepine restores cognitive abilities in a mouse model of KCNQ2 developmental and epileptic encephalopathy

Abstract

Objective: Carbamazepine is the first line treatment for patients affected by KCNQ2 developmental and epileptic encephalopathy. It is efficient to reduce or stop seizures in this context. However, its effect on the neurodevelopmental outcomes is debated. The aim of this study was to evaluate the efficacy of long-term oral administration of carbamazepine in a mouse model of Kcnq2 dysfunction.

Methods: Mice were treated at weaning and during 70 days. The impact on seizures was measured, and blood samples were collected every week. At 3 months of age, all mice were tested using the Water T-maze and Barnes maze tests to evaluate their cognitive abilities. Brain tissue was collected to measure carbamazepine and carbamazepine-epoxide concentrations.

Results: After 70 days of carbamazepine treatment, the impact on seizures was strong in the Kcnq2-DEE mice, with 1 out of 12 treated knock-in mice having a seizure compared to 8 out of 13 mice receiving the vehicle. Carbamazepine efficacy on seizures was progressive and correlated to an accumulation of carbamazepine-epoxide in the brain. The cognitive abilities of treated knock-in mice at 3 months of age were similar to those of wild-type mice.

Significance: In addition to validating this knock-in model as a model of anticonvulsant efficacy, these results reveal that carbamazepine-epoxide accumulates in the brain when given over a long period of time. They also show that chronic treatment with carbamazepine strongly impacts cognitive abilities in a mouse model of Kcnq2-DEE, questioning current treatment strategies in human patients.

Plain language summary: This study evaluated the long-term effects of a treatment with an antiepileptic drug called carbamazepine (CBZ). It was performed in a mouse model of a severe form of genetic epilepsy. The results showed that a chronic treatment with CBZ effectively reduced seizures. Treated mice also showed improved cognitive abilities. An accumulation of a modified form of CBZ was measured in the brain of the treated animals. These findings call for a reevaluation of the long-term effects of CBZ treatment in humans, as the animal data suggest potential beneficial effects that may not yet be fully appreciated in clinical practice.

Keywords: KCNQ2; carbamazepine; chronic treatment; cognitive deficits; developmental and epileptic encephalopathy.

FIGURE 1

Survival and weight curves following chronic treatment with 0.5% carbamazepine (CBZ) in the Kcnq2 ^Thr274Met/+ mouse model. (A) Kaplan–Meier survival plot for the 3 groups of mice during long‐term treatment. Behavioral experiments performed during the study are indicated using gray windows. A red circle depicts an animal dead following a spontaneous seizure. In the untreated knock‐in (KI) group, 2 mice were dead after spontaneous seizure (red circle). All other deaths occurred following exposure to the ultrasonic stimuli. * denotes p < 0.05 (Gehan–Breslow–Wilcoxon test). (B) Weight gain during chronic treatment with 0.5% CBZ. The mean value ± SEM is reported. ns, non significant differences (Pearson correlation, p > 0.999). CBZ, carbamazepine; KI, knock‐in; SEM, standard error of the mean.

FIGURE 2

Phenotypic evaluation during chronic treatment with 0.5% CBZ in the Kcnq2 ^Thr274Met/+ mouse model. (A) Ultrasound‐induced seizures (UIS) at P30 (10 days of treatment), P60 (40 days of treatment) and P90 (70 days of treatment). Data are presented as a percentage of mice having a seizure. 𝜒², *p < 0.05; **p < 0.01; ****p < 0.0001. (B) Time to reach the platform in the Water T‐maze task. Time is expressed in seconds. Data are given as mean ± SEM for all groups. Kruskal–Wallis test, *p < 0.05; **p < 0.01. (C) Errors count in the Barners Maze probe test. Data are given as mean ± SEM for all groups. Kruskal–Wallis test, *p < 0.05; **p < 0.01. CBZ, carbamazepine; KI, knock‐in mice; n, number of mice tested; SEM, standard error of the mean; WT, wild‐type mice.