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...
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| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2025-08-01
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| Series: | Epilepsia Open |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/epi4.70087 |
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| Summary: | 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. |
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| ISSN: | 2470-9239 |