Louis Jordane, Doudka Natalia, Félix Marie-Solenne, Spiga Ghata Adeline, Espanet Camille, Guilhaumou Romain, Milh Mathieu, Villard Laurent
Aix Marseille Univ, Inserm, MMG, U1251, Marseille, France.
Service de Pharmacologie Clinique et Pharmacosurveillance, AP-HM, Marseille, France.
Epilepsia Open. 2025 Aug;10(4):1199-1207. doi: 10.1002/epi4.70087. Epub 2025 Jul 9.
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.
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.
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.
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.
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.
卡马西平是治疗KCNQ2发育性和癫痫性脑病患者的一线药物。在此情况下，它能有效减少或终止癫痫发作。然而，其对神经发育结局的影响存在争议。本研究的目的是评估在Kcnq2功能障碍小鼠模型中长期口服卡马西平的疗效。
小鼠在断奶时及之后70天接受治疗。测量对癫痫发作的影响，每周采集血样。在3月龄时，所有小鼠使用水迷宫和巴恩斯迷宫试验进行测试，以评估其认知能力。收集脑组织以测量卡马西平和卡马西平-环氧化物的浓度。
卡马西平治疗70天后，对Kcnq2-DEE小鼠的癫痫发作影响显著，12只接受治疗的基因敲入小鼠中有1只发生癫痫发作，而接受载体治疗的13只小鼠中有8只发生癫痫发作。卡马西平对癫痫发作的疗效是渐进性的，且与脑中卡马西平-环氧化物的蓄积相关。3月龄时接受治疗的基因敲入小鼠的认知能力与野生型小鼠相似。
除了验证该基因敲入模型作为抗惊厥疗效模型外，这些结果还表明，长期给药时卡马西平-环氧化物会在脑中蓄积。它们还表明，在Kcnq2-DEE小鼠模型中，卡马西平的长期治疗对认知能力有强烈影响，这对人类患者目前的治疗策略提出了质疑。
本研究评估了一种名为卡马西平（CBZ）的抗癫痫药物治疗的长期效果。该研究在一种严重形式的遗传性癫痫小鼠模型中进行。结果表明，CBZ的长期治疗有效减少了癫痫发作。接受治疗的小鼠还表现出认知能力的改善。在接受治疗动物的脑中测量到一种修饰形式的CBZ的蓄积。这些发现呼吁重新评估CBZ治疗对人类的长期影响，因为动物数据表明可能存在尚未在临床实践中得到充分认识的潜在有益效果。
