PDF(Pubmed)
Abstract：
Patients with mutations that alter the function of the sodium channel SCN8A present with a range of clinical features, including mild to severe seizures, developmental delay, intellectual disability, autism, feeding dysfunction, motor impairment, and hypotonia. In an effort to identify compounds that could be potentially beneficial in SCN8A-associated epilepsy, Atkin et al. conducted an in vitro screen which resulted in the identification of 90 compounds that effectively reduced sodium influx into the cells expressing the human SCN8A R1872Q mutation. The top compounds that emerged from this screen included amitriptyline, carvedilol, and nilvadipine. In the current study, we evaluated the ability of these three compounds to increase resistance to 6 Hz or pentylenetetrazole (PTZ)-induced seizures in wild-type CF1 mice and in a mouse line expressing the human SCN8A R1620L mutation. We also evaluated the effects of fenfluramine administration, which was recently associated with a 60%-90% decrease in seizure frequency in three patients with SCN8A-associated epilepsy. While amitriptyline, carvedilol, and fenfluramine provided robust protection against induced seizures in CF1 mice, only carvedilol was able to significantly increase resistance to 6 Hz- and PTZ-induced seizures in RL/+ mutants. These results provide support for further evaluation of carvedilol as a potential treatment for patients with SCN8A mutations.
摘要：
具有改变钠通道SCN8A功能的突变的患者具有一系列临床特征，包括轻度到重度癫痫发作,发育迟缓,智力残疾,自闭症,喂养功能障碍，运动障碍,和低张力。为了确定可能对SCN8A相关癫痫有潜在益处的化合物，阿特金等人。进行了体外筛选，结果鉴定出90种有效减少钠流入表达人SCN8AR1872Q突变的细胞的化合物。从这个屏幕上出现的顶级化合物包括阿米替林，卡维地洛,还有尼伐地平.在目前的研究中,我们评估了这三种化合物在野生型CF1小鼠和表达人SCN8AR1620L突变的小鼠品系中增加对6Hz或戊四唑（PTZ）诱导的癫痫发作的抗性的能力。我们还评估了芬氟拉明给药的效果，最近与3例SCN8A相关癫痫患者的癫痫发作频率降低60%-90%相关。而阿米替林，卡维地洛,芬氟拉明对CF1小鼠的诱发性癫痫发作提供了强大的保护，只有卡维地洛能够显着增加RL/突变体对6Hz和PTZ诱导的癫痫发作的抗性。这些结果为进一步评估卡维地洛作为SCN8A突变患者的潜在治疗提供了支持。
