Retigabine, a Kv7.2/Kv7.3-Channel Opener, Attenuates Drug-Induced Seizures in Knock-In Mice Harboring Kcnq2 Mutations.
Retigabine, a Kv7.2/Kv7.3-Channel Opener, Attenuates Drug-Induced Seizures in Knock-In Mice Harboring Kcnq2 Mutations.
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DOI：
10.1371/journal.pone.0150095
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Hirose S
中科院分区：
文献类型：
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作者：
Ihara Y;Tomonoh Y;Deshimaru M;Zhang B;Uchida T;Ishii A;Hirose S
由KCNQ 2和KCNQ 3编码的异源四聚体电压门控钾通道Kv7.2/Kv7.3在限制新生儿脑中的网络兴奋性中起重要作用。由KCNQ 2突变引起的Kv7.2/Kv7.3功能障碍主要引起新生儿自限性或良性癫痫，但也引起早发性癫痫性脑病。Retigabine（RTG）是一种Kv7.2/ Kv7.3通道开放剂，是治疗KCNQ 2突变所致癫痫的理想药物。因此，我们评估了RTG对两种携带不同Kcnq 2突变的基因敲入小鼠癫痫发作的影响，并与苯巴比妥（PB）的影响进行了比较，苯巴比妥是治疗新生儿癫痫发作的一线抗癫痫药物。受试者是分别携带Y284 C或A306 T Kcnq 2突变的杂合基因敲入小鼠（Kcnq 2 Y284 C/+和Kcnq 2A 306 T/+）及其野生型（WT）同窝仔，年龄为63-100天。用视频脑电图监测系统记录腹腔注射海人酸（KA，12 mg/kg）诱发的癫痫发作。RTG对KA诱导的两种品系的基因敲入小鼠的癫痫发作的影响进行了评估，使用癫痫发作评分从一个修改的拉辛的规模，并与PB。以脑电图棘波数和总持续时间以及录像行为监测来评价RTG和PB的作用。与WT小鼠相比，Kcnq 2 Y284 C/+和Kcnq 2A 306 T/+小鼠均显示出显著更多的KA诱导的癫痫发作。RTG对KA诱导的Kcnq 2 Y284 C/+和Kcnq 2A 306 T/+小鼠癫痫发作均有明显的抑制作用，且作用强于PB。这是第一次报道的证据，RTG改善KA诱导的癫痫发作的基因敲入小鼠携带突变的Kcnq 2，更显着的效果比PB观察到的。RTG或其他Kv7.2通道开放剂可被视为KCNQ 2突变所致癫痫的一线抗癫痫治疗。
The hetero-tetrameric voltage-gated potassium channel Kv7.2/Kv7.3, which is encoded by KCNQ2 and KCNQ3, plays an important role in limiting network excitability in the neonatal brain. Kv7.2/Kv7.3 dysfunction resulting from KCNQ2 mutations predominantly causes self-limited or benign epilepsy in neonates, but also causes early onset epileptic encephalopathy. Retigabine (RTG), a Kv7.2/ Kv7.3-channel opener, seems to be a rational antiepileptic drug for epilepsies caused by KCNQ2 mutations. We therefore evaluated the effects of RTG on seizures in two strains of knock-in mice harboring different Kcnq2 mutations, in comparison to the effects of phenobarbital (PB), which is the first-line antiepileptic drug for seizures in neonates. The subjects were heterozygous knock-in mice (Kcnq2Y284C/+ and Kcnq2A306T/+) bearing the Y284C or A306T Kcnq2 mutation, respectively, and their wild-type (WT) littermates, at 63–100 days of age. Seizures induced by intraperitoneal injection of kainic acid (KA, 12mg/kg) were recorded using a video-electroencephalography (EEG) monitoring system. Effects of RTG on KA-induced seizures of both strains of knock-in mice were assessed using seizure scores from a modified Racine’s scale and compared with those of PB. The number and total duration of spike bursts on EEG and behaviors monitored by video recording were also used to evaluate the effects of RTG and PB. Both Kcnq2Y284C/+ and Kcnq2A306T/+ mice showed significantly more KA-induced seizures than WT mice. RTG significantly attenuated KA-induced seizure activities in both Kcnq2Y284C/+ and Kcnq2A306T/+ mice, and more markedly than PB. This is the first reported evidence of RTG ameliorating KA-induced seizures in knock-in mice bearing mutations of Kcnq2, with more marked effects than those observed with PB. RTG or other Kv7.2-channel openers may be considered as first-line antiepileptic treatments for epilepsies resulting from KCNQ2 mutations.