Pharmacogenetics of KCNQ channel activation in 2 potassium channelopathy mouse models of epilepsy.
Pharmacogenetics of KCNQ channel activation in 2 potassium channelopathy mouse models of epilepsy.
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DOI：
10.1111/epi.13978
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发表时间：
2018-03
期刊：
影响因子：
5.6
通讯作者：
Glasscock E
中科院分区：
文献类型：
--
作者：
Vanhoof-Villalba SL;Gautier NM;Mishra V;Glasscock E
抗癫痫药物是治疗癫痫的主要治疗选择，但其疗效受到药物耐药性和不良反应的限制。在这里，我们研究了雷加宾激活KCNQ通道在预防癫痫发作和神经心脏功能障碍方面的治疗效果，两种不同严重程度的癫痫小鼠模型：重度癫痫的kcnna1−/−模型和轻度癫痫的Kcnq1A340E/A340E模型，这些模型与癫痫猝死（SUDEP）风险增加有关。结合行为、癫痫阈值、电生理和基因表达分析来确定KCNQ激活对小鼠的影响。行为上，Kcna1 - / -小鼠表现出意想不到的高兴奋性，而不是预期的镇静样反应。在氟甲基诱导的癫痫发作试验中，KCNQ激活使Kcnq1品系小鼠的癫痫发作潜伏期降低了≥50%，但对Kcna1品系没有影响，提示遗传背景的影响。然而，在同时进行的脑电图和心电图记录中，KCNQ激活显著降低了Kcna1−/−小鼠的自发发作频率约60%。在Kcnq1A340E/A340E小鼠中，KCNQ激活会产生不良的心脏效应，包括深度心动过缓、心率变异性异常增加和房室传导阻滞。对Kcnq2和Kcnq3 mRNA水平的分析显示，Kcnq2在Kcna1−/−脑中的表达显著升高，表明药物靶点的改变可能导致药物反应的改变。这项研究表明，通道病的治疗策略可能会产生意想不到的结果，而通道缺陷的有效再平衡需要提高对回路和组织水平上通道相互作用的理解。KCNQ通道激活的有效性和不良反应的表现受到遗传背景的很大影响，这可能限制了KCNQ调节作为预防癫痫患者神经心脏功能障碍的一种方式，从而限制了SUDEP的风险。我们的数据还揭示了KCNQ2-5通道在自主控制变时性中的潜在作用。
Anti-seizure drugs are the leading therapeutic choice for treatment of epilepsy, but their efficacy is limited by pharmacoresistance and the occurrence of unwanted side effects. Here, we examined the therapeutic efficacy of KCNQ channel activation by retigabine in preventing seizures and neurocardiac dysfunction in two potassium channelopathy mouse models of epilepsy with differing severity that have been associated with increased risk of sudden unexpected death in epilepsy (SUDEP): the Kcna1−/− model of severe epilepsy and the Kcnq1A340E/A340E model of mild epilepsy. A combination of behavioral, seizure threshold, electrophysiological, and gene expression analyses was used to determine the effects of KCNQ activation in mice. Behaviorally, Kcna1−/− mice exhibited unexpected hyperexcitability instead of the expected sedative-like response. In flurothyl-induced seizure tests, KCNQ activation decreased seizure latency by ≥50% in Kcnq1 strain mice but had no effect in the Kcna1 strain, suggesting the influence of genetic background. However, in simultaneous electroencephalography and electrocardiography recordings, KCNQ activation significantly reduced spontaneous seizure frequency in Kcna1−/− mice by ~60%. In Kcnq1A340E/A340E mice, KCNQ activation produced adverse cardiac effects including profound bradycardia and abnormal increases in heart rate variability and atrioventricular conduction blocks. Analyses of Kcnq2 and Kcnq3 mRNA levels revealed significantly elevated Kcnq2 expression in Kcna1−/− brains, suggesting drug target alterations may contribute to the altered drug responses. This study shows that treatment strategies in channelopathy may have unexpected outcomes and that effective rebalancing of channel defects requires improved understanding of channel interactions at the circuit and tissue levels. The efficacy of KCNQ channel activation and manifestation of adverse effects were greatly affected by genetic background, potentially limiting KCNQ modulation as a way to prevent neurocardiac dysfunction in epilepsy and thereby SUDEP risk. Our data also uncovers a potential role for KCNQ2-5 channels in autonomic control of chronotropy.
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影响因子：
16.2
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