Unexpected Efficacy of a Novel Sodium Channel Modulator in Dravet Syndrome
Unexpected Efficacy of a Novel Sodium Channel Modulator in Dravet Syndrome
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DOI：
10.1038/s41598-017-01851-9
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发表时间：
2017-05-10
影响因子：
4.6
通讯作者：
George, Alfred L., Jr.
中科院分区：
文献类型：
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作者：
Anderson, Lyndsey L.;Hawkins, Nicole A.;George, Alfred L., Jr.
德拉韦综合征是一种影响儿童的癫痫脑病，主要原因是大脑电压门控钠通道基因SCN1A杂合性功能丧失突变。杂合子Scn1a基因敲除(Scn1a(+/-))小鼠概括了Dravet综合征的严重癫痫表型，是公认的动物模型。由于临床观察表明常规的钠通道阻滞剂可能会加重癫痫的病情，我们预测Scn1a(+/-)小鼠的表型将被一种有效的非常规钠通道阻滞剂GS967加剧。出乎意料的是，GS967显著提高了Scn1a(+/-)小鼠的存活率，并抑制了自发性癫痫发作。相反，拉莫三嗪加剧了癫痫的表型。急性分离神经元的电生理记录显示，慢性GS967处理对中间神经元的诱发动作电位放电频率没有影响，但对锥体神经元的异常自发放电有抑制作用，并与显著降低的钠电流密度有关。拉莫三嗪对两种神经元亚型的神经元兴奋性均无影响。此外，长期服用GS967的Scn1a(+/-)小鼠表现出锥体神经元钠电流密度的正常化和海马区NaV1.6蛋白水平的降低，而拉莫三嗪治疗对锥体神经元钠电流和海马区NaV1.6蛋白水平都没有影响。我们的发现证明了一种新的钠通道阻滞剂在Drave氏综合征中出人意料的疗效，并提示了一种涉及NaV1.6继发性变化的潜在机制。
Dravet syndrome, an epileptic encephalopathy affecting children, largely results from heterozygous loss-of-function mutations in the brain voltage-gated sodium channel gene SCN1A. Heterozygous Scn1a knockout (Scn1a(+/-)) mice recapitulate the severe epilepsy phenotype of Dravet syndrome and are an accepted animal model. Because clinical observations suggest conventional sodium channel blocking antiepileptic drugs may worsen the disease, we predicted the phenotype of Scn1a(+/-) mice would be exacerbated by GS967, a potent, unconventional sodium channel blocker. Unexpectedly, GS967 significantly improved survival of Scn1a(+/-) mice and suppressed spontaneous seizures. By contrast, lamotrigine exacerbated the seizure phenotype. Electrophysiological recordings of acutely dissociated neurons revealed that chronic GS967-treatment had no impact on evoked action potential firing frequency of interneurons, but did suppress aberrant spontaneous firing of pyramidal neurons and was associated with significantly lower sodium current density. Lamotrigine had no effects on neuronal excitability of either neuron subtype. Additionally, chronically GS967-treated Scn1a(+/-) mice exhibited normalized pyramidal neuron sodium current density and reduced hippocampal NaV1.6 protein levels, whereas lamotrigine treatment had no effect on either pyramidal neuron sodium current or hippocampal NaV1.6 levels. Our findings demonstrate unexpected efficacy of a novel sodium channel blocker in Dravet syndrome and suggest a potential mechanism involving a secondary change in NaV1.6.