Differential effect of lacosamide on Nav1.7 varients from responsive and non-responsive patients with small fibre neuropathy
Differential effect of lacosamide on Nav1.7 varients from responsive and non-responsive patients with small fibre neuropathy
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DOI：
10.1093/brain/awaa016
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发表时间：
2020-03-01
期刊：
影响因子：
14.5
通讯作者：
Waxman, Stephen G.
中科院分区：
文献类型：
--
作者：
Labau, Julie I. R.;Estacion, Mark;Waxman, Stephen G.
小纤维神经病变是一种常见的疼痛疾病，在许多情况下，现有药物治疗无效。在一小部分小纤维神经病患者中，电压门控钠通道Na(v)1.7的功能获得突变是背根神经节神经元高兴奋性和疼痛的基础。最近的临床研究表明，拉科沙胺以使用依赖的方式阻断钠通道，减轻了一些Na(v)1.7突变患者的疼痛；然而，这些患者中只有一小部分对该药有反应。在这里，我们使用电压钳记录来评估拉科沙胺对来自对治疗有反应或无反应的患者的5种Na(v)1.7变异的影响。我们发现，在临床上可达到的30 JIM浓度下，拉科沙胺作为一种有效的钠通道抑制剂，通过快速和缓慢失活的电压依赖性超极化转移和增强使用依赖性抑制，抑制应答患者携带的Na(v)1.7变异。相比之下，拉科沙胺对无反应患者的Na(v)1.7变异的缓慢失活和使用依赖的影响不那么强大。重要的是，我们发现拉科沙胺选择性地增强了应答者变异的快速失活。综上所述，这些发现开始揭示携带选择性Na(v)1.7变异的小纤维神经病患者对拉科沙胺反应性的生物物理基础。
Small fibre neuropathy is a common pain disorder, which in many cases fails to respond to treatment with existing medications. Gain-of-function mutations of voltage-gated sodium channel Na(v)1.7 underlie dorsal root ganglion neuronal hyperexcitability and pain in a subset of patients with small fibre neuropathy. Recent clinical studies have demonstrated that lacosamide, which blocks sodium channels in a use-dependent manner, attenuates pain in some patients with Na(v)1.7 mutations; however, only a subgroup of these patients responded to the drug. Here, we used voltage-clamp recordings to evaluate the effects of lacosamide on five Na(v)1.7 variants from patients who were responsive or non-responsive to treatment. We show that, at the clinically achievable concentration of 30 JIM, lacosamide acts as a potent sodium channel inhibitor of Na(v)1.7 variants carried by responsive patients, via a hyperpolarizing shift of voltage-dependence of both fast and slow inactivation and enhancement of use-dependent inhibition. By contrast, the effects of lacosamide on slow inactivation and use-dependence in Na(v)1.7 variants from non-responsive patients were less robust. Importantly, we found that lacosamide selectively enhances fast inactivation only in variants from responders. Taken together, these findings begin to unravel biophysical underpinnings that contribute to responsiveness to lacosamide in patients with small fibre neuropathy carrying select Na(v)1.7 variants.