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Differential effect of lacosamide on Nav1.7 variants from responsive and non-responsive patients with small fibre neuropathy.
Brain ( IF 14.5 ) Pub Date : 2020-02-03 , DOI: 10.1093/brain/awaa016
Julie I R Labau 1, 2, 3, 4, 5 , Mark Estacion 1, 2, 3 , Brian S Tanaka 1, 2, 3 , Bianca T A de Greef 4, 6 , Janneke G J Hoeijmakers 4 , Margot Geerts 4 , Monique M Gerrits 7 , Hubert J M Smeets 5 , Catharina G Faber 4 , Ingemar S J Merkies 4, 8 , Giuseppe Lauria 9, 10 , Sulayman D Dib-Hajj 1, 2, 3 , Stephen G Waxman 1, 2, 3
Affiliation  

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 Nav1.7 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 Nav1.7 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 Nav1.7 variants from patients who were responsive or non-responsive to treatment. We show that, at the clinically achievable concentration of 30 μM, lacosamide acts as a potent sodium channel inhibitor of Nav1.7 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 Nav1.7 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 Nav1.7 variants.

中文翻译:

拉科酰胺对来自反应性和非反应性小纤维神经病患者的 Nav1.7 变异体的差异影响。

小纤维神经病是一种常见的疼痛疾病,在许多情况下对现有药物的治疗无效。电压门控钠通道 Nav1.7 的功能获得性突变是一部分小纤维神经病变患者的背根神经节神经元过度兴奋和疼痛的基础。最近的临床研究表明,拉考沙胺以使用依赖性方式阻断钠通道,减轻一些 Nav1.7 突变患者的疼痛;然而,这些患者中只有一部分对药物有反应。在这里,我们使用电压钳记录来评估拉科酰胺对来自对治疗有反应或无反应的患者的五种 Nav1.7 变体的影响。我们表明,在临床可达到的 30 μM 浓度下,拉考沙胺可作为 Nav1 的有效钠通道抑制剂。反应患者携带的 7 个变体,通过快速和慢速失活的电压依赖性的超极化转变和使用依赖性抑制的增强。相比之下,拉科酰胺对来自无反应患者的 Nav1.7 变体的缓慢失活和使用依赖性的影响不那么强烈。重要的是,我们发现拉科酰胺仅在响应者的变体中选择性地增强快速灭活。综上所述,这些发现开始揭示生物物理学基础,这些基础有助于携带选定 Nav1.7 变体的小纤维神经病变患者对拉考沙胺产生反应。拉考沙胺对来自无反应患者的 Nav1.7 变体的缓慢失活和使用依赖性的影响不那么强烈。重要的是,我们发现拉科酰胺仅在响应者的变体中选择性地增强快速灭活。综上所述,这些发现开始揭示生物物理学基础,这些基础有助于携带选定 Nav1.7 变体的小纤维神经病变患者对拉考沙胺产生反应。拉考沙胺对来自无反应患者的 Nav1.7 变体的缓慢失活和使用依赖性的影响不那么强烈。重要的是,我们发现拉科酰胺仅在响应者的变体中选择性地增强快速灭活。综上所述,这些发现开始揭示生物物理学基础,这些基础有助于携带选定 Nav1.7 变体的小纤维神经病患者对拉考沙胺产生反应。
更新日期:2020-04-17
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