Bayraktar Erva, Liu Yuanyuan, Sonnenberg Lukas, Hedrich Ulrike B S, Sara Yildirim, Eltokhi Ahmed, Lyu Hang, Lerche Holger, Wuttke Thomas V, Lauxmann Stephan
Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
Department of Medical Pharmacology, Faculty of Medicine, Hacettepe University, Ankara, Turkey.
Br J Pharmacol. 2023 Apr;180(8):1038-1055. doi: 10.1111/bph.15981. Epub 2022 Dec 19.
Variants in SCN8A, the Na 1.6 channel's coding gene, are characterized by a variety of symptoms, including intractable epileptic seizures, psychomotor delay, progressive cognitive decline, autistic features, ataxia or dystonia. Standard anticonvulsant treatment has a limited impact on the course of disease.
We investigated the therapeutic potential of eslicarbazepine (S-licarbazepine; S-lic), an enhancer of slow inactivation of voltage gated sodium channels, on two variants with biophysical and neuronal gain-of-function (G1475R and M1760I) and one variant with biophysical gain-of-function but neuronal loss-of-function (A1622D) in neuroblastoma cells and in murine primary hippocampal neuron cultures. These three variants cover the broad spectrum of Na 1.6-associated disease and are linked to representative phenotypes of mild to moderate epilepsy (G1475R), developmental and epileptic encephalopathy (M1760I) and intellectual disability without epilepsy (A1622D).
Similar to known effects on Na 1.6 wildtype channels, S-lic predominantly enhances slow inactivation on all tested variants, irrespective of their particular biophysical mechanisms. Beyond that, S-lic exhibits variant-specific effects including a partial reversal of pathologically slowed fast inactivation dynamics (A1622D and M1760I) and a trend to reduce enhanced persistent Na current by A1622D variant channels. Furthermore, our data in primary transfected neurons reveal that not only variant-associated hyperexcitability (M1760I and G1475R) but also hypoexcitability (A1622D) can be modulated by S-lic.
S-lic has not only substance-specific effects but also variant-specific effects. Personalized treatment regimens optimized to achieve such variant-specific pharmacological modulation may help to reduce adverse side effects and improve the overall therapeutic outcome of SCN8A-related disease.
钠1.6通道编码基因SCN8A中的变异具有多种症状，包括顽固性癫痫发作、精神运动发育迟缓、进行性认知衰退、自闭症特征、共济失调或肌张力障碍。标准抗惊厥治疗对疾病进程的影响有限。
我们研究了电压门控钠通道慢失活增强剂艾司利卡西平（S-利卡西平；S-lic）对神经母细胞瘤细胞和小鼠原代海马神经元培养物中两种具有生物物理和神经元功能增益（G1475R和M1760I）以及一种具有生物物理功能增益但神经元功能丧失（A1622D）的变异体的治疗潜力。这三种变异体涵盖了钠1.6相关疾病的广泛范围，并与轻度至中度癫痫（G1475R）、发育性和癫痫性脑病（M1760I）以及无癫痫的智力残疾（A1622D）的代表性表型相关。
与已知对钠1.6野生型通道的作用相似，S-lic主要增强所有测试变异体的慢失活，而不论其特定的生物物理机制如何。除此之外，S-lic还表现出变异体特异性效应，包括病理上减慢的快失活动力学的部分逆转（A1622D和M1760I）以及A1622D变异体通道增强的持续性钠电流减少的趋势。此外，我们在原代转染神经元中的数据表明，不仅变异体相关的兴奋性过高（M1760I和G1475R），而且兴奋性过低（A1622D）都可以被S-lic调节。
S-lic不仅具有物质特异性效应，还具有变异体特异性效应。优化以实现这种变异体特异性药理调节的个性化治疗方案可能有助于减少不良反应并改善SCN8A相关疾病的整体治疗效果。
