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Abstract:
:The antiarrhythmic sodium-channel blocker mexiletine is used to treat patients with myotonia. However, around 30% of patients do not benefit from mexiletine due to poor tolerability or suboptimal response. Safinamide is an add-on therapy to levodopa for Parkinson's disease. In addition to MAOB inhibition, safinamide inhibits neuronal sodium channels, conferring anticonvulsant activity in models of epilepsy. Here, we investigated the effects of safinamide on skeletal muscle hNav1.4 sodium channels and in models of myotonia, in-vitro and in-vivo. Using patch-clamp, we showed that safinamide reversibly inhibited sodium currents in HEK293T cells transfected with hNav1.4. At the holding potential (hp) of -120 mV, the half-maximum inhibitory concentrations (IC50) were 160 and 33 μM at stimulation frequencies of 0.1 and 10 Hz, respectively. The calculated affinity constants of safinamide were dependent on channel state: 420 μM for closed channels and 9 μM for fast-inactivated channels. The p.F1586C mutation in hNav1.4 greatly impaired safinamide inhibition, suggesting that the drug binds to the local anesthetic receptor site in the channel pore. In a condition mimicking myotonia, i.e. hp. of -90 mV and 50-Hz stimulation, safinamide inhibited INa with an IC50 of 6 μM, being two-fold more potent than mexiletine. Using the two-intracellular microelectrodes current-clamp method, action potential firing was recorded in vitro in rat skeletal muscle fibers in presence of the chloride channel blocker, 9-anthracene carboxylic acid (9-AC), to increase excitability. Safinamide counteracted muscle fiber hyperexcitability with an IC50 of 13 μM. In vivo, oral safinamide was tested in the rat model of myotonia. In this model, intraperitoneal injection of 9-AC greatly increased the time of righting reflex (TRR) due to development of muscle stiffness. Safinamide counteracted 9-AC induced TRR increase with an ED50 of 1.2 mg/kg, which is 7 times lower than that previously determined for mexiletine. In conclusion, safinamide is a potent voltage and frequency dependent blocker of skeletal muscle sodium channels. Accordingly, the drug was able to counteract abnormal muscle hyperexcitability induced by 9-AC, both in vitro and in vivo. Thus, this study suggests that safinamide may have potential in treating myotonia and warrants further preclinical and human studies to fully evaluate this possibility.
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最新影响因子:5.62 | 期刊ISSN:0014-4886 | CiteScore:4.51 |
出版周期:Monthly | 是否OA:YES | 出版年份:1959 |
期刊官方网址:http://ees.elsevier.com/yexnr/default.asp?pg=login.asp
期刊投稿地址:http://ees.elsevier.com/yexnr/default.asp?pg=login.asp
自引率:3.00% | 研究方向:医学-神经科学 |
出版地区:UNITED STATES |
SCI期刊coverage:Science Citation Index Expanded(科学引文索引扩展)
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As one of the premier review journals in the neurosciences, Molecular Neurobiology is specifically designed to synthesize and critically assess research trends in experimental and clinical neuroscience at the molecular level. Its distinguished editorial board is comprised of four Nobelists and other preeminent neuroscientists who carefully review papers to ensure their high quality.
分子神经生物学是神经科学领域最重要的评论期刊之一,是专门为在分子水平上综合和批判性地评估实验和临床神经科学的研究趋势而设计的。其杰出的编辑委员会由四名诺贝尔奖获得者和其他杰出的神经科学家组成,他们仔细审查论文以确保其高质量。
大类(学科) | 小类(学科) | 学科排名 |
医学 |
NEUROSCIENCES (神经科学) 2区 |
60/261 |
年度总发文量 | 年度论文发表量 | 年度综述发表量 |
218 | 179 | 39 |
引文计数(2018)
文献(2015-2017)
3681次引用
817篇文献
序号 | 类别 | 排名 | 百分位 |
1 |
大类(学科):Neuroscience
小类(学科):Neurology
|
#18/142
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2 |
大类(学科):Neuroscience
小类(学科):Developmental Neuroscience
|
#5/33
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研究方向:神经系统疾病
接受率: 中等(50%命中)
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研究方向:医学-精神病学
影响因子:5.415
ISSN:0924-977X
研究方向:医学-精神病学
发表一篇学和医学成像类SCI论文
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