Antiepileptic activity of preferential inhibitors of persistent sodium current.
Antiepileptic activity of preferential inhibitors of persistent sodium current.
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DOI：
10.1111/epi.12657
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发表时间：
2014-08
期刊：
影响因子：
5.6
通讯作者：
George AL Jr
中科院分区：
文献类型：
--
作者：
Anderson LL;Thompson CH;Hawkins NA;Nath RD;Petersohn AA;Rajamani S;Bush WS;Frankel WN;Vanoye CG;Kearney JA;George AL Jr
来自基础神经生理学和分子遗传学的证据表明，电压门控钠（NaV）通道传导的持续钠电流是癫痫发病机制的一个因素。许多抗癫痫药物靶向NaV通道，主要通过使用依赖性阻断瞬时钠电流来调节神经元兴奋性，尽管持续电流的抑制也可能有助于这些药物的疗效。我们假设，能够优先抑制持续钠电流的药物或化合物将具有抗癫痫活性。我们在癫痫Scn2aQ54小鼠模型中研究了两种选择性持续钠电流阻断剂雷诺嗪（一种FDA批准的治疗心绞痛的药物）和GS 967（一种对持续电流具有更有效作用的新型化合物）的抗癫痫活性。我们还检查了GS 967在最大电休克模型中的作用，并评估了该化合物对神经元兴奋性、门神经元丢失倾向、苔藓纤维发芽发展和Scn2aQ 54小鼠存活的影响。我们发现雷诺嗪能够使Scn2aQ54小鼠的癫痫发作频率降低约50%。更有效的持续电流阻断剂GS 967在Scn2aQ 54小鼠中将癫痫发作频率降低了90%以上，并在最大电休克模型中保护免受诱导的癫痫发作。GS 967极大地减弱了从Scn2aQ 54小鼠急性分离的锥体神经元的异常自发动作电位放电。除了在体内抑制癫痫发作外，GS 967治疗大大改善了Scn 2aQ 54小鼠的存活率，防止了门神经元丢失，并抑制了海马苔藓纤维发芽的发展。我们的研究结果表明，选择性持续钠电流阻滞剂GS 967具有有效的抗癫痫活性，这种化合物可以为新药的开发提供信息。
Evidence from basic neurophysiology and molecular genetics has implicated persistent sodium current conducted by voltage-gated sodium (NaV) channels as a contributor to the pathogenesis of epilepsy. Many antiepileptic drugs target NaV channels and modulate neuronal excitability mainly by a use-dependent block of transient sodium current, although suppression of persistent current may also contribute to the efficacy of these drugs. We hypothesized that a drug or compound capable of preferential inhibition of persistent sodium current would have antiepileptic activity. We examined the antiepileptic activity of two selective persistent sodium current blockers ranolazine, an FDA-approved drug for treatment of angina pectoris, and GS967, a novel compound with more potent effects on persistent current, in the epileptic Scn2aQ54 mouse model. We also examined the effect of GS967 in the maximal electroshock model and evaluated effects of the compound on neuronal excitability, propensity for hilar neuron loss, development of mossy fiber sprouting and survival of Scn2aQ54 mice. We found that ranolazine was capable of reducing seizure frequency by ~50% in Scn2aQ54 mice. The more potent persistent current blocker GS967 reduced seizure frequency by greater than 90% in Scn2aQ54 mice and protected against induced seizures in the maximal electroshock model. GS967 greatly attenuated abnormal spontaneous action potential firing in pyramidal neurons acutely isolated from Scn2aQ54 mice. In addition to seizure suppression in vivo, GS967 treatment greatly improved the survival of Scn2aQ54 mice, prevented hilar neuron loss, and suppressed the development of hippocampal mossy fiber sprouting. Our findings indicate that the selective persistent sodium current blocker GS967 has potent antiepileptic activity and this compound could inform development of new agents.
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影响因子：
6.1
作者：
Mistry AM;Thompson CH;Miller AR;Vanoye CG;George AL Jr;Kearney JA
通讯作者：
Kearney JA
影响因子：
2.2
作者：
Nissinen, J;Large, CH;Pitkänen, A
通讯作者：
Pitkänen, A
DOI：
10.1523/jneurosci.6042-11.2012
发表时间：
2012-05-23
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Lin WH;Günay C;Marley R;Prinz AA;Baines RA
通讯作者：
Baines RA
影响因子：
3.6
作者：
Stafstrom, Carl E
通讯作者：
Stafstrom, Carl E
影响因子：
5.6
作者：
Buckmaster, PS
通讯作者：
Buckmaster, PS