K+-Channel Openers Suppress Epileptiform Activities Induced by 4-Aminopyridine in Cultured Rat Hippocampal Neurons
K+-Channel Openers Suppress Epileptiform Activities Induced by 4-Aminopyridine in Cultured Rat Hippocampal Neurons
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DOI：
10.1254/jphs.08214fp
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发表时间：
2008-12-01
影响因子：
3.5
通讯作者：
Miyabe, Masayuki
中科院分区：
文献类型：
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作者：
Kobayashi, Kiyoaki;Nishizawa, Yukio;Miyabe, Masayuki
K+通道是神经元兴奋性的关键调节剂，已知某些类型的这些通道的突变会导致癫痫发作。据报道，K+通道的激活可以抑制癫痫放电;然而，作为抗癫痫药物最有效的K+通道开放剂的类型尚不清楚。建立了以钠离子指示剂苯并呋喃三乙酸钠（SBFI）为钠离子指示剂的定量荧光法，用于评价不同化合物对4-氨基吡啶（4-AP）诱导的大鼠海马神经元癫痫样活动的影响。在K+通道开放剂中，K（v）7.2/K（v）7.3通道开放剂瑞替加滨和氟吡汀以及K（Ca）2通道开放剂NS 309、DCEBIO和1-EBIO显示出与常规抗癫痫药物（AED）相似的有效抗癫痫作用。相反，K（Ca）1.1通道开放剂NS 1619、异海松酸和氯唑沙宗表现出中度抑制。Kir 6通道开放剂米诺地尔、克罗卡林和吡那地尔未显示抗癫痫作用。我们的结论是，K（v）7.2/K（v）7.3，K（Ca）2，并在一定程度上，K（Ca）1.1-通道开放剂，但不是K（ir）6-通道开放剂，抑制4-AP诱导的海马神经元癫痫样活动。这些结果表明，这类K+通道的K+通道开放剂可能具有治疗潜力的新类别的抗癫痫药物。
K+ channels are key modulators of neuronal excitability, and mutations in certain types of these channels are known to cause epileptic seizures. Activation of K+ channels is reported to suppress epileptic discharge; however, the types of K+-channel openers that are most effective as anti-epileptic agents are not well understood. We established a quantitative fluorescence assay using the Na+ indicator sodium-binding benzofuran isophthalate (SBFI) for evaluation of various compounds on epileptiform activities induced by 4-aminopyridine (4-AP) in cultured rat hippocampal neurons. Among the K+-channel openers, the K(v)7.2/K(v)7.3-channel openers retigabine and flupirtine and K(Ca)2-channel openers NS309, DCEBIO, and 1-EBIO showed potent anti-epileptic effects similar to conventional antiepileptic drugs (AEDs). In contrast, the K(Ca)1.1-channel openers NS1619, isopimaric acid, and chlorzoxazone demonstrated moderate inhibition. The Kir6-channel openers minoxidil, cromakalim, and pinacidil did not show anti-epileptic effects. We concluded that K(v)7.2/K(v)7.3, K(Ca)2, and, to some extent, K(Ca)1.1-channel openers, but not K(ir)6-channel openers, suppress 4-AP-induced epileptiform activities in hippocampal neurons. These results suggest that the K+-channel openers for this category of K+ channels might have therapeutic potential as new classes of antiepileptic drugs.