Modulation of Sodium Channel Inactivation Gating by a Novel Lactam: Implications for Seizure Suppression in Chronic Limbic Epilepsy
Modulation of Sodium Channel Inactivation Gating by a Novel Lactam: Implications for Seizure Suppression in Chronic Limbic Epilepsy
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DOI：
10.1124/jpet.108.144709
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发表时间：
2009-01-01
影响因子：
3.5
通讯作者：
Patel, Manoj K.
中科院分区：
文献类型：
--
作者：
Jones, Paulianda J.;Merrick, Ellen C.;Patel, Manoj K.
癫痫仍然是一种毁灭性的神经系统疾病，与复发性，无端，自发性癫痫发作有关。目前的治疗包括使用抗癫痫药物（AED）抑制癫痫发作;然而，许多患者对目前的治疗仍然难以治愈或遭受严重的副作用。鉴于这种对更有效和更安全的AED的持续需求，我们基于内酰胺结构类设计了一种新化合物3-羟基-3-（4-甲氧基苯基）1-甲基-1，3-二氢-吲哚-2-酮（YWI 92），并评估了其对人神经元钠通道亚型（hNa（v））1.2电流和海马神经元动作电位放电的调节。此外，我们已经测试了它的AED活性使用慢性和急性大鼠癫痫发作模型。与临床使用的AED拉莫三嗪相似，YWI 92表现出对hNav 1.2通道的强直性阻断，并在使用30秒灭活前脉冲时引起稳态灭活曲线的超极化偏移。YWI 92还延迟了30秒失活前脉冲后通道再启动的时间常数，并在20 Hz刺激频率下表现出使用依赖性阻滞。在膜兴奋性实验中，YWI 92抑制颞叶癫痫动物的CA 1神经元的爆发放电，其浓度对对照动物的CA 1神经元几乎没有影响。在最大电休克急性癫痫发作模型（ED 50 = 22.96 mg/kg）中，这些对神经元活性的作用转化为AED活性，重要的是，在慢性颞叶癫痫模型中，癫痫发作的平均次数减少。值得注意的是，YWI 92在高达500 mg/kg的浓度下没有表现出镇静/共济失调副作用。总之，对失活钠通道更大的亲和力，特别是在长时间去极化前脉冲后，可能对抗惊厥活性和药物耐受性都很重要。
Epilepsy remains a devastating neurological disorder associated with recurrent, unprovoked, spontaneous epileptic seizures. Current treatments involve seizure suppression using antiepileptic drugs (AEDs); however, many patients remain refractory to current treatments or suffer serious side effects. In view of this continued need for more effective and safer AEDs, we have designed a novel compound, 3-hydroxy-3-(4-methoxyphenyl)1-methyl-1,3-dihydro-indol-2-one (YWI92), based on a lactam structural class, and evaluated its modulation of human neuronal sodium channel isoform (hNa(v)) 1.2 currents and hippocampal neuron action potential firing. Furthermore, we have tested its AED activity using a chronic and acute rat seizure model. In a similar manner to lamotrigine, a clinically used AED, YWI92 exhibited tonic block of hNav 1.2 channels and caused a hyperpolarizing shift in the steady-state inactivation curve when using a 30-s inactivating prepulse. YWI92 also delayed the time constants of channel repriming after a 30-s inactivating prepulse and exhibited use-dependent block at 20-Hz stimulation frequency. In membrane excitability experiments, YWI92 inhibited burst firing in CA1 neurons of animals with temporal lobe epilepsy at concentrations that had little effect on CA1 neurons from control animals. These actions on neuronal activity translated into AED activity in the maximal electroshock acute seizure model (ED50 = 22.96 mg/kg), and importantly, in a chronic temporal lobe epilepsy model, in which the mean number of seizures was reduced. Notably, YWI92 exhibited no sedative/ataxic side effects at concentrations up to 500 mg/kg. In summary, greater affinity for inactivated sodium channels, particularly after long depolarizing prepulses, may be important for both anticonvulsant activity and drug tolerability.