Efficacy of Retigabine on Acute Limbic Seizures in Adult Rats.
Efficacy of Retigabine on Acute Limbic Seizures in Adult Rats.
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DOI：
10.14581/jer.15010
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发表时间：
2015-12-01
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影响因子：
--
通讯作者：
Ali, S S
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文献类型：
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作者：
Friedman, L K;Slomko, A M;Ali, S S
背景和目的：瑞替加滨 (RGB) 是一种 K+ 通道正变构调节剂，适用于部分性癫痫发作的辅助治疗，在两种红藻氨酸 (KA) 诱导的癫痫持续状态成人模型中研究了瑞替加滨 (RGB) 的功效，以确定其耐受性。 方法：瑞替加滨在术前 30 分钟或 2 小时以高剂量 (5 mg/kg) 和低剂量 (1-2 mg/kg) 全身给药KA 诱发癫痫持续状态后。在 KA 存在的情况下，还通过海马内显微注射递送高浓度 (1 g/L) 和低浓度 (0.25 g/L) RGB。 结果：在两种模型中均观察到 RGB 的剂量依赖性效应。较低剂量会增加癫痫行为潜伏期，并减少脑电图（EEG）中单脉冲和同步突发事件的数量。较高剂量会恶化癫痫行为，产生严重的共济失调，并增加放电活动。用 RGB 治疗的、对癫痫发作有抵抗力的动物没有表现出明显的损伤或 GluR1 表达的丧失；然而，如果癫痫发作达到 5-6 阶段，就会发生典型的海马损伤和脆弱锥体区 GluR1 亚基蛋白的消耗。结论：只有当癫痫发作显着减弱时，RGB 才具有神经保护作用。在 RGB 存在的情况下，GluR1 在抗性颗粒细胞层中同时受到抑制，这可能会减弱兴奋性传递。本文观察到的双相效应表明，必须仔细检查人体剂量以产生最佳的临床反应。
BACKGROUND AND PURPOSE: The efficacy of retigabine (RGB), a positive allosteric modulator of K+ channels indicated for adjunct treatment of partial seizures, was studied in two adult models of kainic acid (KA)-induced status epilepticus to determine it's toleratbility.METHODS: Retigabine was administered systemiclly at high (5 mg/kg) and low (1-2 mg/kg) doses either 30 min prior to or 2 hr after KA-induced status epilepticus. High (1 g/L) and low (0.25 g/L) concentrations of RGB were also delivered by intrahippocampal microinjection in the presence of KA.RESULTS: Dose-dependent effects of RGB were observed with both models. Lower doses increased seizure behavior latency and reduced the number of single spikes and synchronized burst events in the electroencephalogram (EEG). Higher doses worsened seizure behavior, produced severe ataxia, and increased spiking activity. Animals treated with RGB that were resistant to seizures did not exhibit significant injury or loss in GluR1 expression; however if stage 5-6 seizures were reached, typical hippocampal injury and depletion of GluR1 subunit protein in vulernable pyramidal fields occurred.CONCLUSIONS: RGB was neuroprotective only if seizures were significantly attenuated. GluR1 was simultaneously suppressed in the resistant granule cell layer in presence of RGB which may weaken excitatory transmission. Biphasic effects observed herein suggest that the human dosage must be carefully scrutinized to produce the optimal clinical response.