Chronic limbic epilepsy models for therapy discovery: Protocols to improve efficiency.
Chronic limbic epilepsy models for therapy discovery: Protocols to improve efficiency.
复制标题
用于治疗发现的慢性边缘癫痫模型：提高效率的方案。
DOI：
10.1111/epi.16995
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发表时间：
2021
期刊：
影响因子：
5.6
通讯作者：
Edelbroek,Peter
中科院分区：
文献类型：
--
作者：
Bertram,EdwardH;Edelbroek,Peter
有建议通过将慢性癫痫模型纳入临床前过程来改善癫痫的治疗发现，但不可预测的癫痫发作和长时间维持药物水平的困难一直是使用这些动物的障碍。我们报告了新的协议中，药物通过一个新的慢性胃管大鼠癫痫发作频率较高，以尽量减少这些obstacle.MethodsAdult大鼠自发性边缘癫痫发作后，由海马电刺激引起的边缘癫痫持续状态的发作进行了监测与长期视频脑电图（EEG）。具有预定基线癫痫发作频率的动物接受胃内管给药。卡马西平、左乙拉西坦、苯巴比妥和苯妥英分别采用急性方案（每隔一天增加一次剂量，最多三次给药）或慢性方案（一次给药，一周多次给药）进行试验。获得药物水平与level.ResultsWith急性协议的影响，所有四种药物诱导明确的剂量相关反应。在卡马西平、苯巴比妥和苯妥英的为期一周的给药方案后观察到类似的剂量相关反应，这些反应与人体治疗范围内的药物水平相关。对慢性左乙拉西坦的反应要弱得多。胃管给药途径耐受性良好，超过了几个months.SignificanceUsing大鼠稳定，更高的癫痫发作频率使得有可能确定潜在的药物抑制癫痫发作在一个现实的癫痫模型的药物水平，是类似于人类的治疗水平。急性方案在1周内提供了完全剂量反应。长期给药方案进一步区分了可能长期有效的药物。胃管有助于压力较小、人道和一致的多剂量给药。
ObjectiveThere have been recommendations to improve therapy discovery for epilepsy by incorporating chronic epilepsy models into the preclinical process, but unpredictable seizures and difficulties in maintaining drug levels over prolonged periods have been obstacles to using these animals. We report new protocols in which drugs are administered through a new chronic gastric tube to rats with higher seizure frequencies to minimize these obstacles.MethodsAdult rats with spontaneous limbic seizures following an episode of limbic status epilepticus induced by electrical hippocampal stimulation were monitored with long‐term video– electroencephalography (EEG). Animals with a predetermined baseline seizure frequency received an intragastric tube for drug administration. Carbamazepine, levetiracetam, phenobarbital, and phenytoin were tested with either an acute protocol (an increasing single dose every other day for a maximum of three doses) or with a chronic protocol (multiple administrations of one dose for a week). Drug levels were obtained to correlate the effect with the level.ResultsWith the acute protocol, all four drugs induced a clear dose‐related response. Similar dose‐related responses were seen following the week‐long dosing protocol for carbamazepine, phenobarbital, and phenytoin, and these responses were associated with drug levels that were in the human therapeutic range. The response to chronic levetiracetam was much less robust. The gastric tube route of administration was well tolerated over a number of months.SignificanceUsing rats with stable, higher seizure frequencies made it possible to identify the potential of a drug to suppress seizures in a realistic model of epilepsy with drug levels that are similar to those of human therapeutic levels. The acute protocol provided a full dose response in 1 week. The chronic administration protocol further differentiated drugs that may be effective long term. The gastric tube facilitates a less stressful, humane, and consistent administration of multiple doses.