Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine Hannover, 30559 Hannover, Germany; Center for Systems Neuroscience, 30559 Hannover, Germany.
Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine Hannover, 30559 Hannover, Germany; Center for Systems Neuroscience, 30559 Hannover, Germany.
Neurobiol Dis. 2015 Mar;75:78-90. doi: 10.1016/j.nbd.2014.12.015. Epub 2014 Dec 27.
The pilocarpine rat model, in which status epilepticus (SE) leads to epilepsy with spontaneous recurrent seizures (SRS), is widely used to study the mechanisms of epileptogenesis and develop strategies for epilepsy prevention. SE is commonly interrupted after 30-90min by high-dose diazepam or other anticonvulsants to reduce mortality. It is widely believed that SE duration of 30-60min is sufficient to induce hippocampal damage and epilepsy. However, resistance to diazepam develops during SE, so that an SE that is longer than 30min is difficult to terminate, and SE typically recurs several hours after diazepam, thus forming a bias for studies on epileptogenesis or antiepileptogenesis. We developed a drug cocktail, consisting of diazepam, phenobarbital, and scopolamine that allows complete and persistent SE termination in the lithium-pilocarpine model. A number of novel findings were obtained with this cocktail. (a) In contrast to previous reports with incomplete SE suppression, a SE of 60min duration did not induce epilepsy, whereas epilepsy with SRS developed after 90 or 120min SE; (b) by comparing groups of rats with 60 and 90min of SE, development of epilepsy could be predicted by behavioral hyperexcitability and decrease in seizure threshold, indicating that these read-outs are suited as biomarkers of epileptogenesis; (c) CA1 damage was prevented by the cocktail, but rats exhibited cell loss in the dentate hilus, which was related to development of epilepsy. These data demonstrate that the duration of SE needed for induction of epileptogenesis in this model is longer than previously thought.
匹罗卡品大鼠模型中，癫痫持续状态（SE）会导致自发性反复性癫痫发作（SRS），被广泛用于研究癫痫发生的机制并开发预防癫痫的策略。SE 通常会在 30-90 分钟后通过大剂量地西泮或其他抗惊厥药物中断，以降低死亡率。人们普遍认为，SE 持续 30-60 分钟足以诱导海马损伤和癫痫。然而，SE 期间会产生对地西泮的耐药性，因此超过 30 分钟的 SE 很难终止，而且 SE 通常在停药数小时后复发，从而对癫痫发生或抗癫痫发生的研究形成了偏见。我们开发了一种药物鸡尾酒，由地西泮、苯巴比妥和东莨菪碱组成，可在锂匹罗卡品模型中完全和持续终止 SE。该鸡尾酒产生了许多新的发现。(a) 与之前不完全抑制 SE 的报告相反，60 分钟的 SE 不会引起癫痫，而 90 或 120 分钟 SE 后则会出现伴有 SRS 的癫痫；(b) 通过比较 SE 持续时间为 60 和 90 分钟的大鼠组，行为兴奋性增高和癫痫发作阈值降低可预测癫痫的发展，表明这些指标适合作为癫痫发生的生物标志物；(c) 鸡尾酒可预防 CA1 损伤，但大鼠出现齿状回神经细胞丢失，这与癫痫的发展有关。这些数据表明，该模型中诱导癫痫发生所需的 SE 持续时间比之前认为的要长。
