Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine, Bünteweg 17, D-30559 Hannover, Germany.
Eur J Pharmacol. 2009 Oct 1;619(1-3):15-24. doi: 10.1016/j.ejphar.2009.07.020. Epub 2009 Jul 24.
In recent years, the pilocarpine model of temporal lobe epilepsy has become the most popular and widely used rodent model of this common and difficult-to-treat type of epilepsy. In this model, the cholinomimetic convulsant pilocarpine is used to induce a status epilepticus, which is followed by hippocampal damage and development of spontaneous recurrent seizures. In rats, pilocarpine is either administered alone or in combination with lithium, which allows a conspicuous reduction of the pilocarpine dose required to induce status epilepticus and results in a higher percentage of animals developing status epilepticus. In mice, lithium has only rarely been used in association with pilocarpine, which prompted us to directly compare the pilocarpine and lithium-pilocarpine models in this species. In contrast to rats, pretreatment with lithium in mice did not potentiate the convulsant effect of pilocarpine. The sequence of behavioral changes observed in mice undergoing a status epilepticus was very similar for lithium-pilocarpine compared to pilocarpine administered alone. All mice that survived status epilepticus developed epilepsy with spontaneous recurrent seizures. Epileptic mice exhibited significant increases of anxiety-related behavior and impaired learning and memory. Neuronal damage resulting from status epilepticus was essentially similar in the lithium-pilocarpine and pilocarpine models and was characterized by severe neurodegeneration in the hippocampal formation, resembling hippocampal sclerosis in mesial temporal lobe epilepsy. Mice in which pilocarpine or lithium-pilocarpine did not induce status epilepticus but only single brief seizures did not show any significant differences in behavior, spatial learning or hippocampal histology from controls. Our data demonstrate that the syndromes produced by pilocarpine and lithium-pilocarpine in mice are behaviorally and neuropathologically indistinguishable, and that both models can be used to study the relationship between seizures, neuronal damage and psychopathology.
近年来，匹鲁卡品颞叶癫痫模型已成为最受欢迎且广泛应用于这种常见且难以治疗的癫痫类型的啮齿动物模型。在该模型中，使用拟胆碱能致惊厥剂匹鲁卡品诱导癫痫持续状态，随后出现海马损伤和自发性反复发作。在大鼠中，匹鲁卡品单独或与锂联合使用，这可以显著减少诱导癫痫持续状态所需的匹鲁卡品剂量，并导致更高比例的动物发生癫痫持续状态。在小鼠中，锂很少与匹鲁卡品联合使用，这促使我们在该物种中直接比较匹鲁卡品和锂匹鲁卡品模型。与大鼠相反，在小鼠中预先用锂处理并没有增强匹鲁卡品的惊厥作用。在经历癫痫持续状态的小鼠中观察到的行为变化序列与单独给予匹鲁卡品非常相似。所有存活癫痫持续状态的小鼠均发展为具有自发性反复发作的癫痫。癫痫小鼠表现出明显的焦虑相关行为增加和学习记忆受损。癫痫持续状态引起的神经元损伤在锂匹鲁卡品和匹鲁卡品模型中基本相似，其特征是海马结构中严重的神经退行性变，类似于内侧颞叶癫痫的海马硬化。匹鲁卡品或锂匹鲁卡品未诱导癫痫持续状态但仅引起单次短暂发作的小鼠在行为、空间学习或海马组织学方面与对照组没有任何显著差异。我们的数据表明，匹鲁卡品和锂匹鲁卡品在小鼠中产生的综合征在行为和神经病理学上是无法区分的，并且这两种模型都可以用于研究发作、神经元损伤和精神病理学之间的关系。
