UCB Pharma, CNS Research, Braine-l'Alleud, Belgium.
Exp Neurol. 2012 Dec;238(2):156-67. doi: 10.1016/j.expneurol.2012.08.022. Epub 2012 Aug 28.
Temporal lobe epilepsy (TLE) is the most common form of drug-resistant epilepsy and several rodent models allow studying the pathophysiology of this disorder. One of the best characterized models of TLE is the pilocarpine model. The model has been widely used in rats, but relatively few studies report data obtained with mice. This triggered the present study to perform a comprehensive characterization of the mouse pilocarpine model. We used male NMRI mice (28-32 g) and first established the dose-response relationship for pilocarpine (250-400 mg/kg; ip) to induce status epilepticus (SE). This enabled to define the optimal dose (300 mg/kg) producing the highest SE response (50%) associated with the best survival rate of the animals (90%). The impact of different durations of SE (0.5-3.0 h) on the time to the onset of the first spontaneous recurrent seizures (SRS) was recorded during 5-day continuous video monitoring following the SE. Virtually no "latent" period was observed as the seizures appeared already within 24-48 h after the pilocarpine-induced SE and 0.5 h duration of the SE was sufficient to trigger SRS. Pharmacokinetics assessment showed that these seizures were not associated with residual pilocarpine exposure as it was cleared from the blood and brain already within 24 h post-injection. Consistent with previous reports from the rat pilocarpine model we observed that the extent of hippocampal reorganization and neuronal loss correlates with the duration of SE. However, the shorter durations of SE (0.5-2.0 h) appeared to produce cell loss restricted mainly to the hilus of the dentate gyrus. Interestingly, we also observed that the number of seizures occurring within 5 days after SE appeared to correlate with the degree of hippocampal damage. Continuous 7-week video-EEG monitoring after the SE revealed that SRS were expressed in a particular pattern of clusters. Taken together, the current study provides an in-depth characterization of the mouse pilocarpine model and confirms several features of the epileptogenesis process previously reported from the rat pilocarpine model. However, the mouse pilocarpine model differs by the rapid onset of seizures and an apparent correlation between their numbers and the degree of histopathological changes. Our findings highlight that the pilocarpine model of TLE in mice is associated with brain pathology akin to different stages of human disease and may provide a valuable tool for the discovery of future antiepileptic drugs with disease-modifying properties.
颞叶癫痫（TLE）是最常见的耐药性癫痫形式，几种啮齿动物模型允许研究这种疾病的病理生理学。TLE 的最佳特征模型之一是匹罗卡品模型。该模型已在大鼠中广泛使用，但相对较少的研究报告了使用小鼠获得的数据。这引发了本研究对小鼠匹罗卡品模型进行全面表征。我们使用雄性 NMRI 小鼠（28-32 克），首先建立了匹罗卡品（250-400mg/kg; ip）诱导癫痫持续状态（SE）的剂量反应关系。这使我们能够确定最佳剂量（300mg/kg），产生最高 SE 反应（50%），同时动物的存活率最高（90%）。在 SE 后连续 5 天进行视频监测期间，记录了不同 SE 持续时间（0.5-3.0 小时）对首次自发性复发性癫痫发作（SRS）发作时间的影响。实际上，没有观察到“潜伏期”，因为在匹罗卡品诱导的 SE 后 24-48 小时内已经出现癫痫发作，而 SE 持续 0.5 小时足以引发 SRS。药代动力学评估表明，这些发作与残留的匹罗卡品暴露无关，因为它在注射后 24 小时内已从血液和大脑中清除。与先前来自大鼠匹罗卡品模型的报告一致，我们观察到海马重构和神经元丢失的程度与 SE 的持续时间相关。然而，较短的 SE 持续时间（0.5-2.0 小时）似乎主要导致齿状回门区的细胞丢失。有趣的是，我们还观察到 SE 后 5 天内发生的癫痫发作次数似乎与海马损伤程度相关。SE 后连续 7 周的视频-EEG 监测显示，SRS 以特定的簇模式表达。总之，本研究对小鼠匹罗卡品模型进行了深入的表征，并证实了先前来自大鼠匹罗卡品模型的癫痫发生过程的几个特征。然而，与大鼠匹罗卡品模型相比，小鼠匹罗卡品模型的癫痫发作发作迅速，并且其数量与组织病理学变化程度之间似乎存在相关性。我们的研究结果表明，小鼠 TLE 的匹罗卡品模型与类似于人类疾病不同阶段的脑病理学相关，可能为发现具有疾病修饰特性的新型抗癫痫药物提供有价值的工具。
