Bertoglio Daniele, Amhaoul Halima, Van Eetveldt Annemie, Houbrechts Ruben, Van De Vijver Sebastiaan, Ali Idrish, Dedeurwaerdere Stefanie
Department of Translational Neurosciences, University of Antwerp, Antwerp, Belgium.
Front Neurol. 2017 Nov 6;8:588. doi: 10.3389/fneur.2017.00588. eCollection 2017.
The aim of epilepsy models is to investigate disease ontogenesis and therapeutic interventions in a consistent and prospective manner. The kainic acid-induced (KASE) rat model is a widely used, well-validated model for temporal lobe epilepsy (TLE). As we noted significant variability within the model between labs potentially related to the rat strain used, we aimed to describe two variants of this model with diverging seizure phenotype and neuropathology. In addition, we evaluated two different protocols to induce status epilepticus (SE). Wistar Han (Charles River, France) and Sprague-Dawley (Harlan, The Netherlands) rats were subjected to KASE using the Hellier kainic acid (KA) and a modified injection scheme. Duration of SE and latent phase were characterized by video-electroencephalography (vEEG) in a subgroup of animals, while animals were sacrificed 1 week (subacute phase) and 12 weeks (chronic phase) post-SE. In the 12 weeks post-SE groups, seizures were monitored with vEEG. Neuronal loss (neuronal nuclei), microglial activation (OX-42 and translocator protein), and neurodegeneration (Fluorojade C) were assessed. First, the Hellier protocol caused very high mortality in WH/CR rats compared to SD/H animals. The modified protocol resulted in a similar SE severity for WH/CR and SD/H rats, but effectively improved survival rates. The latent phase was significantly shorter ( < 0.0001) in SD/H (median 8.3 days) animals compared to WH/CR (median 15.4 days). During the chronic phase, SD/H rats had more seizures/day compared to WH/CR animals ( < 0.01). However, neuronal degeneration and cell loss were overall more extensive in WH/CR than in SD/H rats; microglia activation was similar between the two strains 1 week post-SE, but higher in WH/CR rats 12 weeks post-SE. These neuropathological differences may be more related to the distinct neurotoxic effects of KA in the two rat strains than being the outcome of seizure burden itself. The divergences in disease progression and seizure outcome, in addition to the histopathological dissimilarities, further substantiate the existence of strain differences for the KASE rat model of TLE.
癫痫模型的目的是以一致且前瞻性的方式研究疾病的发生发展及治疗干预措施。海藻酸诱导的（KASE）大鼠模型是一种广泛应用且经过充分验证的颞叶癫痫（TLE）模型。由于我们注意到不同实验室使用该模型时存在显著差异，这可能与所用大鼠品系有关，因此我们旨在描述该模型的两种具有不同癫痫发作表型和神经病理学特征的变体。此外，我们评估了两种不同的诱导癫痫持续状态（SE）的方案。使用海利尔海藻酸（KA）和改良注射方案，对法国查尔斯河公司的Wistar Han大鼠和荷兰哈兰公司的Sprague-Dawley大鼠进行KASE造模。在一组动物中，通过视频脑电图（vEEG）对SE持续时间和潜伏期进行特征性分析，同时在SE后1周（亚急性期）和12周（慢性期）处死动物。在SE后12周的组中，用vEEG监测癫痫发作情况。评估神经元丢失（神经元核）、小胶质细胞激活（OX-42和转位蛋白）和神经退行性变（Fluorojade C）。首先，与SD/H动物相比，海利尔方案导致WH/CR大鼠的死亡率非常高。改良方案使WH/CR和SD/H大鼠的SE严重程度相似，但有效提高了存活率。与WH/CR（中位数15.4天）相比，SD/H（中位数8.3天）动物的潜伏期显著缩短（<0.0001）。在慢性期，与WH/CR动物相比，SD/H大鼠每天的癫痫发作次数更多（<0.01）。然而，总体而言，WH/CR大鼠的神经退行性变和细胞丢失比SD/H大鼠更广泛；在SE后1周，两种品系的小胶质细胞激活情况相似，但在SE后12周，WH/CR大鼠的小胶质细胞激活程度更高。这些神经病理学差异可能更多地与KA在两种大鼠品系中的不同神经毒性作用有关，而不是癫痫发作负担本身的结果。除了组织病理学差异外，疾病进展和癫痫发作结果的差异进一步证实了TLE的KASE大鼠模型存在品系差异。
