Abstract
The aim of epilepsy models is to investigate disease ontogenesis and therapeutic interventions in a consistent and prospective manner. The kainic acid-induced status epilepticus (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 (p < 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 (p < 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.
Highlights
Animal models are very important for biomedical researchers to investigate disease ontogenesis or to evaluate pharmacological interventions
Following Hellier protocol, all Sprague-Dawley rats from the Harlan Laboratories (SD/H) rats went into status epilepticus (SE) for at least 4 h without any mortality, and only 1/15 animal did not recover from the SE and died 2 days post-SE (7% mortality) (Figure 2A)
The considerable mortality associated with the Hellier protocol in the WH/CR rats underlines the need for a different SE induction protocol in this strain
Summary
Animal models are very important for biomedical researchers to investigate disease ontogenesis or to evaluate pharmacological interventions. Chronic epilepsy models with high etiological relevance, such as the status epilepticus (SE), febrile seizure, and traumatic brain injury models, have played an important role in disentangling the pathophysiological processes involved in human epilepsy [1, 3,4,5]. The advantage of these chronic models is that they enable to study epileptogenesis in a consistent and prospective manner, which is almost impossible to accomplish in patients due to heterogeneity of disease ontogenesis and interfering factors, such as antiepileptic medication, during clinical studies. In the KASE rat model of TLE, a high proportion of animals is characterized by a histological pattern similar to type 1 HS in patients [13]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
