Post-Kainic Acid Status Epilepticus-Induced Spontaneous Recurrent Seizures Model (rat)
The kainic acid-induced status epilepticus model in rats closely recapitulates many of the characteristics observed in humans with temporal lobe epilepsy, including occurrence of recurrent spontaneous seizures after a latent period.
Status epilepticus (SE; precipitating event) will be induced in adult male Sprague-Dawley CD rats (100-150 g) using a repeated low-dose kainic acid (KA) paradigm (Hellier et al., 1998). Rats will be injected intraperitoneally (IP) with an initial dose of 10 mg/kg KA (Tocris Bioscience, catalogue # 0222) to induce SE. If the animals do not develop a stage 4-5 seizure on Racine scale (Racine, 1972) within an hour, an additional dose of 5 mg/kg KA will be injected every 30 minutes until the onset of sustained generalized seizure activity (at least 2 Stage 4 or 5 seizures is observed within 30 minutes). At the conclusion of the SE monitoring period, rats will be given an injection of lactated Ringer’s solution subcutaneously to prevent dehydration and aid in recovery.
Rats will be assigned to treatment groups (investigational treatment or vehicle) following SE onset and animals will be closely monitored during the post-SE recovery and drug administration period for any signs of poor tolerance to the investigational drug, including changes in body condition score (BCS) and body weight post-SE. Any animal demonstrating poor grooming, BCS <2 for three or more days, or other overt signs of sickness or distress will be removed from the study. Approximately 3 weeks after KA-SE insult, animals will be implanted with cortical EEG recording electrodes and allowed to recover from surgery for 7 days. About 4 weeks post-SE insult, animals in each treatment group will be enrolled for continuous (24h /7d/wk) video-EEG monitoring for a 2-week-long monitoring session. In this approach, animals will complete monitoring by 6- to 8-weeks post-SE; a time in which spontaneous recurrent seizures should be well-established (Barker-Haliski, 2020). The video-EEG files will be manually reviewed by an experienced researcher blinded to treatment condition.
To evaluate the efficacy of an investigational drug/therapy to prevent development of epilepsy, the treatment will be initiated after the induction of SE (precipitating event) and before the appearance of spontaneous recurrent seizures (SRS). The primary outcome measured once the treatment is terminated will be occurrence/absence of SRS, but the effect on seizure burden and sensitivity of SRS to drugs that failed to treat it in prior trials may also be examined. To determine the efficacy of a test drug/therapy to modify the disease, the treatment will be initiated after the appearance of SRS and the outcomes measured following washout period will be the same as described above for the disease prevention paradigm. The exact treatment regimen (the time of the initiation and frequency and duration of the treatment) will be based on various factors such as the effective dose identified in prior studies, pharmacokinetics and mechanism of action, and may vary between the treatments.