Abstracts

Rationale: One in every three patients with epilepsy do not have full control of their seizures on their current antiseizure drug (ASD) regimen. Thus, new drugs are required to treat this refractory population. The majority of models used to evaluate new pharmacological compounds for the treatment of epilepsy rely on single, acutely-induced seizures. A screening platform that relies on a pharmacological compound's ability to control spontaneous, convulsive seizures in a chronically epileptic animal may better differentiate between drugs with superior efficacy to currently available ASDs when administered in a clinical setting. Additionally, a model in which multiple clinically-available ASDs do not provide full seizure control can be classified as a model of pharmacoresistance. However, the rapid screening approach described here must be characterized using prototype ASDs before it can be used for differentiating potential new therapies. Methods: A cohort of animals were treated with a repeated low-dose kainic acid paradigm to induce status epilepticus (SE). During the subsequent twelve weeks, a majority of rats developed spontaneous recurrent seizures as a result of the SE insult. Following implantation with a Millar wireless telemetry device, animals were placed in a 24/7 video-EEG recording suite and evaluated; rats with the highest seizure rates (n=12) were selected to enter the study. A baseline seizure rate was recorded during the first week. Following, we utilized a crossover design wherein half of the animals (n=6) received drug via intraperitoneal injections for five days, and the other half (n=6) received vehicle injections for five days. Injections were performed two or three times daily, based on the pharmacokinetic profile of the drug. Following a two day washout period, animals received the opposing treatment arm for the following five days. Following an additional washout period of two days, the crossover paradigm was repeated, starting with a baseline evaluation period. Video-EEG data was evaluated using a seizure detection algorithm and behavioral seizure scoring using a modified Racine scale. Outcome measures included seizure frequency and severity compared to baseline seizure rates. Results: Carbamazepine (CBZ, 90mg/kg/day), levetiracetam (LEV, 300mg/kg/day), valproic acid (VPA, 600mg/kg/day), and lamotrigine (LTG, 60mg/kg/day) were evaluated in this model. Treatment with CBZ and LEV demonstrated a reduction in seizure frequency compared to vehicle (p < 0.05, student's t-test), whereas LTG and VPA did not. Conclusions: The ultimate goal of this project is to characterize a novel screening method for testing new ASDs that have previously demonstrated favorable efficacy in acute seizure models. This new test will be added to the Anticonvusant Drug Development Program's testing procedures, as overseen by the Epilepsy Therapy Screening Program, as a late-stage evaluation of promising investigational compounds. Funding: NINDS: HHSN271201100029C