Abstracts

Rationale: Repeated low-dose Kainic Acid (KA) treatment in rats is an established acquired epilepsy model of Temporal Lobe Epilepsy (TLE). This model is an integral end-stage differentiation model in the screening flow for assessing investigational compounds for the treatment of epilepsy in the Epilepsy Therapy Screening Program (ETSP). The University of Utah contract site for the ETSP utilizes this model to evaluate potential new therapies using sub-chronic administration for the treatment of epilepsy against this model of spontaneous recurrent seizures. Twelve animals with the most severe epilepsy following a 12-week period of epileptogenesis are selected for the screening experiments. Previous work by Williams et al. has characterized the progression of epilepsy in a repeated low-dose KA model (1). However, this seizure progression has never before been assessed in the animal cohorts utilized for the screening program.

Methods: Thirty rats were implanted with Kaha Telemeters to record EEGs. Rats were housed in a video-EEG (vEEG) suite for 24/7 monitoring immediately following surgery. After a week of recovery, rats were subjected to a low-dose KA treatment. Twenty-one animals (70%) survived the procedure. vEEG data was recorded continuously for 12 weeks. Seizures were first identified using an in-house Seizure Detection algorithm, and then a reviewer visually scored seizures on the Racine scale. Resulting data were analyzed in MATLAB. Average daily seizure burden (ADSB) is defined as the sum of Racine behavioral seizure scores divided by the length in days.

Results: The mean±s.e.m. latent period was 15.5±2.8 days, with a range of 2 to 59 days. The frequency and severity as measured by ADSB of seizures increased over the course of the study, as shown in Figure 1. Importantly, during the period which is used to evaluate animals for cohort generation for drug screening, i.e. the final two weeks of this study, the mean+s.e.m. ADSB was 3.1±0.5. The 12 animals selected to be used in the ETSP challenge had a mean+s.e.m. ADSB of 4.5±0.5.

Figure 1. ADSB over the course of the 12-week study. The red line represents a linear fit of the data. The linear regression demonstrates the increasing seizure burden over time.

Conclusions: This study characterized the period of epileptogenesis as part of the generation of a cohort for a series of studies on investigational compounds for the ETSP. Previously, the protocol for generating cohorts and the timeline for seizure development and progression was based on the literature and not assessed at the contract site. The observed increase in ADSB over time is consistent with prior published literature in this model (1), and confirms that waiting till at least 10 weeks following KA treatment before screening drugs is an appropriate experimental design.

1. Williams PA, et al. Development of spontaneous recurrent seizures after kainate-induced status epilepticus. J Neurosci. 2009;29(7):2103-12

Funding: Please list any funding that was received in support of this abstract.: National Institute of Neurological Disorders and Stroke, Epilepsy Therapy Screening Program, National Institutes of Health and Department of Health and Human Services, Contract No. HHSN271201600048C.