EILAT XVII

Several unmet clinical needs remain, including resistance to anti-seizure medications (ASM) in 30% of epileptic patients.

Preclinical models play an important role in the early discovery of new therapies for the symptomatic treatment of epilepsy.

The rat amygdala-kindling model remains one of the few chronic models available to study epilepsy development. It consists in repetitive subconvulsive electrical stimulations that elicit gradual and progressive enhancement of neuronal activity and behavioral responses, culminating in generalized seizures.

This model is highly predictive for detecting effective drugs acting on seizure propagation, from the initial focal seizure to the secondarily generalized convulsive seizure.

This study was designed to assess the pharmacological profile of different types of ASM in this model. Sprague Dawley rats were chronically implanted with electrodes in the basolateral amygdala (BLA), parietal and prefrontal cortex. The progression of epileptic activity was evaluated in freely moving rats through electroencephalogram (EEG) recordings, accompanied with synchronized video recordings.

Afterdischarges (AD) were defined as spikes and spike-waves appearing in the EEG signal in response to the stimulation. First, we applied a stimulation to determine the AD threshold (ADT) for each rat which is the minimum current intensity needed to evoke an AD. Once ADT was established, the kindling protocol was delivered once a day until the animal reach a stage 5 on Racine’s scale for 3 consecutive days.

Kindled rats were alternately treated with ASM (or respective vehicles): diazepam, ethosuximide, carbamazepine, retigabine and levetiracetam. Differential pharmacological responses were observed, for instance, diazepam at 3 mg/kg produced seizure control as measured by a reduction in motor components of the seizure and a reduction in afterdischarge duration (ADD). Conversely, ethosuximide at 100 mg/kg did not show any effect on motor components of the seizure nor on ADD. We reported distinct effects between focal and cortical EEG responses for the remaining three ASMs, which will be described in further detail in the results section.

This study was intended to highlight translational aspects of the rat amygdala-kindling model to identify new entities with improved tolerability and efficacy on focal and generalized seizures. The combination of this model and a cross-over design will provide a decision-enabling screening platform for the identification of novel compounds for the prevention, treatment, and modification of epilepsy, wherein pharmacoresistant focal seizures constitute the greatest challenge for treatment.