Abstracts

Rationale: More than one-third of the patients with mesial temporal lobe epilepsy remain resistant to anti-epileptic drugs, while about half experience common mild-to-moderate adverse effects such as ataxia, dizziness, sedation as well as motor incoordination. Hence, there is a strong need to develop and test novel anti-epileptic agents. The objective of this work is to evaluate the pharmacokinetics and neurological toxicity of E2730, a novel uncompetitive inhibitor of GABA transporter-1 (GAT-1), and to test its seizure suppression effects in a rat model of chronic drug resistant mesial temporal lobe epilepsy.

Methods: Control healthy Wistar rats were implanted with osmotic pumps delivering either 10, 20 or 100mg/kg/day of E2730 (n=4/group) subcutaneously for one week. Blood samples and behavioural assessments were performed at several timepoints to determine the drug levels in plasma, and to determine any adverse neurological effects such as sedation, ataxia or loss of muscle tone respectively. A subsequent cohort of rats (n=22) were exposed to kainic acid-induced status epilepticus, and 9 weeks later, were randomly assigned to either of the three doses of E2730 or vehicle. The rats were subjected to continuous video-EEG monitoring for one week, then the pumps were replaced by a different dose of the E2730 or vehicle (in randomised order) until each rat had received 4 x one-week treatment periods. The number of seizures recorded on EEG, the mean behavioural seizure class of the seizures and the proportion of animals rendered seizure free were compared between the treatment groups using repeated-measures ANOVA.

Results: Plasma levels following continuous infusion of E2730 showed a clear dose-related increase in the concentration. The drug was well-tolerated at all doses and any sedation or neuromotor impairments were very mild and short lasting, resolving completely within 48 hours of treatment initiation. E2730 treatment in chronically epileptic rats led to seizure suppression in a dose dependent manner, i.e. mean seizures per day following administration of vehicle, 10, 20 or 100mg/kg/day of E2730 = 4.8 ± 1.1, 3.1 ± 1.2, 1.8 ± 0.7, 0.5 ± 0.3(p=0.0006); % animals seizure free = 0%, 19%, 41%, 63% (p=0.0001). Mean seizure class did not differ between the treatment groups.

Conclusions: This study shows that continuous infusion of E2730 by osmotic pumps over 7 days results in a marked, dose dependant suppression of spontaneous recurrent seizures, without any remarkable neurological adverse effects, in a rat model of chronic drug resistant mesial temporal lobe epilepsy. E2730 shows strong promise as an effective new treatment to be translated into clinical trials.

Funding: Please list any funding that was received in support of this abstract.: This work was a research collaboration between Eisai and Monash University.