E2730, an uncompetitive γ‐aminobutyric acid transporter‐1 inhibitor, suppresses epileptic seizures in a rat model of chronic mesial temporal lobe epilepsy

Abstract

ObjectiveMore than one‐third of mesial temporal lobe epilepsy (MTLE) patients are resistant to current anti‐seizure medications (ASMs), while half experience mild‐to‐moderate adverse effects of ASMs. There is therefore a strong need to develop and test novel ASMs. 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 chronic rat model of MTLE.MethodsWe first examined plasma levels and adverse neurological effects of E2730 in healthy Wistar rats. Adult male rats were implanted with osmotic pumps delivering either 10, 20 or 100 mg/kg/day of E2730 subcutaneously for one week. Blood sampling and behavioural assessments were performed at several timepoints. We next examined whether E2730 suppressed seizures in rats with chronic MTLE. These rats were exposed to kainic acid‐induced status epilepticus, and 9 weeks later when chronic epilepsy was established, were assigned to receive one of the three doses of E2730 or vehicle for a week in a randomised cross‐over design. Continuous video‐EEG monitoring was acquired during the treatment period to evaluate epileptic seizures.ResultsPlasma levels following continuous infusion of E2730 showed a clear dose‐related increase in concentration. The drug was well‐tolerated at all doses and any sedation or neuromotor impairment was mild and transient, resolving within 48 hours of treatment initiation. Remarkably, E2730 treatment in chronically epileptic rats led to seizure suppression in a dose‐dependent manner with 65% of rats becoming seizure‐free at the highest dose tested. Mean seizure class did not differ between the treatment groups.SignificanceThis study shows that continuous subcutaneous infusion of E2730 over 7 days results in a marked, dose‐dependent suppression of spontaneous recurrent seizures, with minimal adverse neurological effects, in a rat model of chronic MTLE. E2730 shows strong promise as an effective new ASM to be translated into clinical trials.