E2730, an uncompetitive gamma-aminobutyric acid transporter-1 inhibitor, suppresses epileptic seizures in a rat model of chronic mesial temporal lobe epilepsy
- Author(s)
- Ali, I; Silva, J; Casillas-Espinosa, PM; Braine, E; Yamakawa, GR; Hudson, MR; Brady, RD; Major, B; Thergarajan, P; Haskali, MB; Wright, DK; Jupp, B; Vivash, L; Shultz, SR; Mychasiuk, R; Kwan, P; Jones, NC; Fukushima, K; Sachdev, P; Cheng, JY; O'Brien, TJ;
- Details
- Publication Year 2023-10,Volume 64,Issue #10,Page 2806-2817
- Journal Title
- Epilepsia
- Publication Type
- Research article
- Abstract
- OBJECTIVE: More than one third of mesial temporal lobe epilepsy (MTLE) patients are resistant to current antiseizure medications (ASMs), and 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 gamma-aminobutyric acid transporter-1, and to test its seizure suppression effects in a rat model of chronic MTLE. METHODS: We 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 1 week. Blood sampling and behavioral 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 1 week in a randomized crossover design. Continuous video-electroencephalographic monitoring was acquired during the treatment period to evaluate epileptic seizures. RESULTS: Plasma 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 h 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. SIGNIFICANCE: This 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.
- Publisher
- Wiley
- Keywords
- Humans; Adult; Rats; Male; Animals; *Epilepsy, Temporal Lobe/chemically induced/drug therapy; Rats, Wistar; Seizures/drug therapy; *Epilepsy; Electroencephalography; gamma-Aminobutyric Acid; Disease Models, Animal; Hippocampus; GABA transporter-1; animal model; pharmacokinetics; temporal lobe epilepsy; video-EEG recordings
- Department(s)
- Cancer Imaging
- PubMed ID
- 37539645
- Publisher's Version
- https://doi.org/10.1111/epi.17735
- Open Access at Publisher's Site
https://doi.org/10.1111/epi.17735- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2023-10-25 06:29:56
Last Modified: 2023-10-25 06:33:22