RT Journal Article
SR Electronic
T1 Sustained Inhibition of GABA-AT by OV329 Enhances Neuronal Inhibition and Prevents Development of Benzodiazepine Refractory Seizures
JF eneuro
JO eNeuro
FD Society for Neuroscience
SP ENEURO.0137-24.2024
DO 10.1523/ENEURO.0137-24.2024
VO 11
IS 7
A1 Colmers, Phillip L. W.
A1 Arshad, Muhammad Nauman
A1 Mukherjee, Jayanta
A1 Lin, Shinghong
A1 Ng, Shu Fun Josephine
A1 Sarmiere, Patrick
A1 Davies, Paul A.
A1 Moss, Stephen J.
YR 2024
UL http://www.eneuro.org/content/11/7/ENEURO.0137-24.2024.abstract
AB γ-Aminobutyric acid (GABA) is the principal inhibitory neurotransmitter in the adult brain which mediates its rapid effects on neuronal excitability via ionotropic GABAA receptors. GABA levels in the brain are critically dependent upon GABA-aminotransferase (GABA-AT) which promotes its degradation. Vigabatrin, a low-affinity GABA-AT inhibitor, exhibits anticonvulsant efficacy, but its use is limited due to cumulative ocular toxicity. OV329 is a rationally designed, next-generation GABA-AT inhibitor with enhanced potency. We demonstrate that sustained exposure to OV329 in mice reduces GABA-AT activity and subsequently elevates GABA levels in the brain. Parallel increases in the efficacy of GABAergic inhibition were evident, together with elevations in electroencephalographic delta power. Consistent with this, OV329 exposure reduced the severity of status epilepticus and the development of benzodiazepine refractory seizures. Thus, OV329 may be of utility in treating seizure disorders and associated pathologies that result from neuronal hyperexcitability.