Sustained Inhibition of GABA-AT by OV329 Enhances Neuronal Inhibition and Prevents Development of Benzodiazepine Refractory Seizures

Abstract

γ-Aminobutyric acid (GABA) is the principal inhibitory neurotransmitter in the adult brain which mediates its rapid effects on neuronal excitability via ionotropic GABA_A 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.

Keywords: EEG; GABA; GABA-AT; OV329; seizure; tonic inhibition.