Abstracts

Rationale: γ-aminobutyric acid (GABA) is a major inhibitory neurotransmitter in the central nervous system (CNS) and is primarily catabolized by GABA-AT. In patients with epilepsy, reduced CNS GABA levels are associated with poor seizure control. Increasing GABA levels through GABA-AT inhibition may improve seizure control. Currently, Vigabatrin (VGB) is the only FDA-approved drug employing GABA-AT inhibition as a primary mechanism of action with proven efficacy in seizure reduction. However, clinical use of VGB in epilepsy is associated with retinal damage in chronically treated patients [1, 2].

OV329 is a novel, potent inactivator of GABA-AT [3] under development for the treatment of drug-resistant epilepsy. OV329 activity was assessed following single dose administration in a mouse MTLE model of focal seizure where VGB also improves seizure control [4].

Methods: To induce seizures, mice were injected with kainate in the right dorsal hippocampus using stereotaxic techniques. After injection, the cannula was removed and replaced with a bipolar electrode to record electroencephalography (EEG) in freely moving mice. Following injury, epileptogenesis developed for 4-weeks. Mice exhibiting a hippocampal paroxysmal discharge (HPD) rate above 20 discharges/hour but without any generalized discharges during the validation recording [4], were selected for randomization and enrolled in a cross-over protocol. A single dose of OV329 was administered orally (p.o.; 0.01, 0.1, 1.0 or 10 mg/kg) or intraperitoneally (i.p.; 10 mg/kg). Vehicle control (VC; p.o.) and VGB (100 mg/kg; i.p.) served as controls.

The number and cumulative duration of HPD for each animal was determined using recorded EEGs during a 30-min baseline period (immediately before compound administration), and for 220 min after compound administration. Change from baseline in HPD number and duration were evaluated for each 30 min interval during recording and for the last hour of recording.

Results: No significant suppression of HPDs was observed with VC (n =11), 0.01 (n = 6), 0.1 mg/kg (n = 6), or 1.0 mg/kg (n = 11) OV329 dose levels. OV329 at the 10 mg/kg dose level (p.o., n = 11; i.p., n = 9) and VGB (n = 11), suppressed both number and cumulative duration of HPDs beginning at approximately 2 hr after administration and continuing through the duration of recording (+250 min). Compared to VC, the number of HPDs during the last hour of recording (percent change from baseline) was significantly different for VGB (p < 0.0001) and for 10 mg/kg OV329 (p.o., p < 0.05; i.p., p < 0.01).