Abstracts

Rationale: GABA is the major inhibitory neurotransmitter in the adult CNS, and reduced levels of GABA have been associated with neuronal hyperexcitability, which can lead to seizures and epilepsy. GABA is primarily catabolized by an enzyme known as GABA-amino transferase (GABA-AT). One approach to reduce seizures is by enhancing GABA levels within the CNS through inhibition of GABA-AT. Administration of OV329, a highly potent GABA-AT inhibitor, leads to increased levels of GABA via a mechanism similar to that of vigabatrin (VGB). We previously reported that acute administration of a single dose of OV329 (10mg/kg) significantly suppressed the number of focal seizures in the intrahippocampal kainate (IHK)-Mesial Temporal Lobe Epilepsy (MTLE) mouse model. We performed additional repeat-dosing experiments to assess the potential for efficacy of OV329 at lower doses. OV329 holds the potential to be a next-generation GABA-AT inhibitor with efficacy at a lower dose than VGB, which could result in a better safety profile._x000D_
Methods: MTLE was induced in mice (n=36) by stereotaxic injection of kainate (1 nM) into the right dorsal hippocampus, after which a bipolar electrode was implanted for EEG recording and measurement of hippocampal paroxysmal discharges (HPDs) in freely moving mice to monitor seizures. Four weeks after kainate injury animals were administered 0.3, 1, or 3 mg/kg OV329 or vehicle daily (PO) for 8 days. Mice receiving 1 mg/kg OV329 were crossed over from a group that previously received 0.3 mg/kg OV329 or vehicle followed by a washout period. To establish baseline, EEGs were recorded for 2 hours prior to OV329 administration and continued for ~4 hours following each dose. HPD numbers and duration were evaluated for each 30 min sampling period and reported for the last hour of recording (190-250 min).

Results: The once-daily 3 mg/kg dose of OV329 administered for 8 days significantly reduced the number of HPDs by day 4 with maximum reduction at day 8 compared to the baseline in the MTLE mouse model (70 ± 9% inhibition at day 8; p < 0.05). Changes in baseline ictal duration were observed following 3 mg/kg OV329 treatment, and these persisted for 7 days following the last administration. No effect was observed with repeat administration of either the 1.0 or 0.3 mg/kg dose.