Rationale:
Reductions of GABA-mediated inhibitory signaling have been associated with seizures and epilepsy. One route to increase GABAergic neurotransmission is the inhibition of GABA-amino transferase (GABA-AT), the primary catabolic enzyme of GABA. OV329 is a highly potent mechanism-based GABA-AT inhibitor, that increases levels of GABA within the CNS, reduces seizures in a series of drug-resistant seizure models and is currently being evaluated in a Phase I safety and tolerability study. In this report, OV329 was evaluated in the intra-amygdala kainate (IAK) model of mesial temporal lobe epilepsy (MTLE), a model for drug resistant seizures and disease prevention/modification. IAK is potentially a more severe model of status epilepticus (SE) compared to the intrahippocampal kainate (IHK) model and is more appropriate for assessing antiepileptogenic drug activity.
Methods:
Animals received an implanted EEG electrode within the right dorsal CA1 region of the hippocampus. After a ~3-day recovery period, injury was induced by infusion of a kainate (KA)/saline solution (260 nL, 1.5 mg/ml) in the basolateral amygdala. Vehicle (Veh) or OV329 (40 mg/kg) was administered p.o. 1 hr post-induction of SE as determined by video-EEG. On the seventh day following KA administration, continuous video-EEG recordings for 36 days (~5 weeks) for all animals was initiated. A subset of animals was also evaluated during days 50 – 65 (weeks eight to nine). Seizure frequency, duration, latent period, and severity (Racine score) were evaluated by a blinded observer.
Results:
Across two independent studies following the same protocol, 64% mice in the Veh group (27 of 42) and 42% mice in the OV329 (13 of 31) treated group had at least one seizure at any point during the study. The seizure freedom differences between groups at week five was not significant (p = 0.0952; Fisher’s exact test). At nine weeks after treatment, 80% of Veh (20 of 25) treated animals compared to 50% (9 of 18) of OV329 had at least one seizure (p = 0.0524; Fisher’s exact test). There was no significant reduction in seizure duration, frequency, or severity with OV329 when compared to Veh, however a trend in improvement in seizure freedom over time was observed with OV329 for both the five week and nine week assessments (p = 0.0603 or p = 0.0615 respectively; Mantel-Cox test).
Conclusions:
Results from studies in the IAK model suggest OV329 has potential antiepileptogenic activity following a single dose of 40 mg/kg as far out as nine weeks after treatment. In a previously executed IHK model of MTLE, OV329 was effective at reducing seizures following repeated, low dosing (3.0 mg/kg/day) over eight days. Therefore, evaluating a repeat dosing strategy to control the generation of seizures in the IAK model may lead to a meaningful outcome.
Funding:
These data were generated in whole by the Epilepsy Therapy Screening Program (ETSP), NINDS, National Institutes of Health.