Rationale: Infantile spasms (IS) is a devastating epileptic disorder characterized by brief flexion seizures which typically evolve into severe pharmacoresistant epilepsy. Adrenocorticotropic hormone (ACTH) and vigabatrin (VGB) are the standard of care for treating IS but both have potentially serious adverse effects. OV329, (1), is a novel, potent inactivator of GABA aminotransferase (GABA-AT) under development for the treatment of drug-resistant seizures. In this study, we tested the efficacy of OV329 in controlling seizures and compared its anti-seizure effects to those of ACTH.
Methods:
Flexion seizures: We employed a well characterized N-methyl-D-aspartate (NMDA) mouse model of IS. Mouse pups at P13 were injected with OV329 (at 0.025, 0.01 0.1, 1.0 mg/kg), ACTH (100 IU/kg), or vehicle 30 mins prior to intra-peritoneal (i.p.) injection of NMDA. Mice were then monitored for seizures for 45 minutes.
Behavior: Open field and rotarod testing was performed on days 3, 7, and 14 post-NMDA injection.
Electrophysiology: GABAergic miniature post synaptic inhibitory currents (mIPSCs) and tonic currents were recorded in hippocampal neurons 18-21 days in vitro (DIV) with and without OV329 using patch-clamp electrophysiology.
Results: OV329-treated mice at all doses had a significant decrease in overall seizure severity following NMDA injections. The decrease in seizure severity also corresponded to a reduced death rate. OV329 was highly effective at delaying the onset of NMDA-induced flexion seizures and reduced the total number of flexion seizures during the observation period. In behavioral assays, no differences in latency to fall and spontaneous locomotion were observed in any OV329 treatment groups at all doses compared to vehicle-treated mice. However, the ACTH-treated mice showed a decrease latency to fall and hyperactivity. In electrophysiology experiments, OV329 application for 10 min did not alter mIPSC amplitude, decay or frequency but did significantly increase the amplitude of tonic current.
Conclusions: Flexion seizures is the characteristic phenotype of infantile spasms. Our model demonstrated that OV329 was highly effective in reducing both the latency to first flexion seizure and the total number of flexion seizures. In contrast, ACTH was less effective than OV329 and also had deleterious effects on motor coordination and hyperactivity lasting for several days. Our electrophysiology data suggest that OV329’s inhibition of GABA-AT does not affect properties of GABAergic synapses. Instead, OV329 elevates levels of tonic inhibition. In conclusion, these data indicate that OV329 could be a promising drug to treat IS.
- Juncosa JI, et al. J Am Chem Soc. 2018;140(6):2151-64.
Funding: Please list any funding that was received in support of this abstract.: This study was funded by Ovid Therapeutics Inc and NIH NINDS (NS108378, NS111064, NS111338).