Abstracts

Rationale: Padsevonil (PSL; UCB0942) is characterized by high affinity for the synaptic vesicle 2 proteins and moderate affinity for the benzodiazepine binding site on the GABAA receptor (Wood et al., AES 2017). It displayed potent anticonvulsant activity in a range of acute seizure models (Leclercq et al., AES 2017). The present work describes PSL’s activity in the rat and mouse amygdala kindling models. Additionally, effects of PSL in the mouse amygdala kindling model were compared with those of several antiepileptic drugs (AEDs) with different modes of action. Methods: A bipolar electrode was stereotactically implanted in the basolateral amygdala of male C57BL/6J mice and Sprague Dawley rats. Once-daily supra-threshold stimulations were initiated after recovery from surgery until the development of a fully kindled state (≥5 consecutive stage 5 seizures). Fully-kindled mice and rats were then injected (30 min pre-testing, ip) with different PSL doses to determine median seizure severity score (based on the Racine scale) and afterdischarge duration (EEG activity with an amplitude of at least twice the amplitude of the pre-stimulus recording and a frequency >1 Hz). ED50, the dose protecting 50% of animals against secondarily generalized seizures (stages 3-5), was then calculated for PSL in both models and for levetiracetam, brivaracetam (BRV), valproate (VPA), phenytoin, carbamazepine, lamotrigine, diazepam, topiramate, and retigabine in the mouse model only. Finally, TD50, the dose causing an impairment of motor performance in 50% of mice, was determined in the rotarod test. The therapeutic index (TI) – ratio between doses producing motor impairment (TD50) and doses providing protection (ED50) in mouse amygdala kindling – was calculated. Results: PSL dose-dependently protected both mice and rats against secondarily generalized seizures; complete protection was observed after the highest dose tested (Fig. A,B). Median seizure severity score was reduced in a dose-dependent manner (Fig. C,D). A statistically significant reduction in afterdischarge duration was noted, but this effect did not show clear dose-dependency (Fig. E,F). The ED50 of PSL was equal to 1.2 and 2.4 mg/kg in fully-kindled mice and rats, respectively. PSL displayed a relatively high TI (~10) in the mouse amygdala kindling model when compared with BRV (~3) or VPA (~1). Other AEDs tested in this model displayed only partial protection against generalized seizures and therefore it was not possible to calculate the TI for these compounds (Table). Conclusions: PSL displayed potent activity against fully-kindled seizures in both mice and rats: it afforded complete protection against secondarily generalized seizures and significant reduction in both seizure severity and afterdischarge duration. PSL also demonstrated a high TI in the mouse amygdala kindling model; other AEDs provided limited protection or showed poor separation between doses producing motor impairment and anticonvulsant efficacy. It remains to be established how these effects translate into therapeutic utility of PSL in patients with epilepsy. Funding: UCB Pharma-sponsored.