Abstracts

Rationale: Brivaracetam (BRV) is a promising new antiepileptic drug candidate with high and selective affinity for the synaptic vesicle 2A protein. Previous studies in animal models of partial epilepsy have shown that this correlates to potent and complete seizure suppression against electrical stimulation of naive and fully kindled animals. This includes protective activity against 6Hz seizures in mice, phenytoin-resistant seizures in fully amygdala-kindled mice and protection against seizures in fully amygdala-kindled rats, induced by either threshold or supramaximal stimulation. Systemic administration of the chemoconvulsants pilocarpine and kainic acid to rodents is also known to induce a seizure phenomenology consisting of focal onset followed by secondary generalization of the seizure activity. For that reason we explored if the consistent and significant seizure protection reported with BRV in animal models of partial epilepsy also extend to protection against partial seizures induced by pilocarpine and kainic acid in rats. Methods: Male Sprague Dawley rats (200-300g) were used. Methylscopolamine (1 mg/kg sc) was administered 30 min prior to co-administration of vehicle or BRV (0.2-212 mg/kg ip) and a CD97 dose of pilocarpine (375 mg/kg ip), inducing secondarily generalized seizures (stage 3-5 on the Racine scale) in vehicle treated animals. This was followed by behavioral observation for convulsive behavior of the animals for 120 min and scored according to the Racine scale. BRV (2-212 mg/kg ip) or vehicle was also co-administered with a CD97 dose of kainic acid (13.2 mg/kg sc) inducing stage 4 and 5 Racine scale seizures in vehicle treated animals. This was followed by behavioral observation for convulsive behavior of the animals for 180 min and scored according to the Racine scale. Results: BRV significantly reduced the severity of pilocarpine-induced seizures in rats. The minimum active dose of BRV inducing significant protection against secondarily generalized (stage 3-5) pilocarpine seizures was 2 mg/kg. BRV also significantly reduced the severity of kainic acid-induced seizures. In this more drug-resistant model, the minimum active dose of BRV inducing significant protection against stage 4 and 5 seizures kainic acid seizures was 68 mg/kg. Conclusions: Various studies have shown a potent and complete seizure suppression by BRV in animal models of partial epilepsy, including significant protection against drug resistant seizures. The present results confirm these findings by showing a potent ability of BRV to suppress pilocarpine-induced partial seizures in rats and more drug resistant partial seizures in rats, induced by kainic acid. This supports a promising therapeutic potential of brivaracetam for the treatment of drug refractory partial seizures in epilepsy patients. This study was funded by UCB Pharma.