Abstracts

Rationale: The development of new and innovative antiepileptic medications with different mechanisms of action has been essential to treat the patients still experiencing seizures with the conventional treatments offered. Levetiracetam (LEV), and its newer analog Brivaracetam (BRV) are two such novel drugs targeting the synaptic vesicle protein 2A (SV2A) altering neurotransmitter release and resulting in seizure decrease. However, some psychiatric adverse effects have been reported in patients taking LEV. We hypothesize that BRV, a more potent and specific agonist will exert less behavioral side effects, as it acts through slightly different mechanisms than LEV while still achieving an effective anti-epileptic outcome. Methods: Injection of a single dose of Kainic Acid (KA) (12mg/kg, i.p.), given to half (n=107) of the male Sprague-Dawley rats at P60, induced development of spontaneous recurrent seizures (SRS) with time. One month later, using treatment with LEV (300mg/kg), BRV (30mg/kg) or Saline (i.p), followed an hour later by a series of behavioral tests, we measured the adverse behavioral effects of these anticonvulsants on locomotion, anxiety, memory, depression and social behaviors. Results: Our data demonstrate that both tested drugs exert similar effects in terms of locomotion, anxiety levels, fear learning, depression-like behavior and memory retention in our rats. However, when considering social interactions, as exhibited in the Resident-Intruder test where 2 male rats are put in contact and left to interact for 5 minutes, we first confirmed the epileptiform identity of our KA-Saline rats as they showed 9 times more aggressive behaviors than Sham-Saline rats (P=0.0004, n=12) on top of demonstrating specific neuro-anatomical modifications in the hippocampus. Looking at the Sham groups only, we furthermore observed that rats receiving LEV treatment were 2 times faster than Saline rats to attack at the first encounter (P=0.0075, n=12 in all groups), had 5 times more aggressive behaviors than Saline rats (P=0.0077) and had significantly less social behaviors than Saline rats (P=0.0161). On the other hand, in all cases BRV rats were not significantly different from Saline rats. Conclusions: These results suggest that BRV treatment in rats leads to less aggressive behaviors than LEV treatment at effective anti-epileptic therapeutic doses, while practically no differential effects are seen between these two drugs in other types of behaviors. Since cases of increased aggressiveness have been reported in patients taking LEV, BRV could potentially improve their quality of life. Funding: UCB Pharma