Abstracts

Rationale: Brivaracetam (BRV), currently in Phase III development for epilepsy, is a novel high-affinity synaptic vesicle protein 2A (SV2A) ligand also displaying inhibitory activity at neuronal voltage-dependent sodium channels. BRV has a 10-fold higher affinity for SV2A compared to levetiracetam (Keppra^®), which translates into a higher potency and efficacy in preclinical models of epilepsy. Levetiracetam has been shown not to alter cognitive processes both in preclinical experiments (Lamberty et al. 2000) and clinical trials (Mintz et al. 2007). The purpose of this study was to assess learning performance of rats following treatment with BRV in a model of spatial memory. Methods: The Morris water maze test was used to study spatial memory abilities of male Sprague-Dawley rats (200-300 g, 7 week old). The Morris water maze is a hippocampus-dependent learning task in which rats have to find an escape platform hidden 0.5 cm below the water surface of a 140 cm diameter swimming pool. We used the ‘place-learning’ version in which the platform remains fixed throughout the acquisition phase. The experimental procedure was organized into 4 sessions of 3 consecutive swimming trials. The sessions were run at 24-hr intervals, each trial lasting up to 120 sec. At 24 hr after the last session, a ‘probe test’ was applied, which consisted of 2 consecutive trials lasting 60 sec each, during which the platform was removed from the water. Latency to reach the platform, distance swum and time spent in each of the quadrants were recorded during each session and statistically analyzed by means of 2-way analysis of variance (ANOVA). BRV, or sodium valproate (VPA), was administered daily (i.p. adm) 60 min prior the start of a session. BRV was administered at 2.1, 6.8 and 21 mg/kg, i.e. at doses which produced higher plasma concentrations than those required for its antiepileptic activity in humans (Laveille et al., 2007). Results: Following BRV administration (2.1-21 mg/kg), latency and distance swum to reach the platform decreased in the course of successive sessions, in ways similar to control rats. The time spent in the target quadrant increased over time and reached 50% of the time during the fifth session (probe test). No statistical difference was noted between controls and BRV-treated groups indicating that both groups were equally able to perform the spatial learning task. By contrast, in comparison to control rats, VPA (300 mg/kg) increased latency time and distance swum to reach the platform over the sessions as well as decreased the time spent in the target quadrant during the probe test. This confirms that the test conditions were sensitive to antiepileptic drug-induced cognitive impairment. Conclusions: BRV does not negatively impact normal cognitive function of rats tested for place-learning in the Morris water maze.