Abstracts

Rationale: Brivaracetam (BRV) is a pyrrolidone derivative, with a 20 fold greater affinity for synaptic vesicle protein 2A (SV2A) compared to levetiracetam (LEV). Previously, we demonstrated that both BRV and LEV decrease synaptic transmission in a dose-, time-, and stimulation frequency-dependent manner. In the present study, we investigated whether the effect of BRV on synaptic transmission is more potent and fast acting compared to LEV.Methods: Hippocampal slices (500 m, 3-4 week old SD rats) were cut and maintained in an incubation chamber with either artificial cerebrospinal fluid (ACSF), BRV (0.1, 1, 10, and 30 M ) or LEV (30, 100, 300 M, and 1 mM) for 30 minutes or 3 hrs. Then slices were moved into a submerged perfusion recording chamber for electrophysiology experiments. After 5 minutes of ACSF perfusion to remove the drugs from the recording chamber, three train stimulations (20 pulses at 40 Hz, each 6 minutes apart) were delivered to the Schaffer collateral fibers, and recordings were made from the dendritic layer of CA1. Statistical analyses were performed using two-way repeated-measures ANOVA.Results: Slices incubated in BRV (1, 10, and 30 M) or LEV (30, 100, 300 M, and 1 mM) for 3 hrs showed significant reduction in late synaptic potentials in response to 40 Hz train stimulation compared to control (30 M LEV vs Control p=0.047, all other concentrations vs control p<0.01, ED50 LEV = 45 M, ED50 BRV = 0.5 M). For 30 M BRV and 300 M.LEV, the responses to the 20th pulses were 41% and 54% of the non-drug value, respectively. To determine how quickly the drugs acted, the loading times were systematically varied, from 5 min to 3 hr for the maximally potent concentrations. Synaptic depression increased progressively with longer passive loading times. The degree of synaptic depression became significant for 30 M BRV loaded for 30 min or more and for 1mM LEV loaded for 60 min or longer. Conclusions: Our data suggest that BRV is faster acting and more potent than LEV at decreasing synaptic transmission.