Brivaracetam Modulates Short-Term Synaptic Activity and Low-Frequency Spontaneous Brain Activity by Delaying Synaptic Vesicle Recycling in Two Distinct Rodent Models of Epileptic Seizures.

ABSTRACT

Brivaracetam (BRV) is an anti-seizure drug for the treatment of focal and generalized epileptic seizures shown to augment short-term synaptic fatigue by slowing down synaptic vesicle recycling rates in control animals. In this study, we sought to investigate whether altered short-term synaptic activities could be a pathological hallmark during the interictal periods of epileptic seizures in two well-established rodent models, as well as to reveal BRV's therapeutic roles in altered short-term synaptic activities and low-frequency band spontaneous brain hyperactivity in these models. In our study, the electrophysiological field excitatory post-synaptic potential (fEPSP) recordings were performed in rat hippocampal brain slices from the CA1 region by stimulation of the Schaffer collateral/commissural pathway with or without BRV (30 µM for 3 h) in control or epileptic seizure (induced by pilocarpine (PILO) or high potassium (h-K+)) models. Short-term synaptic activities were induced by 5, 10, 20, and 40-Hz stimulation sequences. The effects of BRV on pre-synaptic vesicle mobilization were visually assessed by staining the synaptic vesicles with FM1-43 dye followed by imaging with a two-photon microscope. In the fEPSP measurements, short-term synaptic fatigue was found in the control group, while short-term synaptic potentiation (STP) was detected in both PILO and h-K+ models. STP was decreased after the slices were treated with BRV (30 µM) for 3 h. BRV also exhibited its therapeutic benefits by decreasing abnormal peak power (frequency range of 8-13 Hz, 31% of variation for PILO model, 25% of variation for h-K+ model) and trough power (frequency range of 1-4 Hz, 66% of variation for PILO model, 49% of variation for h-K+ model), and FM1-43 stained synaptic vesicle mobility (64% of the variation for PILO model, 45% of the variation for h-K+ model) in these epileptic seizure models. To the best of our knowledge, this was the first report that BRV decreased the STP and abnormal low-frequency brain activities during the interictal phase of epileptic seizures by slowing down the mobilization of synaptic vesicles in two rodent models. These mechanistic findings would greatly advance our understanding of BRV's pharmacological role in pathomechanisms of epileptic seizures and its treatment strategy optimization to avoid or minimize BRV-induced possible adverse side reactions.