Brivaracetam augments short‐term depression and slows vesicle recycling

Abstract

SUMMARYObjective: Brivaracetam (BRV) decreases seizure activity in a number of epilepsy models and binds to the synaptic vesicle glycoprotein 2A (SV2A) with a higher affinity than the antiepileptic drug levetiracetam (LEV). Experiments were performed to determine if BRV acted similarly to LEV to induce or augment short-term depression (STD) under high-frequency neuronal stimulation and slow synaptic vesicle recycling. Methods: Electrophysiologic field excitatory postsynaptic potential (fEPSP) recordings were made from CA1 synapses in rat hippocampal slices loaded with BRV or LEV during intrinsic activity or with BRV actively loaded during hypertonic stimulation. STD was examined in response to 5 or 40 Hz stimulus trains. Presynaptic release of FM1-43 was visualized using two-photon microscopy to assess drug effects upon synaptic vesicle mobilization. Results: When hippocampal slices were incubated in 0.1-30 lM BRV or 30 lM-1 mM LEV for 3 h, the relative CA1 field EPSPs decreased over the course of a high-frequency train of stimuli more than for control slices. This STD was frequency-and concentrationdependent, with BRV being 100-fold more potent than LEV. The extent of STD depended on the length of the incubation time for both drugs. Pretreatment with LEV occluded the effects of BRV. Repeated hypertonic sucrose treatments and train stimulation successfully unloaded BRV from recycling vesicles and reversed BRVs effects on STD, as previously reported for LEV. At their maximal concentrations, BRV slowed FM1-43 release to a greater extent than in slices loaded with LEV during prolonged stimulation. Significance: BRV, similar to LEV, entered into recycling synaptic vesicles and produced a frequency-dependent decrement of synaptic transmission at 100-fold lower concentrations than LEV. In addition, BRV slowed synaptic vesicle mobilization more effectively than LEV, suggesting that these drugs may modify multiple functions of the synaptic vesicle protein SV2A to curb synaptic transmission and limit epileptic activity. KEY WORDS: Antiepileptic drugs, Anticonvulsants, Epilepsy, Brivaracetam, Levetiracetam, SV2A, Synaptic vesicle recycling, Short-term depression.Brivaracetam (BRV) is an antiepileptic drug that recently showed positive outcome in phase III clinical trials for treatment of partial-onset seizures.1 BRV and the closely related compounds levetiracetam (LEV) and seletracetam (SEL) bind to synaptic vesicle glycoprotein 2A (SV2A), with BRV affinity about 20-fold greater than LEV.2,3 Several mechanisms have been proposed for the antiepileptic action of LEV, including interference with SV2A or blocking of calcium currents. 4 In contrast, BRV does not bind to calcium channels and its effect on sodium channels does not alter sustained activity.3,5

Brivaracetam does not modulate ionotropic channels activated by glutamate, γ‐aminobutyric acid, and glycine in hippocampal neurons

“…1 However, BRV displays a 15-30-fold higher affinity than LEV in binding to the native or recombinant SV2A protein 3 and was recently reported to also reveal a differential interaction to SV2A from LEV. 4 This correlates with previous findings showing BRV to possess a different pharmacological profile from LEV in preclinical seizure and epilepsy models consisting of both more potent and more complete seizure suppression. 4 This correlates with previous findings showing BRV to possess a different pharmacological profile from LEV in preclinical seizure and epilepsy models consisting of both more potent and more complete seizure suppression.…”

Effects of antiepileptic drugs on cortical excitability in humans: A TMS‐EMG and TMS‐EEG study

“…This effect may be explained by its specific binding to the presynaptic vesicle protein SV2A. This protein is expressed on excitatory and inhibitory neurons throughout the central nervous system (Klein et al, ), but BRV may exert its antiepileptic effects predominantly through depression of excitatory neurotransmission (Yang et al, ).The current BRV findings are in agreement with previous TMS‐EMG studies that reported a depression of MEP input–output curves under levetiracetam (Reis et al, ; Sohn, Kaelin‐Lang, Jung, & Hallett, ).…”

Progress report on new antiepileptic drugs: A summary of the Thirteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XIII)

“…Recent experiments with an SV2A allosteric modulator demonstrated that brivaracetam's interaction with SV2A differs from that of levetiracetam, likely inducing or stabilizing different SV2A protein conformations . This probably explains findings from electrophysiologic studies in rat hippocampal slices showing a superior ability of brivaracetam to inhibit synaptic transmission and vesicle release, which correlates with its distinct pharmacodynamic properties …”