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

Abstract

Brivaracetam (BRV) is a selective, high-affinity ligand for synaptic vesicle protein 2A (SV2A), recently approved as adjunctive treatment for drug-refractory partial-onset seizures in adults. BRV binds SV2A with higher affinity than levetiracetam (LEV), and was shown to have a differential interaction with SV2A. Because LEV was reported to interact with multiple excitatory and inhibitory ligand-gated ion channels and that may impact its pharmacological profile, we were interested in determining whether BRV directly modulates inhibitory and excitatory ionotropic receptors in central neurons. Voltage-clamp experiments were performed in primary cultures of mouse hippocampal neurons. At a supratherapeutic concentration of 100 μm, BRV was devoid of any direct effect on currents gated by γ-aminobutyric acidergic type A, glycine, kainate, N-methyl-d-aspartate, and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid. Similarly to LEV, BRV reveals a potent ability to oppose the action of negative modulators on the inhibitory receptors. In conclusion, these results show that BRV contrasts with LEV by not displaying any direct action on inhibitory or excitatory postsynaptic ligand-gated receptors at therapeutic concentrations and thereby support BRV's role as a selective SV2A ligand. These findings add further evidence to the validity of SV2A as a relevant antiepileptic drug target and emphasize the potential for exploring further presynaptic mechanisms as a novel approach to antiepileptic drug discovery.

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

“…Subjects received a single oral dose of CBZ, BRV, or TGB in a double‐blinded, randomized, placebo‐controlled crossover design. The study was exploratory but, given the previous pharmaco‐TMS‐EEG data, we expected suppression of the P180 under CBZ and, possibly, an increase of N45 under BRV, although the detailed modes of action of BRV and levetiracetam are different, with levetiracetam but not BRV showing relevant inhibitory action on glutamatergic neurotransmission through AMPA and NMDA receptors (Lee, Chen, & Liou, ; Niespodziany et al, ).…”

Mechanisms Underlying Aggressive Behavior Induced by Antiepileptic Drugs: Focus on Topiramate, Levetiracetam, and Perampanel

“…The high rate of AB with LEV may not necessarily be related to SV2A, since it has been suggested that BRV, which has a 15–30 times higher affinity to SV2A than LEV, is associated with a lower incidence of AB than LEV [6, 22, 23, 95]. Interestingly, it seems that BRV does not modulate NMDA, AMPA, or kainate receptors [96, 97]. These findings suggest that LEV's negative modulating effect on AMPA receptors contributes to increased AB.…”

BRIVA-LIFE-A multicenter retrospective study of the long-term use of brivaracetam in clinical practice

“…This group carries the major burden of epilepsy, with increased rates of cognitive and behavioral problems, comorbidities, and reduced quality of life. [3][4][5] This mechanistic divergence between the two may explain the differences in outcomes observed in clinical trials. 2 The two AEDs bind to different sites on SV2A, and at therapeutically relevant concentrations, BRV has no effect on ligand-gated receptors or voltage-gated potassium and calcium channels.…”

“…2 The two AEDs bind to different sites on SV2A, and at therapeutically relevant concentrations, BRV has no effect on ligand-gated receptors or voltage-gated potassium and calcium channels. [3][4][5] This mechanistic divergence between the two may explain the differences in outcomes observed in clinical trials.…”