Evidence for a differential interaction of brivaracetam and levetiracetam with the synaptic vesicle 2A protein

Abstract

SUMMARYObjective: Brivaracetam (BRV) and levetiracetam (LEV) are effective antiepileptic drugs that bind selectively to the synaptic vesicle 2A (SV2A) protein. However, BRV differs from LEV in that it exhibits more potent and complete seizure suppression in animal models including in amygdala-kindled mice, where BRV afforded nearly complete seizure suppression. This raises the possibility that aside from potency differences, BRV and LEV may interact differently with the SV2A protein, which is not apparent in radioligand-binding competition studies. In this study, we used a recently identified SV2A allosteric modulator, UCB1244283, that appears to induce conformational changes in SV2A, to probe the binding properties of labeled BRV and LEV. The synaptic vesicle 2A (SV2A) protein is an integral transmembrane glycoprotein expressed in neurons and endocrine cells, where it specifically localizes to secretory vesicles.1,2 It is notable that the SV2A protein was shown to bind the antiepileptic drugs (AEDs) levetiracetam 3 (LEV) and brivaracetam 4 (BRV), and was also shown to be the molecular target of their anticonvulsant activity.5 A strong positive correlation has been demonstrated between anticonvulsant potency in animal models and SV2A binding affinity, [4][5][6] and seizure protection correlates with SV2A occupancy. 4 In addition, the anticonvulsant activity of LEV is reduced in SV2A-deficient animals. 6 It has also been shown that LEV reverses the synaptic deficits produced by overexpression of the SV2A protein.7 These data suggest that the incidence of seizures are affected by both increased and decreased expression of SV2A and are reduced by treatment with LEV. Although there is good evidence suggesting that the SV2A protein is the molecular target of action for the antiepileptic drugs BRV and LEV, little is known about the precise function of the SV2A protein or how these drugs may affect SV2A function.A recent review concluded that, although the SV2A protein is involved in normal synaptic vesicle function, its precise role remains unclear. 8 Experimental evidence suggests that the SV2A protein has a role in either regulating synaptic exocytosis or as a vesicular transporter. Different studies have shown that SV2A regulates neurotransmitter release,

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

“…Brivaracetam's binding affinity for SV2A is selective and approximately 15‐ to 30‐fold higher than that of levetiracetam . 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 …”

Synaptic Vesicle Glycoprotein 2A Ligands in the Treatment of Epilepsy and Beyond

“…These were revealed by further studies with the SV2A allosteric modulator UCB1244283 on human recombinant SV2A expressed in HEK293 cells, and in human cortex [88, 95]. In cells expressing human SV2A, [ 3 H]brivaracetam labeled twice as many sites than [ 3 H]levetiracetam.…”

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.…”