The Integrated Effects of Brivaracetam, a Selective Analog of Levetiracetam, on Ionic Currents and Neuronal Excitability.

Te-Yu Hung,Sheng-Nan Wu,Chin-Wei Huang

doi:10.3390/biomedicines9040369

Abstract

Brivaracetam (BRV) is recognized as a novel third-generation antiepileptic drug approved for the treatment of epilepsy. Emerging evidence has demonstrated that it has potentially better efficacy and tolerability than its analog, Levetiracetam (LEV). This, however, cannot be explained by their common synaptic vesicle-binding mechanism. Whether BRV can affect different ionic currents and concert these effects to alter neuronal excitability remains unclear. With the aid of patch clamp technology, we found that BRV concentration dependently inhibited the depolarization-induced M-type K+ current (IK(M)), decreased the delayed-rectifier K+ current (IK(DR)), and decreased the hyperpolarization-activated cation current in GH3 neurons. However, it had a concentration-dependent inhibition on voltage-gated Na+ current (INa). Under an inside-out patch configuration, a bath application of BRV increased the open probability of large-conductance Ca2+-activated K+ channels. Furthermore, in mHippoE-14 hippocampal neurons, the whole-cell INa was effectively depressed by BRV. In simulated modeling of hippocampal neurons, BRV was observed to reduce the firing of the action potentials (APs) concurrently with decreases in the AP amplitude. In animal models, BRV ameliorated acute seizures in both OD-1 and lithium-pilocarpine epilepsy models. However, LEV had effects in the latter only. Collectively, our study demonstrated BRV’s multiple ionic mechanism in electrically excitable cells and a potential concerted effect on neuronal excitability and hyperexcitability disorders.

Highlights

Brivaracetam (BRV; Brivact®, Brivlera®, UCB34714, C11 H20 N2 O2 ), a chemical analog of levetiracetam (LEV), is an orally or intravenously bioavailable racetam derivative with anticonvulsant properties that has appeared in a growing number of research papers [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33]
It has been demonstrated that BRV can interfere with the functional activities of neurons or endocrine cells by binding with high affinity to the synaptic or endocrine vesicle protein 2A
In a final seriesseizures of studies, we evaluated themodels, effects of LEV on acute seiin different animal including a sodium channel agonism-based OD-1 zures in different animal a sodium channel agonism-based OD-1 model modelmodels

Summary

Introduction

Brivaracetam (BRV; Brivact® , Brivlera® , UCB34714, C11 H20 N2 O2 ), a chemical analog of levetiracetam (LEV), is an orally or intravenously bioavailable racetam derivative with anticonvulsant (antiepileptic) properties that has appeared in a growing number of research papers [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33]. BRV has been reported to attenuate pain behavior in a murine model of neuropathic pain [2,39]. It has been demonstrated that BRV can interfere with the functional activities of neurons (e.g., hippocampal neurons) or endocrine cells (e.g., pituitary lactotrophs) by binding with high affinity to the synaptic or endocrine vesicle protein 2A (SV2A) [9,15,39,41,42,43,44,45]. SV2A has been recognized as an important broad marker for neuroendocrine cells [41]. It has been reported to be 10–30-fold more potent than LEV, with high efficacy in a wide range of experimental models of focal and generalized seizures

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