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

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          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 ( I K(M)), decreased the delayed-rectifier K + current ( I K(DR)), and decreased the hyperpolarization-activated cation current in GH3 neurons. However, it had a concentration-dependent inhibition on voltage-gated Na + current ( I Na). Under an inside-out patch configuration, a bath application of BRV increased the open probability of large-conductance Ca 2+-activated K + channels. Furthermore, in mHippoE-14 hippocampal neurons, the whole-cell I Na 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.

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          A randomized, double-blind, placebo-controlled, multicenter, parallel-group study to evaluate the efficacy and safety of adjunctive brivaracetam in adult patients with uncontrolled partial-onset seizures.

          Brivaracetam (BRV), a selective and high-affinity synaptic vesicle protein 2A ligand, is in development as adjunctive treatment for partial-onset (focal) seizures (POS). This phase 3 study (N01358; NCT01261325) aimed to confirm the efficacy and safety/tolerability of BRV in adults (≥ 16-80 years) with POS.
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            Contribution of persistent Na+ current and M-type K+ current to somatic bursting in CA1 pyramidal cells: combined experimental and modeling study.

            The intrinsic firing modes of adult CA1 pyramidal cells vary along a continuum of "burstiness" from regular firing to rhythmic bursting, depending on the ionic composition of the extracellular milieu. Burstiness is low in neurons exposed to a normal extracellular Ca(2+) concentration ([Ca(2+)](o)), but is markedly enhanced by lowering [Ca(2+)](o), although not by blocking Ca(2+) and Ca(2+)-activated K(+) currents. We show, using intracellular recordings, that burstiness in low [Ca(2+)](o) persists even after truncating the apical dendrites, suggesting that bursts are generated by an interplay of membrane currents at or near the soma. To study the mechanisms of bursting, we have constructed a conductance-based, one-compartment model of CA1 pyramidal neurons. In this neuron model, reduced [Ca(2+)](o) is simulated by negatively shifting the activation curve of the persistent Na(+) current (I(NaP)) as indicated by recent experimental results. The neuron model accounts, with different parameter sets, for the diversity of firing patterns observed experimentally in both zero and normal [Ca(2+)](o). Increasing I(NaP) in the neuron model induces bursting and increases the number of spikes within a burst but is neither necessary nor sufficient for bursting. We show, using fast-slow analysis and bifurcation theory, that the M-type K(+) current (I(M)) allows bursting by shifting neuronal behavior between a silent and a tonically active state provided the kinetics of the spike generating currents are sufficiently, although not extremely, fast. We suggest that bursting in CA1 pyramidal cells can be explained by a single compartment "square bursting" mechanism with one slow variable, the activation of I(M).
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              Circuit Mechanisms of Seizures in the Pilocarpine Model of Chronic Epilepsy: Cell Loss and Mossy Fiber Sprouting

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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                Biomedicines
                Biomedicines
                biomedicines
                Biomedicines
                MDPI
                2227-9059
                01 April 2021
                April 2021
                : 9
                : 4
                : 369
                Affiliations
                [1 ]Department of Pediatrics, Chi-Mei Medical Center, Tainan 71004, Taiwan; yuchin3344@ 123456hotmail.com
                [2 ]Department of Physiology, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan
                [3 ]Department of Neurology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan
                Author notes
                Author information
                https://orcid.org/0000-0002-5208-3253
                https://orcid.org/0000-0003-3335-2187
                Article
                biomedicines-09-00369
                10.3390/biomedicines9040369
                8067033
                33916190
                10973769-8067-4389-b0ef-fc2c5c1ccb7c
                © 2021 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( https://creativecommons.org/licenses/by/4.0/).

                History
                : 14 February 2021
                : 26 March 2021
                Categories
                Article

                brivaracetam,m-type k+ current,voltage-gated na+ current,large-conductance ca2+-activated k+ channel,neuron,seizure

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