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布立西坦对电压门控钠电流有不同影响，且不损害神经元的持续重复放电。

Brivaracetam differentially affects voltage-gated sodium currents without impairing sustained repetitive firing in neurons.

作者信息

Niespodziany Isabelle, André Véronique Marie, Leclère Nathalie, Hanon Etienne, Ghisdal Philippe, Wolff Christian

机构信息

UCB Pharma SA, Neurosciences Therapeutic Area, Braine l'Alleud, Belgium.

出版信息

CNS Neurosci Ther. 2015 Mar;21(3):241-51. doi: 10.1111/cns.12347. Epub 2014 Dec 1.

DOI:10.1111/cns.12347
PMID:25444522
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4359682/
Abstract

AIMS

Brivaracetam (BRV) is an antiepileptic drug in Phase III clinical development. BRV binds to synaptic vesicle 2A (SV2A) protein and is also suggested to inhibit voltage-gated sodium channels (VGSCs). To evaluate whether the effect of BRV on VGSCs represents a relevant mechanism participating in its antiepileptic properties, we explored the pharmacology of BRV on VGSCs in different cell systems and tested its efficacy at reducing the sustained repetitive firing (SRF).

METHODS

Brivaracetam investigations on the voltage-gated sodium current (I(Na)) were performed in N1E-155 neuroblastoma cells, cultured rat cortical neurons, and adult mouse CA1 neurons. SRF was measured in cultured cortical neurons and in CA1 neurons. All BRV (100-300 μM) experiments were performed in comparison with 100 μM carbamazepine (CBZ).

RESULTS

Brivaracetam and CBZ reduced IN a in N1E-115 cells (30% and 40%, respectively) and primary cortical neurons (21% and 47%, respectively) by modulating the fast-inactivated state of VGSCs. BRV, in contrast to CBZ, did not affect I(Na) in CA1 neurons and SRF in cortical and CA1 neurons. CBZ consistently inhibited neuronal SRF by 75-93%.

CONCLUSIONS

The lack of effect of BRV on SRF in neurons suggests that the reported inhibition of BRV on VGSC currents does not contribute to its antiepileptic properties.

摘要

目的

布瓦西坦（BRV）是一种处于III期临床开发阶段的抗癫痫药物。BRV与突触囊泡2A（SV2A）蛋白结合，也被认为可抑制电压门控钠通道（VGSCs）。为评估BRV对VGSCs的作用是否代表其抗癫痫特性的相关机制，我们在不同细胞系统中探究了BRV对VGSCs的药理学作用，并测试了其减少持续性重复放电（SRF）的疗效。

方法

在N1E-155神经母细胞瘤细胞、培养的大鼠皮层神经元和成年小鼠CA1神经元中进行布瓦西坦对电压门控钠电流（I(Na)）的研究。在培养的皮层神经元和CA1神经元中测量SRF。所有BRV（100 - 300 μM）实验均与100 μM卡马西平（CBZ）进行比较。

结果

布瓦西坦和CBZ通过调节VGSCs的快速失活状态，分别使N1E-115细胞中的I(Na)降低30%和40%，使原代皮层神经元中的I(Na)降低21%和47%。与CBZ不同，BRV对CA1神经元中的I(Na)以及皮层和CA1神经元中的SRF均无影响。CBZ持续抑制神经元SRF达75 - 93%。

结论

BRV对神经元SRF无影响表明，所报道的BRV对VGSC电流的抑制作用对其抗癫痫特性无贡献。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/59b4/6495348/4fa430b0e104/CNS-21-241-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/59b4/6495348/b78a3e66d2a4/CNS-21-241-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/59b4/6495348/83f1d45ba0bd/CNS-21-241-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/59b4/6495348/b791b2c6d3ce/CNS-21-241-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/59b4/6495348/01fc52796558/CNS-21-241-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/59b4/6495348/4fa430b0e104/CNS-21-241-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/59b4/6495348/b78a3e66d2a4/CNS-21-241-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/59b4/6495348/83f1d45ba0bd/CNS-21-241-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/59b4/6495348/b791b2c6d3ce/CNS-21-241-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/59b4/6495348/01fc52796558/CNS-21-241-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/59b4/6495348/4fa430b0e104/CNS-21-241-g005.jpg

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