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Summary   Aims  Brivaracetam ( BRV ) is an antiepileptic drug in Phase  III  clinical development.  BRV  binds to synaptic vesicle 2A ( SV 2A) protein and is also suggested to inhibit voltage‐gated sodium channels ( VGSC s). To evaluate whether the effect of  BRV  on  VGSC s represents a relevant mechanism participating in its antiepileptic properties, we explored the pharmacology of  BRV  on  VGSC s 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 N   a ) were performed in N1E‐155 neuroblastoma cells, cultured rat cortical neurons, and adult mouse  CA 1 neurons.  SRF  was measured in cultured cortical neurons and in  CA 1 neurons. All  BRV  (100–300 μM) experiments were performed in comparison with 100 μM carbamazepine ( CBZ ).    Results  Brivaracetam and  CBZ  reduced  I N   a  in N1E‐115 cells (30% and 40%, respectively) and primary cortical neurons (21% and 47%, respectively) by modulating the fast‐inactivated state of  VGSC s.  BRV , in contrast to  CBZ , did not affect  I N   a  in  CA 1 neurons and  SRF  in cortical and  CA 1 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.

Brivaracetam Differentially Affects Voltage‐Gated Sodium Currents Without Impairing Sustained Repetitive Firing in Neurons