title: Brivaracetam differentially affects voltage-gated sodium currents without impairing sustained repetitive firing in neurons.
abstract: OBJECTIVE
  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.
authors.affiliation: UCB Pharma SA, Neurosciences Therapeutic Area, Braine l'Alleud, Belgium.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Niespodziany
authors.forename: Véronique Marie
authors.initials: VM
authors.lastname: André
authors.forename: Nathalie
authors.initials: N
authors.lastname: Leclère
authors.forename: Etienne
authors.initials: E
authors.lastname: Hanon
authors.forename: Philippe
authors.initials: P
authors.lastname: Ghisdal
authors.forename: Christian
authors.initials: C
authors.lastname: Wolff
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D056547:CA1 Region, Hippocampal / Q000187:drug effects / Q000502:physiology; D002220:Carbamazepine / Q000494:pharmacology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000502:physiology; D017326:Clinical Trials, Phase III as Topic; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D018408:Patch-Clamp Techniques; D017208:Rats, Wistar; D046509:Tissue Culture Techniques; D061567:Voltage-Gated Sodium Channel Blockers / Q000494:pharmacology*; D061566:Voltage-Gated Sodium Channels / Q000378:metabolism
chemical_list: D000927:Anticonvulsants; D061567:Voltage-Gated Sodium Channel Blockers; D061566:Voltage-Gated Sodium Channels; D002220:Carbamazepine
keywords: Action potential firing; Antiepileptic drug; Neurons; Voltage-gated sodium channel