title: Loss of β1 accessory Na+ channel subunits causes failure of carbamazepine, but not of lacosamide, in blocking high-frequency firing via differential effects on persistent Na+ currents.
abstract: OBJECTIVE
  In chronic epilepsy, a substantial proportion of up to 30% of patients remain refractory to antiepileptic drugs (AEDs). An understanding of the mechanisms of pharmacoresistance requires precise knowledge of how AEDs interact with their targets. Many commonly used AEDs act on the transient and/or the persistent components of the voltage-gated Na(+) current (I(NaT) and I(NaP) , respectively). Lacosamide (LCM) is a novel AED with a unique mode of action in that it selectively enhances slow inactivation of fast transient Na(+) channels. Given that functional loss of accessory Na(+) channel subunits is a feature of a number of neurologic disorders, including epilepsy, we examined the effects of LCM versus carbamazepine (CBZ) on the persistent Na(+) current (I(NaP) ), in the presence and absence of accessory subunits within the channel complex.
  
  
  METHODS
  Using patch-clamp recordings in intact hippocampal CA1 neurons of Scn1b null mice, I(NaP) was recorded using slow voltage ramps. Application of 100 μm CBZ or 300 μm LCM reduced the maximal I(NaP) conductance in both wild-type and control mice.
  
  
  RESULTS
  As shown previously by our group in Scn1b null mice, CBZ induced a paradoxical increase of I(NaP) conductance in the subthreshold voltage range, resulting in an ineffective block of repetitive firing in Scn1b null neurons. In contrast, LCM did not exhibit such a paradoxical increase, and accordingly maintained efficacy in blocking repetitive firing in Scn1b null mice.
  
  
  CONCLUSIONS
  These results suggest that the novel anticonvulsant LCM maintains activity in the presence of impaired Na(+) channel β(1) subunit expression and thus may offer an improved efficacy profile compared with CBZ in diseases associated with an impaired expression of β sub-units as observed in epilepsy.
authors.affiliation: Department of Epileptology, University of Bonn, Sigmund-Freud-Strasse 25, Bonn, Germany
authors.forename: Mischa
authors.initials: M
authors.lastname: Uebachs
authors.forename: Christina
authors.initials: C
authors.lastname: Albus
authors.forename: Thoralf
authors.initials: T
authors.lastname: Opitz
authors.forename: Lori
authors.initials: L
authors.lastname: Isom
authors.forename: Isabelle
authors.initials: I
authors.lastname: Niespodziany
authors.forename: Christian
authors.initials: C
authors.lastname: Wolff
authors.forename: Heinz
authors.initials: H
authors.lastname: Beck
mesh_terms: D000081:Acetamides / Q000494:pharmacology*; D000200:Action Potentials / Q000187:drug effects* / Q000502:physiology; D000818:Animals; D002220:Carbamazepine / Q000494:pharmacology*; D002478:Cells, Cultured; D000078334:Lacosamide; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D021122:Protein Subunits / Q000172:deficiency / Q000502:physiology; D062547:Voltage-Gated Sodium Channel beta-1 Subunit / Q000172:deficiency* / Q000502:physiology
chemical_list: D000081:Acetamides; D021122:Protein Subunits; C524974:Scn1b protein, mouse; D062547:Voltage-Gated Sodium Channel beta-1 Subunit; D002220:Carbamazepine; D000078334:Lacosamide