Carbamazepine and topiramate modulation of transient and persistent sodium currents studied in HEK293 cells expressing the Na(v)1.3 alpha-subunit.
OBJECTIVE
The transient and the persistent Na(+) current play a distinct role in neuronal excitability. Several antiepileptic drugs (AEDs) modulate the transient Na(+) current and block the persistent Na(+) current; both effects contribute to their antiepileptic properties. The interactions of the AEDs carbamazepine (CBZ) and topiramate (TPM) with the persistent and transient Na(+) current were investigated.


METHODS
HEK293 cells stably expressing the alpha-subunit of the Na(+) channel Na(V)1.3 were used to record Na(+) currents under voltage-clamp by using the patch-clamp technique in whole-cell configuration and to investigate the effects of CBZ and TPM.


RESULTS
The persistent Na(+) current was present in all cells and constituted 10.3 +/- 3.8% of the total current. CBZ partially blocked the persistent Na(+) current in a concentration-dependent manner [median effective concentration (EC(50)), 16 +/- 4 microM]. CBZ also shifted the steady-state inactivation of the transient Na(+) current to negative potentials (EC(50), 14 +/- 11 microM). TPM partially blocked the persistent Na(+) current with a much higher affinity (EC(50), 61 +/- 37 nM) than it affected the steady-state inactivation of the transient Na(+) current (EC(50), 3.2 +/- 1.8 microM). For the latter effect, TPM was at most half as effective as CBZ.


CONCLUSIONS
The persistent Na(+) current flowing through the alpha-subunit of the Na(V)1.3 channel is partially blocked by CBZ at about the same therapeutic concentrations at which it modulates the transient Na(+) current, adding a distinct aspect to its anticonvulsant profile. The TPM-induced partial block of the persistent Na(+) current, already effective at low concentrations, could be the dominant action of this drug on the Na(+) current.
Sun
Guang-chun
GC
Center for NeuroScience, Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, The Netherlands.
Werkman
Taco R
TR
Battefeld
Arne
A
Clare
Jeffrey J
JJ
Wadman
Wytse J
WJ
D000200:Action Potentials / Q000187:drug effects* / Q000502:physiology; D000927:Anticonvulsants / Q000494:pharmacology*; D001921:Brain; D002220:Carbamazepine / Q000494:pharmacology*; D002460:Cell Line; D002478:Cells, Cultured; D005632:Fructose / Q000031:analogs & derivatives* / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D006801:Humans; D062554:NAV1.5 Voltage-Gated Sodium Channel; D009431:Neural Conduction / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D015222:Sodium Channels / Q000187:drug effects* / Q000502:physiology; D000077236:Topiramate
D000927:Anticonvulsants; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D015222:Sodium Channels; D000077236:Topiramate; D005632:Fructose; D002220:Carbamazepine