Carbamazepine and topiramate modulation of transient and persistent sodium currents studied in HEK293 cells expressing the Na(v)1.3 alpha-subunit.
Epilepsia. 2007-04-01; 48(4): 774-782
DOI: 10.1111/j.1528-1167.2007.01001.x
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1. Epilepsia. 2007 Apr;48(4):774-82. Epub 2007 Mar 22.
Carbamazepine and topiramate modulation of transient and persistent sodium
currents studied in HEK293 cells expressing the Na(v)1.3 alpha-subunit.
Sun GC(1), Werkman TR, Battefeld A, Clare JJ, Wadman WJ.
Author information:
(1)Center for NeuroScience, Swammerdam Institute for Life Sciences, University of
Amsterdam, Amsterdam, The Netherlands.
PURPOSE: 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.
DOI: 10.1111/j.1528-1167.2007.01001.x
PMID: 17381447 [Indexed for MEDLINE]