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.
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.
Authors: Carlos G Vanoye; Christina A Gurnett; Katherine D Holland; Alfred L George; Jennifer A Kearney Journal: Neurobiol Dis Date: 2013-10-21 Impact factor: 5.996
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