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Epilepsia. 2012 Nov;53(11):1959-67. doi: 10.1111/j.1528-1167.2012.03675.x. Epub 2012 Sep 27.

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.

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1
Department of Epileptology, University of Bonn, Sigmund-Freud-Strasse 25, Bonn, Germany

Abstract

PURPOSE:

  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.

KEY FINDINGS:

  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.

SIGNIFICANCE:

  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.

[Indexed for MEDLINE]
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