Loss of β 1 accessory Na + channel subunits causes failure of carbamazepine, but not of lacosamide, in blocking high‐frequency firing via differential effects on persistent Na + currents
Summary 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 tr...
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Published in | Epilepsia (Copenhagen) Vol. 53; no. 11; pp. 1959 - 1967 |
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Main Authors | , , , , , , |
Format | Journal Article |
Language | English |
Published |
01.11.2012
|
Subjects | |
Online Access | Get full text |
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Summary: | Summary
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 μ
m
CBZ or 300 μ
m
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. |
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Bibliography: | ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 |
ISSN: | 0013-9580 1528-1167 |
DOI: | 10.1111/j.1528-1167.2012.03675.x |