Format

Send to

Choose Destination
Eur J Pharmacol. 2010 Sep 15;643(1):13-20. doi: 10.1016/j.ejphar.2010.05.063. Epub 2010 Jun 16.

Effect of carbamazepine and oxcarbazepine on wild-type and mutant neuronal nicotinic acetylcholine receptors linked to nocturnal frontal lobe epilepsy.

Author information

1
Department of Biotechnology and Biosciences, University of Milano-Bicocca, Piazza della Scienza 2, 20126 Milano, Italy.

Abstract

Carbamazepine (5H-dibenz[b,f]azepine-5-carboxamide) and oxcarbazepine (10,11-dihydro-10-oxo-5H-dibenz[b,f]azepine-5-carboxamide) are widely used for the treatment of partial epilepsy. Recent work indicates that these drugs, in addition to targeting voltage-gated Na(+) channels, can modulate ligand-gated channels. These compounds appear to be particularly effective for treatment of nocturnal frontal lobe epilepsy, which can be caused by mutant neuronal nicotinic receptors. We compared the effects of carbamazepine and oxcarbazepine on heteromeric nicotinic receptors to better understand the underlying mechanism of the effect of these drugs in epileptic patients. Receptors were expressed in cell lines and studied by patch-clamp methods at -60 mV. For alpha2beta4 receptors activated with 100 microM nicotine, IC(50) for carbamazepine was 49 microM. Receptors in which alpha2 was substituted with alpha2-I279 N, linked to autosomal dominant nocturnal frontal lobe epilepsy, had an IC(50) of 21 microM. For oxcarbazepine, the IC(50) was larger than 500 microM for wild-type receptors and approximately 100 microM for mutant receptors. A similar inhibition was observed in the presence of 10 microM nicotine, indicating a non-competitive mechanism. The monohydroxy derivative (MHD) of oxcarbazepine, clinically the most relevant compound, was tested on both alpha2beta4 and alpha4beta2 receptors, to obtain a broader view of its possible physiological effects. At the typical concentration present in blood (100 microM), MHD produced an approximate 40% channel block on alpha4beta2, but no significant effect on alpha2beta4 receptors. Oxcarbazepine and MHD retarded the channel deactivation, suggesting that these compounds produce open channel block. These results may explain the particular efficacy of these drugs in nocturnal frontal lobe epilepsy.

PMID:
20561518
DOI:
10.1016/j.ejphar.2010.05.063
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center