Abstracts

ALTERED ANTICONVULSANT DRUG EFFECTS ON VOLTAGE-DEPENDENT SODIUM CHANNELS IN CHRONIC EPILEPSY: POTENTIAL IMPLICATIONS FOR PHARMACORESISTANCE

Abstract number : 2.052
Submission category :
Year : 2003
Submission ID : 3736
Source : www.aesnet.org
Presentation date : 12/6/2003 12:00:00 AM
Published date : Dec 1, 2003, 06:00 AM

Authors :
Stefan Remy, Bernd W. Urban, Christian E. Elger, Heinz Beck Department of Epileptology, University of Bonn, Bonn, Germany; Department of Anesthesiology, University of Bonn, Bonn, Germany

Insensitivity to anticonvulsant drugs is a crucial problem in the treatment of epilepsy, but the underlying mechanisms are unknown. We have tested whether pharmaco-resistance might be due to reduced pharmacosensitivity of one major target of anticonvulsant drugs, the voltage-dependent sodium channel.
Using patch-clamp techniques we evaluated the sensitivity of voltage-dependent sodium channels in dentate granule neurons to carbamazepine (CBZ, 128 [micro]M), phenytoin (PHT, 100 [micro]M), lamotrigine (LTG, 100 [micro]M) and valproate (VPA, 600 [micro]M) in the pilocarpine model of epilepsy. In the case of CBZ, we extended these investigations to neurons obtained from epilepsy patients.
All substances except LTG caused a shift in the voltage-dependence of fast inactivation in a hyperpolarizing direction (CBZ: 11.9, PHT: 3.7, VPA, 1.7 mV) in control animals. The voltage-dependence of activation was shifted in a depolarizing direction to a varying extent (1.5, 4.1 and 4.6 mV for PHT, LTG and VPA, respectively). No significant differences to pilocarpine-treated animals were observed with respect to the pharmacosensitivity of voltage-dependence. CBZ, LTG and PHT potently slowed the time course of fast recovery from inactivation (3, 2.2- and 1.9-fold increase in the fast recovery time constant), while VPA had no effect. The effects of CBZ on fast recovery were completely lost, while the effects of PHT on this parameter were reduced in chronic epilepsy (by 35%). We further investigated this issue in human tissue from CBZ-resistant epilepsy patients, in whom fast recovery from inactivation proved also insensitive to CBZ. This loss of sensitivity results in a pronounced loss of use-dependent sodium channel block by CBZ.
Taken together, these results suggest that reduced pharmacosensitivity of sodium channels may contribute to the development of resistance to CBZ and perhaps PHT, while other mechanisms may underlie resistance to LTG and VPA.
[Supported by: The graduate program 246 and the Sonderforschungsbereich TR3 of the Deutsche Forschungsgemeinschaft and a University of Bonn Medical Center grant [apos]BONFOR[apos]]