A NOVEL MECHANISM UNDERLYING PHARMACO-RESISTANCE IN CHRONIC EPILEPSY: REDUCED PHARMACOSENSITIVITY OF VOLTAGE-DEPENDENT SODIUM CHANNELS
Abstract number :
1.003
Submission category :
Year :
2002
Submission ID :
3444
Source :
www.aesnet.org
Presentation date :
12/7/2002 12:00:00 AM
Published date :
Dec 1, 2002, 06:00 AM
Authors :
Stefan Remy, Jian Chen, Siegrun Gabriel, Thomas N. Lehmann, Christian E. Elger, Uwe Heinemann, Albert Becker, Heinz Beck. Epileptology, University of Bonn Medical Center, Bonn, Germany; Physiology, Charité, Berlin, Germany; Neurosurgery, Charité, Berlin,
RATIONALE: 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.
METHODS: We have examined changes in the sensitivity of voltage-dependent sodium channels in hippocampal dentate granule cells to carbamazepine both in human and experimental epilepsy using patch-clamp techniques. We have also determined the sensitivity of seizure-activity elicited in-vitro to carbamazepine in human hippocampal slices from epilepsy patients with differing clinical responsiveness to this drug.
RESULTS: First, we demonstrate that the use-dependent block of sodium channels by carbamazepine that normally leads to frequency-dependent inhibition of sodium channels is completely lost in hippocampal dentate granule neurons, both in experimental epilepsy and in epilepsy patients clinically resistant to carbamazepine. Similarly, seizure activity induced in human hippocampal slices is virtually unaffected by carbamazepine in patients with carbamazepine-resistant epilepsy, but not in patients clinically responsive to this drug. The changes in sodium channel pharmacosensitivity in experimental epilepsy are associated with down-regulation of the accessory beta1 sodium channel subunit as well as the pore-forming Nav1.2 and Nav1.6 subunits in dentate granule neurons, determined using real-time PCR. Expression of Nav1.1, Nav1.3 and Nav1.5 subunits was not significantly altered.
CONCLUSIONS: These data suggest that the loss of sodium channel carbamazepine sensitivity may underlie the markedly diminished capacity of carbamazepine to inhibit high-frequency firing and seizure activity in pharmaco-resistant epilepsy, with the molecular basis for this change remaining elusive. Nevertheless, development of compounds acting on altered sodium channels may be a promising approach for rational drug design in chronic epilepsy.
[Supported by: SFB 6006, Graduate Program of the DFG [ssquote]Pathogenesis of central nervous diseases[ssquote], Joint German-Israeli Research Program of the MOS and BMBF/DLR]