Carbamazepine-resistance in the epileptic dentate gyrus of human hippocampal slices

Carbamazepine-resistance in the epileptic dentate gyrus of human hippocampal slices

Author Jandova, Katerina Google Scholar
Paesler, Dennis Google Scholar
Antônio, Leandro Leite Autor UNIFESP Google Scholar
Raue, Claudia Google Scholar
Ji, Shengbo Google Scholar
Njunting, Marleisje Google Scholar
Kann, Oliver Google Scholar
Kovacs, Richard Google Scholar
Meencke, Heinz-Joachim Google Scholar
Cavalheiro, Esper Abrão Autor UNIFESP Google Scholar
Heinemann, Uwe Google Scholar
Gabriel, Siegrun Google Scholar
Lehmann, Thomas-Nicolas Google Scholar
Institution Charite Univ Med Berlin
Charles Univ
Universidade Federal de São Paulo (UNIFESP)
Epilepsy Ctr Berlin Brandenburg
Abstract Overexpression of drug efflux pumps at the blood brain barrier (BBB) has been suggested to be one important factor contributing to drug resistance in epilepsy. This would imply that resected brain tissue of drug-resistant patients is drug-sensitive in absence of the BBB. Here we studied the effects of carbamazepine (CBZ) at therapeutically relevant concentration on epileptiform activity electrophysiologically recorded in acute hippocampal slices of patients with mesial temporal lobe epilepsy (MTLE; 28 patients, 49 slices) or extra-hippocampal tumours (tumour; 6 patients, 11 slices). Epileptiform activity was induced by hilar stimulation (0.067 Hz) during elevation of extracellular potassium concentration ([K+](o)) and remained self-sustained in presence of 10-12 mM [K+](o). Quantitative analysis of data revealed that epileptiform activity in tissue of tumour-patients was predominantly suppressed by CBZ, indicating that the 'epilepsy model' used is CBZ-sensitive. in contrast, epileptiform activity in tissue of drug-resistant MTLE patients was resistant to CBZ in 82% of patients, partially suppressed in 11% and completely suppressed in 7%. the effects of CBZ in tissue of MTLE patients did not depend on the type of activity, hippocampal pathology, excitability of the tissue, or equilibration time of the drug. Considering that CBZ has direct access to all compartments of the slice, our results suggest that CBZ-resistance mechanisms are located within the parenchyma of the dentate gyrus and contribute to drug resistance in the majority of MTLE patients. BBB-located drug-resistance mechanisms per se may play a minor role in this region, because CBZ-sensitivity was only observed in 7% of CBZ-resistant patients.
Keywords drug resistance
Language English
Date 2006-12-01
Published in Brain. Oxford: Oxford Univ Press, v. 129, p. 3290-3306, 2006.
ISSN 0006-8950 (Sherpa/Romeo, impact factor)
Publisher Oxford Univ Press
Extent 3290-3306
Access rights Open access Open Access
Type Article
Web of Science ID WOS:000242471100021

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