Brain Advance Access originally published online on September 2, 2006
Brain 2006 129(12):3290-3306; doi:10.1093/brain/awl218
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Carbamazepine-resistance in the epileptic dentate gyrus of human hippocampal slices
1 Institute of Neurophysiology Berlin, Germany 2 Department of Neurosurgery, Charité-Medical University of Berlin Berlin, Germany 3 Institute of Physiology, 1st Faculty of Medicine, Charles University Prague Prague, Czech Republic 4 Laboratorio de Neurologia Experimental, Universidade Federal de Sao Paulo-Escola Paulista de Medicina Sao Paulo, Brazil 5 Epilepsy Center of Berlin–Brandenburg Berlin, Germany
Correspondence to: Prof. Dr Uwe Heinemann, Institut für Neurophysiologie, Charité-Universitätsmedizin Berlin, Tucholskystrasse 2, 10117 Berlin, Germany E-mail: uwe.heinemann{at}charite.de
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.
Key Words: drug resistance; electrophysiology; epilepsy; hippocampus; human
Abbreviations: AED, anti-epileptic drug; BBB, blood brain barrier; CBZ, carbamazepine; HS, hippocampal sclerosis; high K-ACSF, high K+-containing artificial cerebrospinal fluid; MTLE, mesial temporal lobe epilepsy; SLE, seizure- like event
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Received April 20, 2006. Revised June 25, 2006. Accepted July 24, 2006.
*These authors contributed equally to this work.