Article
Multidrug transporter-inhibition in temporal lobe epilepsy – a study in resected tissue from pharmacoresistant, chronic epilepsy patients
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Authors
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N. Sandow
- Department of Neurosurgery, Charité - Universitätsmedizin Berlin; Institute of Neurophysiology, Charité - Universitätsmedizin Berlin
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S. Gabriel
- Institute of Neurophysiology, Charité - Universitätsmedizin Berlin
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T.N. Lehmann
- Department of Neurosurgery, Helios Kliniken Bad Saarow
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P. Horn
- Department of Neurosurgery, Charité - Universitätsmedizin Berlin
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P. Vajkoczy
- Department of Neurosurgery, Charité - Universitätsmedizin Berlin
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U. Heinemann
- Institute of Neurophysiology, Charité - Universitätsmedizin Berlin
| Published: | April 28, 2011 |
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Outline
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Objective: 30% of epilepsies are pharmacoresistant. Temporal pole resection is often the only therapeutic option. Two concepts that may be responsible for pharmacoresistance in epilepsy are part of the current discussion: a) the target hypothesis favors changes in target conformation of antiepileptic drugs (AED) while b) the transporter hypothesis focuses on a decrease in AED-concentrations at their place of action by ATP-dependent drug efflux pumps located in the blood-brain-barrier (BBB) and / or the brain parenchyma. To determine the role of the temporal cortex in pharmacoresistant epilepsy, as well as the contribution of BBB or parenchymally expressed drug efflux pumps (Multidrug transporter 1 – MDTI) we performed this electrophysiological study on resected human temporal cortex specimens from patients suffering from pharmacoresistant temporal lobe epilepsy.
Methods: In a series of 49 patients, 166 slices of the temporal cortex were investigated for: 1) their potential to generate epileptiform activity after induction by elevation of extracellular K+ and 50μM bicuculline, 2) pharmacoresistance to common antiepileptic drugs such as phenytoin (PHT), carbamazepin (CBZ) and valproate (VPT) and 3) the efficacy of multidrug transporter-inhibitors (verapamil – VPM, probenecid – PBN) in restoring potency of AEDs.
Results: In 85% of experiments in 96% of patient probes, epileptiform activity was successfully induced by elevation of extracellular K+ and perfusion with 50μM bicuculline. In pathological tissue interictal spiking occurred significantly more often than seizure-like events (p≤0.001, chi-Quadrat). Only in 8.1% of experiments was the epileptiform activity sensitive to an antiepileptic drug (CBZ, PHT or VPA), showing that resected temporal cortex tissue is mostly pharmacoresistant. In 12.3% of cases AED-resistance was sensitive to a co-application of AED and MDTI (VPM and PBN), which puts the efficacy of multidrug transporter-inhibitors to restore the potency of AEDs in question.
Conclusions: This study demonstrated that 1) epileptiform activity can be induced in most of the temporal cortex specimens resected, 2) mechanisms located at the BBB may play a negligible role as epileptiform activity in a BBB-deprived model is pharmacoresistant and 3) multidrug transporter-inhibition is not sufficient to restore AED potency in this in vitro model.
