Blood-brain barrier dysfunction can contribute to pharmacoresistance of seizures
Salar S, Maslarova A, Lippmann K, Nichtweiss J, Weissberg I, Sheintuch L, Kunz WS, Shorer Z, Friedman A, Heinemann U (2014)
Publication Type: Journal article
Publication year: 2014
Journal
Book Volume: 55
Pages Range: 1255-1263
Journal Issue: 8
DOI: 10.1111/epi.12713
Abstract
Summary Objective We tested the hypothesis that interstitial albumin can contribute to pharmacoresistance, which is common among patients with focal epilepsies. These patients often present with an open blood-brain barrier (BBB), resulting in diffusion of drug-binding albumin into the brain interstitial space. Methods Seizure-like events (SLEs) induced by 100 μm 4-aminopyridine (4-AP) were monitored using extracellular field potential recordings from acute rat entorhinal cortex-hippocampus slices. Effects of standard antiepileptic drugs (phenytoin, valproic acid, carbamazepine, and phenobarbital) were studied in the presence of albumin applied acutely or by intraventricular injection. Unbound antiepileptic drugs (AEDs) were detected by ultrafiltration and high-performance liquid chromatography (HPLC). Results Contrary to the absence of albumin, conventional AEDs failed to suppress SLEs in the rat entorhinal cortex in the presence of albumin. This effect was partially caused by buffering of phenytoin and carbamazepine (CBZ) by albumin. Increasing CBZ concentration from 50 μm to 100 μm resulted in block of SLEs. In slices obtained from animals that were pretreated with intraventricular albumin application 24 h prior to experiment, CBZ suppressed SLEs similar to control slices. We also found that application of serum-like electrolytes transformed SLEs into late recurrent discharges (LRDs), which were no longer responding to CBZ. Significance A dysfunctional BBB with acute extravasation of serum albumin into the brain's interstitial space could contribute to pharmacoresistance. In such instances, choice of an AED with low albumin binding affinity may help in seizure control. © 2014 International League Against Epilepsy.
Authors with CRIS profile
Involved external institutions
Ben-Gurion University of the Negev (BGU) / אוניברסיטת בן-גוריון בנגב
Israel (IL)
Charité - Universitätsmedizin Berlin
Germany (DE)
Rheinische Friedrich-Wilhelms-Universität Bonn
Germany (DE)
Israel (IL)
Charité - Universitätsmedizin Berlin
Germany (DE)
Rheinische Friedrich-Wilhelms-Universität Bonn
Germany (DE)
How to cite
APA:
Salar, S., Maslarova, A., Lippmann, K., Nichtweiss, J., Weissberg, I., Sheintuch, L.,... Heinemann, U. (2014). Blood-brain barrier dysfunction can contribute to pharmacoresistance of seizures. Epilepsia, 55(8), 1255-1263. https://dx.doi.org/10.1111/epi.12713
MLA:
Salar, Seda, et al. "Blood-brain barrier dysfunction can contribute to pharmacoresistance of seizures." Epilepsia 55.8 (2014): 1255-1263.
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