Drug resistance in cortical and hippocampal slices from resected tissue of epilepsy patients: no significant impact of p-glycoprotein and multidrug resistance-associated proteins.
Drug resistant patients undergoing epilepsy surgery have a good chance to become sensitive to anticonvulsant medication, suggesting that the resected brain tissue is responsible for drug resistance. Here, we address the question whether P-glycoprotein (Pgp) and multidrug resistance-associated proteins (MRPs) expressed in the resected tissue contribute to drug resistance in vitro. Effects of anti-epileptic drugs [carbamazepine (CBZ), sodium valproate, phenytoin] and two unspecific inhibitors of Pgp and MRPs [verapamil (VPM) and probenecid (PBN)] on seizure-like events (SLEs) induced in slices from 35 hippocampal and 35 temporal cortex specimens of altogether 51 patients (161 slices) were studied. Although in slice preparations the blood brain barrier is not functional, we found that SLEs predominantly persisted in the presence of anticonvulsant drugs (90%) and also in the presence of VPM and PBN (86%). Following subsequent co-administration of anti-epileptic drugs and drug transport inhibitors, SLEs continued in 63% of 143 slices. Drug sensitivity in slices was recognized either as transition to recurrent epileptiform transients (30%) or as suppression (7%), particularly by perfusion with CBZ in PBN containing solutions (43, 9%). Summarizing responses to co-administration from more than one slice per patient revealed that suppression of seizure-like activity in all slices was only observed in 7% of patients. Patients whose tissue was completely or partially sensitive (65%) presented with higher seizure frequencies than those with resistant tissue (35%). However, corresponding subgroups of patients do not differ with respect to expression rates of drug transporters. Our results imply that parenchymal MRPs and Pgp are not responsible for drug resistance in resected tissue.
Institute of Neurophysiology, Charité Universitätsmedizin Berlin , Berlin , Germany ; Department of Neurosurgery, Charité Universitätsmedizin Berlin , Berlin , Germany.
Nora
N
Sandow
Institute of Neurophysiology, Charité Universitätsmedizin Berlin , Berlin , Germany.
Simon
S
Kim
Institute of Neurophysiology, Charité Universitätsmedizin Berlin , Berlin , Germany.
Claudia
C
Raue
Institute of Neurophysiology, Charité Universitätsmedizin Berlin , Berlin , Germany.
Dennis
D
Päsler
Institute of Neurophysiology, Charité Universitätsmedizin Berlin , Berlin , Germany.
Zin-Juan
ZJ
Klaft
Institute of Neurophysiology, Charité Universitätsmedizin Berlin , Berlin , Germany ; Laboratorio de Neurologia Experimental, Universidade Federal de São Paulo-Escola Paulista de Medicina , São Paulo , Brazil.
Leandro Leite
LL
Antonio
Institute of Neurophysiology, Charité Universitätsmedizin Berlin , Berlin , Germany.
Jan Oliver
JO
Hollnagel
Institute of Neurophysiology, Charité Universitätsmedizin Berlin , Berlin , Germany.
Richard
R
Kovacs
Institute of Neurophysiology, Charité Universitätsmedizin Berlin , Berlin , Germany ; Institute of Physiology and Pathophysiology, University of Heidelberg , Heidelberg , Germany.
Oliver
O
Kann
Department of Neurosurgery, Charité Universitätsmedizin Berlin , Berlin , Germany.
Peter
P
Horn
Department of Neurosurgery, Charité Universitätsmedizin Berlin , Berlin , Germany.
Peter
P
Vajkoczy
Epilepsy Center of Berlin-Brandenburg, Ev. Krankenhaus Königin Elisabeth Herzberge , Berlin , Germany.
Martin
M
Holtkamp
Epilepsy Center of Berlin-Brandenburg, Ev. Krankenhaus Königin Elisabeth Herzberge , Berlin , Germany.
Heinz-Joachim
HJ
Meencke
Laboratorio de Neurologia Experimental, Universidade Federal de São Paulo-Escola Paulista de Medicina , São Paulo , Brazil.
Esper A
EA
Cavalheiro
Institute of Forensic Medicine - Forensic Toxicology, Charité Universitätsmedizin Berlin , Berlin , Germany.
Fritz
F
Pragst
Institute of Neurophysiology, Charité Universitätsmedizin Berlin , Berlin , Germany.
Siegrun
S
Gabriel
Department of Neurosurgery, Charité Universitätsmedizin Berlin , Berlin , Germany.
Thomas-Nicolas
TN
Lehmann
Institute of Neurophysiology, Charité Universitätsmedizin Berlin , Berlin , Germany.
Uwe
U
Heinemann
TLE; carbamazepine; phenytoin; probenecid; seizure-like events; sodium valproate; surgically resected tissue; verapamil