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

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.

[1]  Y. Yonekawa,et al.  Distribution and functional activity of P-glycoprotein and multidrug resistance-associated proteins in human brain microvascular endothelial cells in hippocampal sclerosis , 2006, Epilepsy Research.

[2]  L. Martinian,et al.  Vascular colocalization of P‐glycoprotein, multidrug‐resistance associated protein 1, breast cancer resistance protein and major vault protein in human epileptogenic pathologies , 2006, Neuropathology and applied neurobiology.

[3]  S. Remy,et al.  Molecular and cellular mechanisms of pharmacoresistance in epilepsy. , 2006, Brain : a journal of neurology.

[4]  C. Baumgartner,et al.  A Pilot Study on Brain‐to‐Plasma Partition of 10,11‐Dyhydro‐10‐hydroxy‐5H‐dibenzo(b,f)azepine‐5‐carboxamide and MDR1 Brain Expression in Epilepsy Patients Not Responding to Oxcarbazepine , 2005, Epilepsia.

[5]  Jakub Otáhal,et al.  Metabolic dysfunction during neuronal activation in the ex vivo hippocampus from chronic epileptic rats and humans. , 2005, Brain : a journal of neurology.

[6]  Ellen B. Wolpert,et al.  Evaluation of the role of P-glycoprotein in the uptake of paroxetine, clozapine, phenytoin and carbamazapine by bovine retinal endothelial cells , 2005, Neuropharmacology.

[7]  Wolfgang Löscher,et al.  Drug resistance in brain diseases and the role of drug efflux transporters , 2005, Nature Reviews Neuroscience.

[8]  M. Bowlby,et al.  Pharmacological characterization of antiepileptic drugs and experimental analgesics on low magnesium-induced hyperexcitability in rat hippocampal slices , 2005, Brain Research.

[9]  T. Freund,et al.  Impaired and repaired inhibitory circuits in the epileptic human hippocampus , 2005, Trends in Neurosciences.

[10]  Wolfgang Löscher,et al.  Role of drug efflux transporters in the brain for drug disposition and treatment of brain diseases , 2005, Progress in Neurobiology.

[11]  P. Kwan,et al.  Potential Role of Drug Transporters in the Pathogenesis of Medically Intractable Epilepsy , 2005, Epilepsia.

[12]  C. Marras,et al.  Expression of Drug Resistance Proteins Pgp, MRP1, MRP3, MRP5 AND GST-π in Human Glioma , 2005, Journal of Neuro-Oncology.

[13]  D. Keppler,et al.  Expression and immunolocalization of the multidrug resistance proteins, MRP1–MRP6 (ABCC1–ABCC6), in human brain , 2004, Neuroscience.

[14]  Uwe Heinemann,et al.  Stimulus and Potassium-Induced Epileptiform Activity in the Human Dentate Gyrus from Patients with and without Hippocampal Sclerosis , 2004, The Journal of Neuroscience.

[15]  H. Neels,et al.  Therapeutic drug monitoring of old and newer anti-epileptic drugs , 2004, Clinical chemistry and laboratory medicine.

[16]  A. Vezzani,et al.  Significance of MDR1 and multiple drug resistance in refractory human epileptic brain , 2004 .

[17]  M R Gaab,et al.  Expression of multidrug transporters in dysembryoplastic neuroepithelial tumors causing intractable epilepsy. , 2004, Clinical neuropathology.

[18]  J. C. Baayen,et al.  Expression and Cellular Distribution of Multidrug Resistance–related Proteins in the Hippocampus of Patients with Mesial Temporal Lobe Epilepsy , 2004, Epilepsia.

[19]  G. Sevlever,et al.  Multidrug resistance proteins in tuberous sclerosis and refractory epilepsy. , 2004, Pediatric neurology.

[20]  W. Pardridge,et al.  Brain Microvascular P-Glycoprotein and a Revised Model of Multidrug Resistance in Brain , 2000, Cellular and Molecular Neurobiology.

[21]  E. Neher,et al.  The equilibration time course of [K+]0 in cat cortex , 1973, Experimental Brain Research.

[22]  J. P. Dreier,et al.  Regional and time dependent variations of low Mg2+ induced epileptiform activity in rat temporal cortex slices , 2004, Experimental Brain Research.

[23]  Uwe Heinemann,et al.  Pharmacological and electrographic properties of epileptiform activity induced by elevated K2+ and lowered Ca2+ and Mg2+ concentration in rat hippocampal slices , 2004, Experimental Brain Research.

[24]  W. Löscher,et al.  Brain Access and Anticonvulsant Efficacy of Carbamazepine, Lamotrigine, and Felbamate in ABCC2/MRP2‐Deficient TR− Rats , 2003, Epilepsia.

[25]  W. Haefeli,et al.  Interaction of Antiepileptic Drugs with Human P-Glycoprotein in Vitro , 2003, Journal of Pharmacology and Experimental Therapeutics.

[26]  Dirk Troost,et al.  Overexpression of the Human Major Vault Protein in Gangliogliomas , 2003, Epilepsia.

[27]  H. Wieser,et al.  Antiepileptic drug treatment before and after selective amygdalohippocampectomy , 2003, Epilepsy Research.

[28]  C. Elger,et al.  Anticonvulsant pharmacology of voltage‐gated Na+ channels in hippocampal neurons of control and chronically epileptic rats , 2003, The European journal of neuroscience.

[29]  E. Aronica,et al.  Expression and cellular distribution of multidrug transporter proteins in two major causes of medically intractable epilepsy: focal cortical dysplasia and glioneuronal tumors , 2003, Neuroscience.

[30]  Christian E Elger,et al.  A novel mechanism underlying drug resistance in chronic epilepsy , 2003, Annals of neurology.

[31]  Wolfgang Löscher,et al.  Role of multidrug transporters in pharmacoresistance to antiepileptic drugs. , 2002, The Journal of pharmacology and experimental therapeutics.

[32]  M Thom,et al.  Drug resistance in epilepsy: expression of drug resistance proteins in common causes of refractory epilepsy. , 2002, Brain : a journal of neurology.

[33]  D. Begley,et al.  Drug resistance in epilepsy: the role of the blood-brain barrier. , 2002, Novartis Foundation symposium.

[34]  Z. Borhegyi,et al.  Preservation of perisomatic inhibitory input of granule cells in the epileptic human dentate gyrus , 2001, Neuroscience.

[35]  M. Mayberg,et al.  Overexpression of Multiple Drug Resistance Genes in Endothelial Cells from Patients with Refractory Epilepsy , 2001, Epilepsia.

[36]  R. Bendayan,et al.  Drug transporters in the central nervous system: brain barriers and brain parenchyma considerations. , 2001, Pharmacological reviews.

[37]  W. Löscher,et al.  P-glycoprotein and multidrug resistance-associated protein are involved in the regulation of extracellular levels of the major antiepileptic drug carbamazepine in the brain , 2001, Neuroreport.

[38]  D. Dlugos,et al.  The early identification of candidates for epilepsy surgery. , 2001, Archives of neurology.

[39]  M. Pirmohamed,et al.  Carbamazepine is not a substrate for P-glycoprotein. , 2001, British journal of clinical pharmacology.

[40]  M. Thom,et al.  Multidrug-resistance protein 1 in focal cortical dysplasia , 2001, The Lancet.

[41]  W. Lanksch,et al.  Alterations of Neuronal Connectivity in Area CA1 of Hippocampal Slices from Temporal Lobe Epilepsy Patients and from Pilocarpine‐Treated Epileptic Rats , 2000, Epilepsia.

[42]  C. Baumgartner,et al.  Qualitätsleitlinien auf dem Gebiet der prächirurgischen Epilepsiediagnostik und operativen Epilepsietherapie , 2000 .

[43]  Z. Borhegyi,et al.  Changes in the distribution and connectivity of interneurons in the epileptic human dentate gyrus , 2000, Neuroscience.

[44]  C. Binnie,et al.  Pre‐surgical evaluation for epilepsy surgery – European Standards , 2000, European journal of neurology.

[45]  M. Vreugdenhil,et al.  Modulation of Sodium Currents in Rat CA1 Neurons by Carbamazepine and Valproate After Kindling Epileptogenesis , 1999, Epilepsia.

[46]  A. Rabinowicz,et al.  Tuberous sclerosis associated with MDR1 gene expression and drug-resistant epilepsy. , 1999, Pediatric neurology.

[47]  S. Benbadis.  Is the underlying cause of epilepsy a major prognostic factor for recurrence? , 1999, Neurology.

[48]  C E Elger,et al.  Carbamazepine Effects on Na+ Currents in Human Dentate Granule Cells from Epileptogenic Tissue , 1999, Epilepsia.

[49]  C. Adam,et al.  Is the underlying cause of epilepsy a major prognostic factor for recurrence? , 1998, Neurology.

[50]  C. Kuo,et al.  A common anticonvulsant binding site for phenytoin, carbamazepine, and lamotrigine in neuronal Na+ channels. , 1998, Molecular pharmacology.

[51]  Martin Vreugdenhil,et al.  Effect of valproic acid on sodium currents in cortical neurons from patients with pharmaco-resistant temporal lobe epilepsy , 1998, Epilepsy Research.

[52]  W. Lanksch,et al.  Effects of barium on stimulus-induced changes in [K+]o and field potentials in dentate gyrus and area CA1 of human epileptic hippocampus , 1998, Neuroscience Letters.

[53]  S. Cole,et al.  Multidrug Resistance Protein , 1998, The Journal of Biological Chemistry.

[54]  M. Avoli,et al.  Sodium channels as molecular targets for antiepileptic drugs , 1998, Brain Research Reviews.

[55]  Y. Yaari,et al.  Role of intrinsic burst firing, potassium accumulation, and electrical coupling in the elevated potassium model of hippocampal epilepsy. , 1997, Journal of neurophysiology.

[56]  M. Barnes.  European Federation of Neurological Societies Task Force , 1997 .

[57]  A. Ebner,et al.  Systematic Testing of Medical Intractability for Carbamazepine, Phenytoin, and Phenobarbital or Primidone in Monotherapy for Patients Considered for Epilepsy Surgery , 1996, Epilepsia.

[58]  J. Engel,et al.  Surgery for seizures. , 1996, The New England journal of medicine.

[59]  I. Romero,et al.  Transporting therapeutics across the blood-brain barrier. , 1996, Molecular medicine today.

[60]  M. O’Connor,et al.  Longitudinal variation in cell density and mossy fiber reorganization in the dentate gyrus from temporal lobe epileptic patients , 1995, Brain Research.

[61]  Ramesh Bm.  National Family Health Survey: summary of basic findings. , 1995 .

[62]  N. Barbaro,et al.  MDR1 Gene Expression in Brain of Patients with Medically Intractable Epilepsy , 1995, Epilepsia.

[63]  M. Baulac,et al.  Carbamazepine and Its Epoxide: An Open Study of Efficacy and Side Effects After Carbamazepine Dose Increment in Refractory Partial Epilepsy , 1994, Therapeutic drug monitoring.

[64]  P. Saggau,et al.  Spontaneous interictal-like activity originates in multiple areas of the CA2-CA3 region of hippocampal slices. , 1994, Journal of neurophysiology.

[65]  Jerome Engel,et al.  Surgical treatment of the epilepsies , 1993 .

[66]  Jerome Engel,et al.  Outcome with respect to epileptic seizures. , 1993 .

[67]  A. Wyler,et al.  A grading system for mesial temporal pathology (hippocampal sclerosis) from anterior temporal lobectomy , 1992 .

[68]  CR Houser,et al.  Altered patterns of dynorphin immunoreactivity suggest mossy fiber reorganization in human hippocampal epilepsy , 1990, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[69]  G. Cascino,et al.  Mossy fiber synaptic reorganization in the epileptic human temporal lobe , 1989, Annals of neurology.

[70]  J. H. Kim,et al.  Hippocampal interneuron loss and plasticity in human temporal lobe epilepsy , 1989, Brain Research.

[71]  J. Pretorius,et al.  Glutamate decarboxylase-immunoreactive neurons are preserved in human epileptic hippocampus , 1989, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[72]  J. Schwarz,et al.  Phenytoin and Carbamazepine: Potential‐ and Frequency‐Dependent Block of Na Currents in Mammalian Myelinated Nerve Fibers , 1989, Epilepsia.

[73]  R. Dingledine,et al.  Potassium-induced spontaneous electrographic seizures in the rat hippocampal slice. , 1988, Journal of neurophysiology.

[74]  S J Korn,et al.  Epileptiform burst activity induced by potassium in the hippocampus and its regulation by GABA-mediated inhibition. , 1987, Journal of neurophysiology.

[75]  D. Johnston,et al.  Epileptiform activity induced by changes in extracellular potassium in hippocampus. , 1985, Journal of neurophysiology.

[76]  W. Catterall,et al.  Voltage clamp analysis of the inhibitory actions of diphenylhydantoin and carbamazepine on voltage-sensitive sodium channels in neuroblastoma cells. , 1985, Molecular pharmacology.

[77]  S. Johannessen,et al.  Single‐Drug Therapy with Carbamazepine in Patients with Epilepsy: Serum Levels and Clinical Effect , 1980, Epilepsia.

[78]  J. Winn,et al.  Brain , 1878, The Lancet.