Drug resistance in epilepsy: expression of drug resistance proteins in common causes of refractory epilepsy.

Epilepsy is resistant to drug treatment in about one-third of cases, but the mechanisms underlying this drug resistance are not understood. In cancer, drug resistance has been studied extensively. Amongst the various resistance mechanisms, overexpression of drug resistance proteins, such as multi-drug resistance gene-1 P-glycoprotein (MDR1) and multidrug resistance-associated protein 1 (MRP1), has been shown to correlate with cellular resistance to anticancer drugs. Previous studies in human epilepsy have shown that MDR1 and MRP1 may also be overexpressed in brain tissue from patients with refractory epilepsy; expression has been shown in glia and neurones, which do not normally express these proteins. We examined expression of MDR1 and MRP1 in refractory epilepsy from three common causes, dysembryoplastic neuroepithelial tumours (DNTs; eight cases), focal cortical dysplasia (FCD; 14 cases) and hippocampal sclerosis (HS; eight cases). Expression was studied immunohistochemically in lesional tissue from therapeutic resections and compared with expression in histologically normal adjacent tissue. With the most sensitive antibodies, in all eight DNT cases, reactive astrocytes within tumour nodules expressed MDR1 and MRP1. In five of eight HS cases, reactive astrocytes within the gliotic hippocampus expressed MDR1 and MRP1. Of 14 cases of FCD, MDR1 and MRP1 expression was noted in reactive astrocytes in all cases. In five FCD cases, MRP1 expression was also noted in dysplastic neurones. In FCD and DNTs, accentuation of reactivity was noted around lesional vessels. Immunoreactivity was always more frequent and intense in lesional reactive astrocytes than in glial fibrillary acidic protein-positive reactive astrocytes in adjacent histologically normal tissue. MDR1 is able to transport some antiepileptic drugs (AEDs), and MRP1 may also do so. The overexpression of these drug resistance proteins in tissue from patients with refractory epilepsy suggests one possible mechanism for drug resistance in patients with these pathologies. We propose that overexpressed resistance proteins lower the interstitial concentration of AEDs in the vicinity of the epileptogenic pathology and thereby render the epilepsy caused by these pathologies resistant to treatment with AEDs.

[1]  T. Ishikawa,et al.  Transient induction of the MRP/GS-X pump and gamma-glutamylcysteine synthetase by 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3- nitrosourea in human glioma cells. , 1997, Cancer research.

[2]  T. Grogan,et al.  Multidrug resistance protein (MRP) expression in retinoblastoma correlates with the rare failure of chemotherapy despite cyclosporine for reversal of P-glycoprotein. , 1997, Cancer research.

[3]  Costan,et al.  Methods to detect P-glycoprotein-associated multidrug resistance in patients' tumors: consensus recommendations. , 1996, Cancer research.

[4]  K. Yaffe,et al.  Reversible MRI abnormalities following seizures , 1995, Neurology.

[5]  A. Sartorelli,et al.  Choroid plexus epithelial expression of MDR1 P glycoprotein and multidrug resistance-associated protein contribute to the blood-cerebrospinal-fluid drug-permeability barrier. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[6]  V. Jay,et al.  Enhanced expression of microtubule‐associated protein 2 in large neurons of cortical dysplasia , 1996, Annals of neurology.

[7]  N. Mulder,et al.  Transport of glutathione conjugates into secretory vesicles is mediated by the multidrug‐resistance protein 1 , 1998, International journal of cancer.

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

[9]  J. Wellmer,et al.  Neurochemical Profile of Glioneuronal Lesions from Patients with Pharmacoresistant Focal Epilepsies , 1995, Journal of neuropathology and experimental neurology.

[10]  V. Ling.  Multidrug resistance: molecular mechanisms and clinical relevance , 1997, Cancer Chemotherapy and Pharmacology.

[11]  D D Breimer,et al.  Multidrug resistance protein 1 protects the choroid plexus epithelium and contributes to the blood-cerebrospinal fluid barrier. , 2000, The Journal of clinical investigation.

[12]  C. Daumas-Duport.  Dysembryoplastic Neuroepithelial Tumours , 1993, Brain pathology.

[13]  M. Hung,et al.  Cross-reactivity of C219 anti-p170(mdr-1) antibody with p185(c-erbB2) in breast cancer cells: cautions on evaluating p170(mdr-1) , 1997, Journal of the National Cancer Institute.

[14]  D. Hipfner,et al.  Monoclonal Antibodies That Inhibit the Transport Function of the 190-kDa Multidrug Resistance Protein, MRP , 1999, The Journal of Biological Chemistry.

[15]  Jean M. H. van den Elsen,et al.  Antibody C219 recognizes an alpha-helical epitope on P-glycoprotein. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[16]  U. Brinkmann,et al.  Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[17]  A. Hamberger,et al.  Biochemical correlates to cortical dysplasia, gliosis, and astrocytoma infiltration in human epileptogenic cortex , 1993, Neurochemical Research.

[18]  D. Bergen.  Antiepileptic Drugs, 4th Ed , 1996, Neurology.

[19]  E. Schuetz,et al.  Modulators and substrates of P-glycoprotein and cytochrome P4503A coordinately up-regulate these proteins in human colon carcinoma cells. , 1996, Molecular pharmacology.

[20]  D. Hipfner,et al.  Epitope mapping of monoclonal antibodies specific for the 190-kDa multidrug resistance protein (MRP). , 1998, British Journal of Cancer.

[21]  M. Barrand,et al.  Multidrug Resistance‐Related Transport Proteins in Isolated Human Brain Microvessels and in Cells Cultured from These Isolates , 1998, Journal of neurochemistry.

[22]  Lacueva,et al.  Detection of P‐glycoprotein in frozen and paraffin‐embedded gastric adenocarcinoma tissues using a panel of monoclonal antibodies , 1998, Histopathology.

[23]  S. Cole,et al.  Multidrug resistance mediated by the ATP‐binding cassette transporter protein MRP , 1998, BioEssays : news and reviews in molecular, cellular and developmental biology.

[24]  S. Sisodiya,et al.  Over-expression of P-glycoprotein in malformations of cortical development. , 1999, Neuroreport.

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

[26]  D. Hipfner,et al.  Structural, mechanistic and clinical aspects of MRP1. , 1999, Biochimica et biophysica acta.

[27]  C. Meijer,et al.  Immunochemical detection of the multidrug resistance-associated protein MRP in human multidrug-resistant tumor cells by monoclonal antibodies. , 1994, Cancer research.

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

[29]  P. Sonneveld.  Multidrug resistance in haematological malignancies , 2000, Journal of internal medicine.

[30]  J. Merlin,et al.  Modulation of daunorubicin cellular resistance by combination of P-glycoprotein blockers acting on drug efflux and intracellular drug sequestration in Golgi vesicles. , 2000, Cytometry.

[31]  A. Stringaro,et al.  Intracellular P‐glycoprotein expression is associated with the intrinsic multidrug resistance phenotype in human colon adenocarcinoma cells , 2000, International journal of cancer.

[32]  M. Flens,et al.  Tissue distribution of the multidrug resistance protein. , 1996, The American journal of pathology.

[33]  L. Ratner,et al.  Multidrug resistance transporters and modulation , 2000, Current opinion in oncology.

[34]  S. Brenner,et al.  The structure of the nervous system of the nematode Caenorhabditis elegans. , 1986, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[35]  E. Gray,et al.  The Fine Structure of the Nervous System , 1971 .

[36]  Josemir W Sander,et al.  Some Aspects of Prognosis in the Epilepsies: A Review , 1993, Epilepsia.

[37]  N. Vilaboa,et al.  Regulation of Multidrug Resistance 1 (MDR1)/P-glycoprotein Gene Expression and Activity by Heat-Shock Transcription Factor 1 (HSF1)* , 2000, The Journal of Biological Chemistry.

[38]  R. Guerrini.  Dysplasias of cerebral cortex and epilepsy , 1996 .

[39]  S. Shorvon.  Abnormal Cortical Development and Epilepsy: from Basic to Clinical Science , 2001 .

[40]  M. Kool,et al.  Specific detection of multidrug resistance proteins MRP1, MRP2, MRP3, MRP5, and MDR3 P-glycoprotein with a panel of monoclonal antibodies. , 2000, Cancer research.

[41]  T. Ishikawa,et al.  Posttranscriptional Regulation ofMRP/GS-XPump and γ-Glutamylcysteine Synthetase Expression by 1-(4-Amino-2-methyl-5-pyrimidinyl) methyl-3- (2-chloroethyl)-3-nitrosourea and by Cycloheximide in Human Glioma Cells , 1997 .

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

[43]  A. Schinkel,et al.  P-Glycoprotein, a gatekeeper in the blood-brain barrier. , 1999, Advanced drug delivery reviews.

[44]  M. Kool,et al.  A family of drug transporters: the multidrug resistance-associated proteins. , 2000, Journal of the National Cancer Institute.

[45]  M. Kuwano,et al.  Expression of multidrug resistance protein gene in patients with glioma after chemotherapy. , 1998, Journal of neuro-oncology.

[46]  V. Poukens,et al.  Neuronal cytoskeletal abnormalities in human cerebral cortical dysplasia , 1994, Acta Neuropathologica.