Research paperExpression and cellular distribution of multidrug transporter proteins in two major causes of medically intractable epilepsy: focal cortical dysplasia and glioneuronal tumors
Section snippets
Subjects
The 30 cases included in this study were obtained from the files of the departments of neuropathology of the Academical Medical Center (University of Amsterdam) and the University Medical Center in Utrecht. Patients underwent resection of FCD or GG for medically intractable epilepsy. Tissue was obtained and used in a manner compliant with the Declaration of Helsinki. Two neuropathologists reviewed all cases independently, and confirmed the diagnosis of FCD or GG. For the FCD we followed the
Case material and histological features
The clinical features of the cases included in this study are summarized in Table 1. There were 15 FCD and 15 GG and all patients had a history of chronic pharmaco-resistant epilepsy. Postoperatively, 10 patients with FCD (67%) and 11 patients with GG (73%) were completely seizure free. The long-term follow-up of seizure outcome after surgery in glioneuronal tumors (including that of most of the lesions of the present series) has been presented elsewhere (Aronica et al., 2001b). In this study
Discussion
The present study describes the immunocytochemical expression and cellular distribution of proteins involved as extrusion pumps in multidrug resistance in two major causes of pediatric medically intractable epilepsy, FCD and glioneuronal tumors (GG). The findings can be summarized as follows: (1) compared with expression in normal brain, both FCD and GG showed intralesional induction of MRP1 and P-gp expression involving both glial and neuronal cells; (2) overexpression of MRP1 was localized in
Conclusions
The data presented in this study demonstrate that the overexpression of multidrug transporter protein is a common feature of both FCD and GG. This overexpression is likely responsible for, or at least contributes to, the intrinsic drug resistance of these developmental lesions. The cell-specific expression of MRP1 and P-gp would impair drug responsiveness at three consecutive steps: (1) at the level of the endothelial cells in lesional capillaries (P-gp), leading to a decreased tissue drug
Acknowledgements
This work was supported by the “Christelijke Vereniging voor de Verpleging van Lijders aan Epilepsie” (J. A. Gorter, E. Aronica), the Stichting AZUA-funds (E. Aronica), the National Epilepsy Fund “Power of the Small” and Hersenstichting Nederland (NEF 02-10; E. Aronica). We thank W. P. Meun for expert photography.
References (73)
- et al.
Glioneuronal tumors and medically intractable epilepsya clinical study with long-term follow-up of seizure outcome after surgery
Epilepsy Res
(2001) - et al.
Mechanisms underlying epileptogenesis in cortical malformations
Epilepsy Res
(1999) - et al.
High levels of P-glycoprotein detected in isolated brain capillaries
Biochim Biophys Acta
(1993) - et al.
Astrocytes in kindlingrelevance to epileptogenesis
Epilepsy Res
(1996) - et al.
Tuberous sclerosis associated with MDR1 gene expression and drug-resistant epilepsy
Pediatr Neurol
(1999) - et al.
The (patho)physiological functions of the MRP family
Drug Resist Updat
(2000) - et al.
Expression of multidrug resistance protein 1 (MRP1) in the rat cochlea with special reference to the blood-inner ear barrier
Brain Res
(2001) - et al.
Multidrug-resistance protein 1 in focal cortical dysplasia
Lancet
(2001) - et al.
Selective coexpression of NMDAR2A/B and NMDAR1 subunit proteins in dysplastic neurons of human epileptic cortex
Exp Neurol
(1999) - et al.
Expression of various multidrug resistance-associated protein (MRP) homologues in brain microvessel endothelial cells
Brain Res
(2000)
Drug resistance in epilepsythe role of the blood-brain barrier
Novartis Found Symp
Intracellular P-glycoprotein in multidrug resistant tumor cells
Ital J Anat Embryol
Expression of connexin 43 and connexin 32 gap junction proteins in epilepsy-associated brain tumors and in the perilesional epileptic cortex
Acta Neuropathol
Upregulation of metabotropic glutamate receptor subtype mGluR3 and mGluR5 in reactive astrocytes in a rat model of mesial temporal lobe epilepsy
Eur J Neurosci
Ionotropic and metabotropic glutamate receptor protein expression in glioneuronal tumours from patients with intractable epilepsy
Neuropathol Appl Neurobiol
Expression of BDNF and tyrosine kinase B (TrkB) receptor proteins in glioneuronal tumors from patients with intractable epilepsycolocalization with NMDA receptor
Acta Neuropathol
Biochemical and clinical aspects of efflux pump related resistance to anti-cancer drugs
Anticancer Res
Gangliogliomasan intriguing tumor entity associated with focal epilepsies
J Neuropathol Exp Neurol
Detection of P-glycoprotein in the nuclear envelope of multidrug resistant cells
Histochem J
Neurodevelopmental disorders as a cause of seizuresneuropathologic, genetic, and mechanistic considerations
Brain Pathol
Molecular and functional MDR1-Pgp and MRPs expression in human glioblastoma multiforme cell lines
Int J Cancer
[Expression of P-glycoprotein as a multidrug resistance gene product in human reactive astrocytes and astrocytoma]
Zentralbl Pathol
Overexpression of multiple drug resistance genes in endothelial cells from patients with refractory epilepsy
Epilepsia
Neuropathologic findings in cortical resections (including hemispherectomies) performed for the treatment of intractable childhood epilepsy
Acta Neuropathol
Immunochemical detection of the multidrug resistance-associated protein MRP in human multidrug-resistant tumor cells by monoclonal antibodies
Cancer Res
Tissue distribution of the multidrug resistance protein
Am J Pathol
Brain microvascular P-glycoprotein and a revised model of multidrug resistance in brain
Cell Mol Neurobiol
Functional role for the 170- to 180-kDa glycoprotein specific to drug-resistant tumor cells as revealed by monoclonal antibodies
Proc Natl Acad Sci USA
Pathology of temporal lobectomy for refractory seizures in childrenreview of 20 cases including some unique malformative lesions
J Neurosurg
Detection of P-glycoprotein in multidrug-resistant cell lines by monoclonal antibodies
Nature
Childhood ganglioglioma and medically intractable epilepsya clinicopathological study of 15 patients and a review of the literature
Pediatr Neurosurg
Mdr1 mRNA expression differs between grade III astrocytomas and glioblastomas
Clin Neuropathol
World Health Organization classification of tumours: pathology and genetics of tumours of the nervous system
Detection of P-glycoprotein in frozen and paraffin-embedded gastric adenocarcinoma tissues using a panel of monoclonal antibodies
Histopathology
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