Expression and cellular distribution of multidrug transporter proteins in two major causes of medically intractable epilepsy: focal cortical dysplasia and glioneuronal tumors

Multidrug Resistance-Associated Proteins: Expression and Function in the Central Nervous System

“…Immunohistochemical studies in neurons from normal human tissue adjacent to dysembryoplastic neuroepithelial tumors, glioblastomas, and cerebral hemorrhages support the presence of MRP4, MRP5, and MRP8, but not MRP2 protein in human brain sections (Nies et al, 2004;Vogelgesang et al, 2004;Bortfeld et al, 2006). In contrast, neurons adjacent to MRP1-staining dysplastic neurons (from resected epileptic or glioma tissue samples) are devoid of MRP1 (Sisodiya et al, 2001;Aronica et al, 2003;Nies et al, 2004). Likewise, perilesional tissue obtained from surgical resections of gliomas and cerebral hemorrhage showed no MRP3 expression and inconsistent MRP6 staining in pyramidal neurons (Nies et al, 2004).…”

“…Human astrocytes maintained in culture show considerable amounts of MRP1 protein expression when probed with the MRP1-specific monoclonal antibody MRPr1 (Spiegl-Kreinecker et al, 2002). However, MRP1 expression in resting astrocytes in situ has yet to be established (Aronica et al, 2003;Nies et al, 2004). Recently Nies et al (2004) showed strong MRP4 and MRP5 staining in both resting and reactive astrocytes present in resected perilesional glioma and cerebral hemorrhage biopsy samples.…”

“…Although the reasons for the observed resistance to antiepileptic drugs (AEDs) is probably multifactorial (Sisodiya et al, 2002), increasingly evidence supports increased expression of various MRP isoforms as one contributory mechanism [see Loscher and Potschka (2002) for a detailed account of the role of drug transporters in AED pharmacoresistance]. Immunocytochemical studies have positively identified the MRP1 152 protein in dysplastic neurons, reactive astrocytes, and balloon cells (glial elements of focal cortical dysplasia) of malformations commonly observed in refractory epilepsy, i.e., human focal cortical dysplasia, dysembryoplastic neuroepithelial tumors, and hippocampal sclerosis samples (Sisodiya et al, 2001(Sisodiya et al, , 2002Aronica et al, 2003). Generally, the MRP1 staining was more prominent in the epileptic lesions, compared with surrounding normal tissue samples.…”

The complexity of roles of P-glycoprotein in refractory epilepsy: Pharmacoresistance, epileptogenesis, SUDEP and relapsing marker after surgical treatment

“…This P-gp induced expression depends on the frequency and intensity of seizures and is related to a progressive increase of the pharmacoresistant phenotype [45]. Furthermore, the induced "de novo" expression of P-gp in previously non-expressive cells as observed particularly in neurons from epileptogenic brain areas, suggests a differential role of this transporter, perhaps related to the intrinsic convulsive mechanism [29,33,46].…”

Prospective Randomized Controlled Trial of Nimodipine as Add-On Therapy in the Treatment of Focal Refractory Epilepsy Patients: A Pilot Study

“…In the last years, there is increasing evidence that drug efflux transporters (namely P-gp protein [P-glycoprotein] and MDRP [multidrug resistant protein] may play a role in drug-resistant epilepsy by limiting gastrointestinal absorption and brain access of antiepileptic drugs [7][8][9][10][11][12][13].…”