title: Vascular colocalization of P-glycoprotein, multidrug-resistance associated protein 1, breast cancer resistance protein and major vault protein in human epileptogenic pathologies.
abstract: Multidrug transporters, such as P-glycoprotein (P-gp), multidrug-resistance associated protein 1 (MRP1) and breast cancer resistance protein (BCRP), are associated with multidrug resistance in cancers; other molecules, such as major vault protein (MVP), have a similar association with drug-resistant cancer. These proteins are postulated to generate drug resistance in epilepsy. They have been shown individually to be up-regulated in epileptogenic brain tissue. In any consideration of the function, inhibition or evasion of the activity of such proteins, the colocalization of such proteins needs to be understood. We systematically determined the presence of such colocalization, focusing on microvascular endothelium from epileptogenic human brain tissue. Double labelling immunofluorescence and confocal laser scanning microscopy were used to determine colocalization of P-gp, MRP1, BCRP and MVP in one case of hippocampal sclerosis and two cases of focal cortical dysplasia type IIb. Endothelial colocalization was examined with double labelling using antibodies to CD34 and Factor VIII. The presence of P-gp, BCRP and MVP in microvascular endothelium was confirmed. P-gp, BCRP and MVP colocalized in microvascular endothelium, though not all proteins appeared to be identically distributed within this tissue. MRP1 did not colocalize to endothelium. These findings were not unexpected but required formal confirmation. The demonstrated colocalization of P-gp, BCRP and MVP in microvascular endothelium in epileptogenic human brain tissue has important implications for functional experiments (including single knock-out mice studies), work with specific and broad-spectrum inhibitors of transport function, and any eventual trials of treatment of refractory epilepsy involving modulation of the function of these proteins.
authors.affiliation: Department of Clinical and Experimental Epilepsy, Institute of Neurology, University College London, London WC1N 3BG, UK. sisodiya@ion.ucl.ac.uk
authors.forename: S M
authors.initials: SM
authors.lastname: Sisodiya
authors.forename: L
authors.initials: L
authors.lastname: Martinian
authors.forename: G L
authors.initials: GL
authors.lastname: Scheffer
authors.forename: P
authors.initials: P
authors.lastname: van der Valk
authors.forename: R J
authors.initials: RJ
authors.lastname: Scheper
authors.forename: B N
authors.initials: BN
authors.lastname: Harding
authors.forename: M
authors.initials: M
authors.lastname: Thom
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D018432:Drug Resistance, Multiple; D004730:Endothelium, Vascular / Q000378:metabolism*; D004827:Epilepsy / Q000378:metabolism*; D006624:Hippocampus / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D018613:Microscopy, Confocal; D009363:Neoplasm Proteins / Q000378:metabolism*; D020394:Vault Ribonucleoprotein Particles / Q000378:metabolism*; D000099187:Major Vault Protein
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D009363:Neoplasm Proteins; D020394:Vault Ribonucleoprotein Particles; D000099187:Major Vault Protein; C116614:ABCG2 protein, human