Expression and cellular distribution of multidrug transporter proteins in two major causes of medically intractable epilepsy: focal cortical dysplasia and glioneuronal tumors.
The cell-specific distribution of multidrug resistance extrusion pumps was studied in developmental glioneuronal lesions, including focal cortical dysplasia (15 cases) and ganglioglioma (15 cases) from patients with medically intractable epilepsy. Lesional, perilesional, as well as normal brain regions were examined for the expression of the multidrug resistance gene 1 encoded P-glycoprotein (P-gp) and the multidrug resistance-associated protein 1 (MRP1) by immunocytochemistry. In normal brain MRP1 expression was below detection, whereas P-gp staining was present only in blood vessels. MRP1 and P-gp immunoreactivity was observed in dysplastic neurons of 11/15 cases of focal cortical dysplasia, as well as in the neuronal component of 14/15 ganglioglioma. Glial cells with astrocytic morphology within the lesion showed multidrug-resistant protein immunoreactivity (P-gp>MRP1). Moderate to strong MRP1 and P-gp immunoreactivity was observed in a population of large ballooned neuroglial cells. P-gp appeared to be most frequently expressed in glial fibrillary acidic protein-positive balloon cells (glial type), whereas MRP1 was more frequently expressed in microtubule-associated protein 2-positive balloon cells (neuronal type). In both types of lesions strong P-gp immunoreactivity was found in lesional vessels. Perilesional regions did not show increased staining in vessels or in neuronal cells compared with normal cortex. The predominant intralesional cell-specific distribution of multidrug transporter proteins supports the hypothesis of a constitutive overexpression as common mechanism underlying the intrinsic pharmaco-resistance to antiepileptic drugs of both malformative and neoplastic glioneuronal developmental lesions.
Aronica
E
E
Department of (Neuro)Pathology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 Amsterdam, The Netherlands. e.aronica@amc.uva.nl
Gorter
J A
JA
Jansen
G H
GH
van Veelen
C W M
CW
van Rijen
P C
PC
Leenstra
S
S
Ramkema
M
M
Scheffer
G L
GL
Scheper
R J
RJ
Troost
D
D
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000293:Adolescent; D000328:Adult; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002540:Cerebral Cortex / Q000002:abnormalities / Q000378:metabolism*; D002648:Child; D002675:Child, Preschool; D004727:Endothelium / Q000378:metabolism / Q000473:pathology; D004827:Epilepsy / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D005260:Female; D018303:Ganglioglioma / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D008297:Male; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008875:Middle Aged; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009457:Neuroglia / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000378:metabolism; D016708:Synaptophysin / Q000378:metabolism; D014746:Vimentin / Q000378:metabolism
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D005904:Glial Fibrillary Acidic Protein; D008869:Microtubule-Associated Proteins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D016708:Synaptophysin; D014746:Vimentin; C418606:neugrin; C421109:multidrug resistance-associated protein 1