Expression and cellular distribution of multidrug resistance-related proteins in the hippocampus of patients with mesial temporal lobe epilepsy.
OBJECTIVE
This study investigated the cellular distribution of different multidrug resistance (MDR)-related proteins such as P-glycoprotein (P-gp), the multidrug resistance-associated proteins (MRP) 1 and 2, and the major vault protein (MVP) in normal and sclerotic hippocampus of patients with medically refractory mesial temporal lobe epilepsy (MTLE).


METHODS
Single- and double-label immunocytochemistry was used on brain sections of control hippocampus and of hippocampus of refractory MTLE patients.


RESULTS
In TLE cases with hippocampal sclerosis (HS), all four MDR proteins examined that had low or no expression in control tissue were upregulated, albeit with different cellular distribution patterns. P-gp immunoreactivity (IR) was observed in astrocytes in regions with diffuse reactive gliosis. In 75% of HS cases, strong P-gp IR was detected in blood vessels, with prominent endothelial labeling. Reactive astrocytes displayed low MRP1 IR. However, glial MRP1 expression was noted in glial endfoot processes around blood vessels. Neuronal MRP1 expression was observed in hypertrophic hilar neurons and in a few residual neurons of the CA1 region. Hippocampal MRP2 expression was observed in the large majority of HS cases in blood vessels. Hypertrophic hilar neurons and blood vessels within the sclerotic hippocampus expressed major vault protein (MVP).


CONCLUSIONS
These findings indicate that MDR proteins are upregulated in concert in the hippocampus of patients with refractory MTLE, supporting their role in the mechanisms underlying drug resistance. The specific cell-distribution patterns within the sclerotic hippocampus suggest different cellular functions, not necessarily linked only to clinical drug resistance.
Aronica
Eleonora
E
Department of (Neuro) Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. e.aronica@amc.uva.nl
Gorter
Jan A
JA
Ramkema
Marja
M
Redeker
Sandra
S
Ozbas-Gerçeker
Filiz
F
van Vliet
Edwin A
EA
Scheffer
George L
GL
Scheper
Rik J
RJ
van der Valk
Paul
P
Baayen
Johannes C
JC
Troost
Dirk
D
Ozbas-Gerçerer
Filiz
F
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000032:analysis / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D001808:Blood Vessels / Q000737:chemistry / Q000378:metabolism; D001927:Brain Diseases / Q000378:metabolism; D019742:Chemokines, CC / Q000032:analysis / Q000378:metabolism; D018432:Drug Resistance, Multiple; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D004833:Epilepsy, Temporal Lobe / Q000378:metabolism*; D005260:Female; D006624:Hippocampus / Q000098:blood supply / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D026901:Membrane Transport Proteins / Q000032:analysis / Q000378:metabolism; D008875:Middle Aged; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000032:analysis / Q000378:metabolism*; D017966:Pyramidal Cells / Q000737:chemistry / Q000378:metabolism; D012598:Sclerosis; D014018:Tissue Distribution; D015854:Up-Regulation; D020394:Vault Ribonucleoprotein Particles / Q000737:chemistry / Q000378:metabolism; D000099187:Major Vault Protein
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D019742:Chemokines, CC; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D020394:Vault Ribonucleoprotein Particles; D000099187:Major Vault Protein; C000715087:ABCC2 protein, human; C070959:Ccl6 protein, mouse