In vivo down-regulation of mouse brain capillary P-glycoprotein: a preliminary investigation.
Over-expression of blood-brain barrier P-glycoprotein is considered as a major hurdle in the treatment of various CNS disorders. A down-regulation strategy is considered as one means to counteract disease- or therapy-associated induction of P-glycoprotein. Here, we evaluated whether a targeting of P-glycoprotein can be achieved in mouse brain capillary endothelial cells using siRNA. A 4-day treatment paradigm with once daily hydrodynamic intravenous injections of siRNA resulted in a significant reduction of the P-glycoprotein-labeled area in the hippocampal hilus and parietal cortex. P-glycoprotein expression proved to be down-regulated in these brain regions by 31 and 16%, respectively. An impact of siRNA administration on density of brain capillaries was excluded by quantification of the endothelial cell marker GLUT-1. In conclusion, the study provides first preliminary evidence that a down-regulation of P-glycoprotein can be achieved in brain capillary endothelial cells by administration of siRNA in vivo.
Fuest
Christina
C
Inst of Pharmacology, Toxicology, and Pharmacy, Ludwig-Maximilians-University Munich, 80539 Munich, Germany.
Bankstahl
Marion
M
Winter
Petra
P
Helm
Mark
M
Pekcec
Anton
A
Potschka
Heidrun
H
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D001921:Brain / Q000098:blood supply* / Q000378:metabolism; D002196:Capillaries / Q000378:metabolism*; D015536:Down-Regulation; D042783:Endothelial Cells / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D006624:Hippocampus / Q000098:blood supply / Q000378:metabolism; D007150:Immunohistochemistry; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010296:Parietal Lobe / Q000098:blood supply / Q000378:metabolism; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D051272:Glucose Transporter Type 1; D034741:RNA, Small Interfering; C495678:Slc2a1 protein, mouse