Size-selective loosening of the blood-brain barrier in claudin-5-deficient mice.
Tight junctions are well-developed between adjacent endothelial cells of blood vessels in the central nervous system, and play a central role in establishing the blood-brain barrier (BBB). Claudin-5 is a major cell adhesion molecule of tight junctions in brain endothelial cells. To examine its possible involvement in the BBB, claudin-5-deficient mice were generated. In the brains of these mice, the development and morphology of blood vessels were not altered, showing no bleeding or edema. However, tracer experiments and magnetic resonance imaging revealed that in these mice, the BBB against small molecules (<800 D), but not larger molecules, was selectively affected. This unexpected finding (i.e., the size-selective loosening of the BBB) not only provides new insight into the basic molecular physiology of BBB but also opens a new way to deliver potential drugs across the BBB into the central nervous system.
Nitta
Takehiro
T
Department of Cell Biology, Faculty of Medicine, Kyoto University, Japan.
Hata
Masaki
M
Gotoh
Shimpei
S
Seo
Yoshiteru
Y
Sasaki
Hiroyuki
H
Hashimoto
Nobuo
N
Furuse
Mikio
M
Tsukita
Shoichiro
S
D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000235:genetics*; D001921:Brain / Q000098:blood supply* / Q000196:embryology / Q000648:ultrastructure; D062507:Claudin-5; D004730:Endothelium, Vascular / Q000196:embryology* / Q000378:metabolism* / Q000648:ultrastructure; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005333:Fetus; D005456:Fluorescent Dyes / Q000494:pharmacology; D019786:Gadolinium DTPA / Q000493:pharmacokinetics; D007150:Immunohistochemistry; D008279:Magnetic Resonance Imaging; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency* / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008854:Microscopy, Electron; D015335:Molecular Probes / Q000494:pharmacology; D008970:Molecular Weight; D018919:Neovascularization, Physiologic / Q000235:genetics*; D011930:Reaction Time / Q000187:drug effects / Q000235:genetics; D019108:Tight Junctions / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure
D062507:Claudin-5; C491511:Cldn5 protein, mouse; D005456:Fluorescent Dyes; D008565:Membrane Proteins; D015335:Molecular Probes; D019786:Gadolinium DTPA