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¹ Department of Cell Biology, Faculty of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan
² Department of Neurosurgery, Faculty of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8507, Japan
³ KAN Research Institute, Kyoto Research Park, Shimogyo-ku, Kyoto 606-8317, Japan
⁴ Department of Physiology, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto 602-0841, Japan
⁵ Department of Molecular Cell Biology, Institute of DNA Medicine, Jikei University School of Medicine, Minato-ku, Tokyo 105-8461, Japan

Address correspondence to Shoichiro Tsukita, Dept. of Cell Biology, Faculty of Medicine, Kyoto University, Yoshida-Konoe, Sakyo-ku, Kyoto 606-8501, Japan. Tel.: 81-75-753-4372. Fax: 81-75-753-4660. E-mail: htsukita{at}mfour.med.kyoto-u.ac.jp

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.

Key Words: tight junction; central nervous system; endothelial cells; blood vessel; drug delivery

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