title: Nitric oxide mediates cyclosporine-induced impairment of the blood-brain barrier in cocultures of mouse brain endothelial cells and rat astrocytes.
abstract: The present study was designed to clarify the involvement of nitric oxide (NO) signaling in the adverse effect of cyclosporine on the blood-brain barrier. Cyclosporine increased the permeability of sodium-fluorescein and the cellular accumulation of rhodamine 123, a substrate of P-glycoprotein, in mouse brain endothelial (MBEC4) cells. This effect was markedly enhanced two- to threefold when MBEC4 cells were cocultured with rat astrocytes or C6 glioma cells. Direct and continuous electrochemical measurement of NO demonstrated that cyclosporine dose-dependently increased histamine- and phenylephrine-evoked NO production in MBEC4 cells and astrocytes, respectively. A NO synthase inhibitor (NG-monomethyl-L-arginine) blocked slightly and markedly cyclosporine-induced impairment of the endothelial barrier in the monolayer and coculture system, respectively. These findings suggest that cyclosporine impairs the brain endothelial barrier function by accelerating NO production in the brain endothelial and astroglial cells. This event may be interpreted as triggering the occurrence of cyclosporine neurotoxicity.
authors.affiliation: Department of Pharmaceutical Care and Health Sciences, Faculty of Pharmaceutical Sciences, Fukuoka University, 8-19-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Dohgu
authors.forename: Atsushi
authors.initials: A
authors.lastname: Yamauchi
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Nakagawa
authors.forename: Fuyuko
authors.initials: F
authors.lastname: Takata
authors.forename: Mamiko
authors.initials: M
authors.lastname: Kai
authors.forename: Takashi
authors.initials: T
authors.lastname: Egawa
authors.forename: Mikihiko
authors.initials: M
authors.lastname: Naito
authors.forename: Takashi
authors.initials: T
authors.lastname: Tsuruo
authors.forename: Yasufumi
authors.initials: Y
authors.lastname: Sawada
authors.forename: Masami
authors.initials: M
authors.lastname: Niwa
authors.forename: Yasufumi
authors.initials: Y
authors.lastname: Kataoka
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000502:physiology; D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000378:metabolism; D001921:Brain / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D018920:Coculture Techniques; D016572:Cyclosporine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019793:Fluorescein / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009569:Nitric Oxide / Q000096:biosynthesis / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D020112:Rhodamine 123 / Q000378:metabolism; D019323:omega-N-Methylarginine / Q000494:pharmacology
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D004791:Enzyme Inhibitors; D020112:Rhodamine 123; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D016572:Cyclosporine; D019001:Nitric Oxide Synthase; D019793:Fluorescein