Adverse effect of cyclosporin A on barrier functions of cerebral microvascular endothelial cells after hypoxia-reoxygenation damage in vitro.
Hypoxia and post-hypoxic reoxygenation induces disruption of the blood-brain barrier (BBB). Alterations of the BBB function after hypoxia/reoxygenation (H/R) injury remain unclear. Cyclosporin A (CsA), a potent immunosuppressant, induces neurotoxic effects by entering the brain, although the transport of CsA across the BBB is restricted by P-glycoprotein (P-gp), a multidrug efflux pump, and tight junctions of the brain capillary endothelial cells. The aim of this study was to evaluate whether the BBB after H/R damage is vulnerable to CsA-induced BBB dysfunction. We attempted to establish a pathophysiological BBB model with immortalized mouse brain capillary endothelial (MBEC4) cells. The effects of CsA on permeability and P-gp activity of the MBEC4 cells were then examined. Exposure to hypoxia for 4 h and reoxygenation for 1 h (H/R (4 h/1 h)) produced a significant decrease in P-gp function of MBEC4 cells, without changing cell viability and permeability for sodium fluorescein and Evan's blue-albumin at 7 days after H/R (4 h/1 h). CsA-induced hyperpermeability and P-gp dysfunction in MBEC4 monolayers at 7 days after H/R (4 h/1 h) were exacerbated. The possibility that CsA penetrates the BBB with incomplete functions in the vicinity of cerebral infarcts to induce neurotoxicity has to be considered.
Dohgu
Shinya
S
Department of Pharmaceutical Care and Health Sciences, Faculty of Pharmaceutical Sciences, Fukuoka University, 8-19-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan.
Nishioku
Tsuyoshi
T
Sumi
Noriko
N
Takata
Fuyuko
F
Nakagawa
Shinsuke
S
Naito
Mikihiko
M
Tsuruo
Takashi
T
Yamauchi
Atsushi
A
Shuto
Hideki
H
Kataoka
Yasufumi
Y
D000418:Albumins / Q000493:pharmacokinetics; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000378:metabolism; D002199:Capillary Permeability / Q000187:drug effects; D002461:Cell Line, Transformed; D016572:Cyclosporine / Q000633:toxicity*; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D005070:Evans Blue / Q000493:pharmacokinetics; D019793:Fluorescein / Q000493:pharmacokinetics; D005456:Fluorescent Dyes / Q000493:pharmacokinetics; D005947:Glucose / Q000493:pharmacokinetics; D000860:Hypoxia / Q000378:metabolism*; D007166:Immunosuppressive Agents / Q000633:toxicity*; D066298:In Vitro Techniques; D051379:Mice; D008807:Mice, Inbred BALB C; D010100:Oxygen / Q000494:pharmacology
D000418:Albumins; D005456:Fluorescent Dyes; D007166:Immunosuppressive Agents; D005070:Evans Blue; D016572:Cyclosporine; D005947:Glucose; D010100:Oxygen; D019793:Fluorescein