Adverse effect of cyclosporin A on barrier functions of cerebral microvascular endothelial cells after hypoxia-reoxygenation damage in vitro.

Abstract

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.

• Authors: Shinya Dohgu, Tsuyoshi Nishioku, Noriko Sumi, Fuyuko Takata, Shinsuke Nakagawa, Mikihiko Naito, Takashi Tsuruo, Atsushi Yamauchi, Hideki Shuto, Yasufumi Kataoka
• Journal: Cellular and molecular neurobiology (Cell Mol Neurobiol) Vol. 27 Issue 7 Pg. 889-99 (Nov 2007) ISSN: 0272-4340 [Print] United States
• PMID: 17934807 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Albumins
• Fluorescent Dyes
• Immunosuppressive Agents
• Evans Blue
• Cyclosporine
• Glucose
• Oxygen
• Fluorescein

Topics

• Albumins (pharmacokinetics)
• Animals
• Blood-Brain Barrier (drug effects, metabolism)
• Capillary Permeability (drug effects)
• Cell Line, Transformed
• Cyclosporine (toxicity)
• Endothelial Cells (cytology, drug effects, metabolism)
• Evans Blue (pharmacokinetics)
• Fluorescein (pharmacokinetics)
• Fluorescent Dyes (pharmacokinetics)
• Glucose (pharmacokinetics)
• Hypoxia (metabolism)
• Immunosuppressive Agents (toxicity)
• In Vitro Techniques
• Mice
• Mice, Inbred BALB C
• Oxygen (pharmacology)