Indomethacin and cyclosporin a inhibit in vitro ischemia-induced expression of ICAM-1 and chemokines in human brain endothelial cells.
Brain inflammation has been implicated in the development of brain edema and secondary brain damage in ischemia and trauma. Mechanisms involved in leukocyte infiltration across the blood-brain barrier are still unknown. In this study, we show that human cere-bromicrovascular endothelial cells (HCEC) subjected to a 4 h in vitro ischemia (hypoxia + glucose deprivation) followed by a 4-24 h recovery express elevated levels of ICAM-1, IL-8, and MCP-1 mRNAs (semi-quantitative RT-PCR) and secrete increased amounts of the immunoreactive chemokines IL-8 and MCP-1 (ELISA). The ischemia-induced expression of ICAM-1 in HCEC, and the expression/release of IL-8 and MCP-1 in HCEC were abolished by the non-steroid anti-inflammatory drug, indomethacin (100-300 microM). The immunosuppressant cyclosporin A (50 microM) partially reduced the ischemia-stimulated IL-8 and MCP-1 secretion by HCEC. Both indomethacin and cyclosporin A also inhibited the ischemia-induced neutrophil chemotaxis elicited by HCEC media. The study indicates that in vitro ischemia augments the expression of adhesion molecules and leukocyte chemoattractants at the site of the BBB. This ischemic pro-inflammatory activation of HCEC may constitute a key event in initiating post-ischemic inflammation, and it can be suppressed by the anti-inflammatory drugs, indomethacin and cyclosporin A.
Zhang
W
W
Institute for Biological Sciences, National Research Council of Canada, Ottawa, Canada.
Smith
C
C
Monette
R
R
Hutchison
J
J
Stanimirovic
D B
DB
D001812:Blood-Brain Barrier / Q000187:drug effects / Q000276:immunology; D001929:Brain Edema / Q000276:immunology*; D002545:Brain Ischemia / Q000276:immunology*; D015687:Cell Hypoxia / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D018925:Chemokines / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000276:immunology; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism*; D007962:Leukocytes / Q000187:drug effects / Q000276:immunology
D018925:Chemokines; D018799:Intercellular Adhesion Molecule-1; D016572:Cyclosporine; D007213:Indomethacin