Inhibitory effects of dimethylacetyl-beta-cyclodextrin on lipopolysaccharide-induced macrophage activation and endotoxin shock in mice.
The potential use of hydrophilic cyclodextrins (CyDs) as an inhibitor for lipopolysaccharide (LPS) was examined. Of the five CyDs used in this study, dimethylacetyl-beta-cyclodextrin (DMA7-beta-CyD) had greater inhibitory activity than other CyDs against the production of nitric oxide (NO) and various proinflammatory cytokines including tumor necrosis factor-alpha (TNF-alpha) in murine macrophages stimulated with two serotypes of LPS and lipid A. The inhibitory effect of DMA7-beta-CyD on NO production was also observed in macrophages stimulated with lipoteichoic acid (LTA), but not peptidoglycan (PGN), polyinosinic-polycytidylic acid (poly I:C) or CpG oligonucleotide (CpG-ODN). Several studies have suggested that the inhibitory effects of DMA7-beta-CyD could be ascribed to the interaction with LPS. Simultaneous administration of DMA7-beta-CyD not only intraperitoneally but also intravenously and intraperitoneal injection of aqueous solution containing LPS and d-galactosamine in murine endotoxin shock model suppressed fatality. Also, DMA7-beta-CyD decreased blood level of TNF-alpha as well as serum levels of aspartate transaminase (AST) and alanine transaminase (ALT) in mice. In conclusion, DMA7-beta-CyD may have promise as a new therapeutic agent for endotoxin shock induced by LPS.
Arima
Hidetoshi
H
Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Kumamoto 862-0973, Japan.
Motoyama
Keiichi
K
Matsukawa
Akihiro
A
Nishimoto
Yoji
Y
Hirayama
Fumitoshi
F
Uekama
Kaneto
K
D000818:Animals; D001219:Aspartate Aminotransferases; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism / Q000648:ultrastructure; D002470:Cell Survival / Q000187:drug effects; D003505:Cyclodextrins / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D004347:Drug Interactions; D005688:Galactosamine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008024:Ligands; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology*; D008262:Macrophage Activation / Q000187:drug effects*; D019402:Macrophage Inflammatory Proteins; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D012772:Shock, Septic / Q000188:drug therapy / Q000517:prevention & control*; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000187:drug effects; D047392:beta-Cyclodextrins / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
D003505:Cyclodextrins; D008024:Ligands; D008070:Lipopolysaccharides; D019402:Macrophage Inflammatory Proteins; D016328:NF-kappa B; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D047392:beta-Cyclodextrins; C506364:dimethylacetyl-beta-cyclodextrin; D009569:Nitric Oxide; D005688:Galactosamine; D001219:Aspartate Aminotransferases