title: Inhibitory effects of dimethylacetyl-beta-cyclodextrin on lipopolysaccharide-induced macrophage activation and endotoxin shock in mice.
abstract: 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.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Kumamoto 862-0973, Japan.
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Arima
authors.forename: Keiichi
authors.initials: K
authors.lastname: Motoyama
authors.forename: Akihiro
authors.initials: A
authors.lastname: Matsukawa
authors.forename: Yoji
authors.initials: Y
authors.lastname: Nishimoto
authors.forename: Fumitoshi
authors.initials: F
authors.lastname: Hirayama
authors.forename: Kaneto
authors.initials: K
authors.lastname: Uekama
mesh_terms: 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*
chemical_list: 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