Inhibitory effects of 2,6-Di-O-methyl-3-O-acetyl-beta-cyclodextrins with various degress of substitution of acetyl group on macrophage activation and endotoxin shock induced by lipopolysaccharide

摘要

The effects of 2,6-di-O-methyl-3-O-acetyl-beta-cyclodextrins (DMA-beta-CyD) with various degrees of substitution (DS) of an acetyl group of 1.5,3.8,6.3 and 7,which are abbreviated to DMA2-beta-CyD,DMA4-beta-CyD,DMA6-beta-CyD and DMA7-beta-CyD,respectively,on murine macrophage activation and endotoxin shock induced by lipopolysaccharide (LPS) were examined.Of four DMA-beta-CyDs used in the present study,cytotoxicity of DMA-beta-CyDs in RAW264.7 cells,a murine macrophage-like cell line,decreased with an increase in the DS values of DMA-beta-CyD,and DMA7-beta-CyD had no cytotoxicity on RAW264.7 cells up to 100 mM.DMA2-beta-CyD and DMA7-beta-CyD at the concentration of 5 mM had greater inhibitory effects on nitric oxide (NO) production in RAW264.7 cells stimulated with LPS than DMA4-beta-CyD and DMA6-beta-CyD.In addition,these inhibitory effects of DMA2-beta-CyD and DMA7-beta-CyD were concentration-dependent.In the in vivo study,all of the mice died within 12 h after intraperitoneal administration of the solution containing LPS and D-galactosamine.When 100 mM DMA7-beta-CyD was concomitantly administered with both LPS and D-galactosamine intraperitoneally in mice,the survival rate significantly increased,but DMA4-beta-CyD and DMA6-beta-CyD did not.In conclusion,we revealed that DS values of DMA-beta-CyDs strikingly affect not only the cytotoxic activity but also the inhibitory effects of LPS-induced NO production in RAW264.7 cells and fatality of endotoxin shock mice induced by LPS and D-galactosamine.These results suggest the potential use of DMA7-beta-CyD as an antagonist of LPS-induced endotoxin shock.