Inhibitory Effects of 2,6-Di-O-methyl-3-O-acetyl-β-cyclodextrins with Various Degrees of Substitution of Acetyl Group on Macrophage Activation and Endotoxin Shock Induced by Lipopolysaccharide

  • Keiichi Motoyama
  • Hidetoshi Arima
  • Fumitoshi Hirayama
  • Kaneto Uekama
Article
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Abstract

The effects of 2,6-di-O-methyl-3-O-acetyl-β-cyclodextrins (DMA-β-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-β-CyD, DMA4-β-CyD, DMA6-β-CyD and DMA7-β-CyD, respectively, on murine macrophage activation and endotoxin shock induced by lipopolysaccharide (LPS) were examined. Of four DMA-β-CyDs used in the present study, cytotoxicity of DMA-β-CyDs in RAW264.7 cells, a murine macrophage-like cell line, decreased with an increase in the DS values of DMA-β-CyD, and DMA7-β-CyD had no cytotoxicity on RAW264.7 cells up to 100 mM. DMA2-β-CyD and DMA7-β-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-β-CyD and DMA6-β-CyD. In addition, these inhibitory effects of DMA2-β-CyD and DMA7-β-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-β-CyD was concomitantly administered with both LPS and d-galactosamine intraperitoneally in mice, the survival rate significantly increased, but DMA4-β-CyD and DMA6-β-CyD did not. In conclusion, we revealed that DS values of DMA-β-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-β-CyD as an antagonist of LPS-induced endotoxin shock.

Keywords

degree of substitution dimethylacetyl-β-cyclodextrin endotoxin shock lipopolysaccharide nitric oxide 

Abbreviation

CyDs

cyclodextrins

DMA-β-CyD

2,6-di-O-methyl-3-O-acetyl-β-cyclodextrin

DM-β-CyD

2,6-di-O-methyl-β-CyD

DM-α-CyD

2,6-di-O-methyl-α-CyD

DS

degree of the substitution

iNOS

inducible nitric oxide synthase

LPS

lipopolysaccharide

NO

nitric oxide

RT-PCR

reverse transcriptase-polymerase chain reaction

TLR-4

Toll-like receptor-4

TNF-α

tumor necrosis factor-α

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Notes

Acknowledgements

This work was partially supported by a Grant-in-aid of Sagawa Foundation for Promotion of Frontier Science and Grant-in-aid of Japan Science and Technology Agency.

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Copyright information

© Springer Science+Business Media, Inc. 2006

Authors and Affiliations

  • Keiichi Motoyama
    • 1
  • Hidetoshi Arima
    • 1
  • Fumitoshi Hirayama
    • 1
  • Kaneto Uekama
    • 1
  1. 1.Graduate School of Pharmaceutical SciencesKumamoto UniversityKumamotoJapan

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