Planta Med 2004; 70(1): 17-22
DOI: 10.1055/s-2004-815449
Original Paper
Pharmacology
© Georg Thieme Verlag Stuttgart · New York

Suppression of Infection-Induced Endotoxin Shock in Mice by a Citrus Flavanone Naringin

Kiichiro Kawaguchi1 , Sei-ichi Kikuchi1 , Ryoichi Hasunuma2 , Hiroko Maruyama3 , Roland Ryll2 , Yoshio Kumazawa2
  • 1Medicinal Plant Garden, School of Pharmaceutical Sciences, Kitasato University, Japan
  • 2Department of Biosciences, School of Science, Kitasato University, Japan
  • 3Department of Pathology, School of Allied Health Sciences, Kitasato University, Japan
This study was supported in part by grant-in-aid for Research on Health Sciences focusing on Drug from the Japan Health Sciences Foundation (KH31031) to Y.K., and a grant-in-aid for Scientific Research (Project 12 and 15) from the School of Pharmaceutical Sciences, Kitasato University to K.K.
Further Information

Publication History

Received: June 23, 2003

Accepted: November 22, 2003

Publication Date:
06 February 2004 (online)

Abstract

The protective effect of the Citrus flavanone naringin was demonstrated in an endotoxin shock model based on Salmonella infection. Intraperitoneal (i. p.) infection with 108 CFU Salmonella typhimurium aroA caused lethal shock in lipopolysaccharide (LPS) -responder but not LPS-non-responder mice. Administration of 1 mg naringin 3 h before infection resulted in protection from lethal shock, similar to LPS-non-responder mice. The protective effect of naringin was time- and dose-dependent. Treatment with naringin resulted not only in a significant decrease in bacterial numbers in spleens and livers, but also in a decrease in plasma LPS levels. In addition, naringin markedly suppressed TNF-α and normalized the activated states of blood coagulation factors such as prothrombin time, fibrinogen concentration and platelet numbers caused by infection. Interestingly, treatment with naringin suppressed high levels of soluble CD14 and high mobility group-1 molecule caused by infection.

References

  • 1 Beutler B, Poltorak A. Positional cloning LPS, and the general role of toll-like receptors in the innate immune response.  Eur Cytokine Network. 2000;  11 143-52
  • 2 Beutler B, Cerami A. Cachectin/tumor necrosis factor: an endogenous mediator of shock and inflammation.  Annu Rev Biochem. 1985;  57 505-16
  • 3 Old L J. Tumor necrosis factor (TNF).  Science. 1985;  230 630-2
  • 4 Hasunuma R, Morita H, Tanaka S, Roland R, Freudenberg M A, Galanos C, Kumazawa Y. Differential clearance and induction of host responses by various administered or released lipopolysaccharides.  J Endotoxin Res. 2001;  7 421-9
  • 5 Azumi S, Tanimura A, Tanamato K. A novel inhibition of bacterial endotoxin derived from cinnamon bark.  Biochem Biophys Res Commun. 1997;  234 506-10
  • 6 Galanos C, Freudenberg M A, Reutter W. Galactosamine-induced sensitization to the lethal effects of endotoxin.  Proc Natl Acad Sci USA. 1979;  76 5939-43
  • 7 Kawaguchi K, Kikuchi S, Hasegawa H, Maruyama H, Morita H, Kumazawa Y. Suppression of lipopolysaccharide-induced tumor necrosis factor-release and liver injury in mice by naringin.  Eur J Pharmacol. 1999;  368 245-50
  • 8 Kawaguchi K, Hasunuma R, Kikuchi S, Roland R, Morikawa K, Kumazawa Y. Time- and dose-dependent effect of fosfomycin on suppression of infection-induced endotoxin shock in mice.  Biol Pharm Bull. 2002;  25 1658-61
  • 9 Ng T B, Ling J M, Wang Z T, Cai J N, Xu G J. Examination of coumarins, flavonoids and polysaccharopeptide for antibacterial activity.  Gen Pharmacol. 1996;  27 1237-40
  • 10 Morita H, Hasunuma R, Hoshino M, Fujihara M, Tanaka S, Yamamoto S, Kumazawa Y. Difference in clearance of exogenously administered smooth-form LPS following host response among normal, sensitized and LPS-tolerant mice.  J Endotoxin Res. 1997;  4 415-23
  • 11 Wang H, Bloom O, Zhang M, Vishnubhakat J M, Ombrellino M, Che J, Frazier A, Yang H, Ivanova S, Borovikova L, Manogue K R, Faist E, Abraham E, Andersson J, Andersson U, Molina P E, Abumrad N N, Sama A, Tracey K J. HMG-1 as a late mediator of endotoxin lethality in mice.  Science. 1999;  285 248-51
  • 12 Takahashi K, Morikawa A, Kato Y, Sugiyama T, Koide N, Mu M M, Yoshida T, Yokochi T. Flavonoids protect mice from two types of lethal shock induced by endotoxin.  FEMS Immunol Med Microbiol. 2001;  31 29-33
  • 13 Mammen E F. The hematological manifestations of sepsis.  J Antimicrob Chemother. 1998;  41 A17-A24
  • 14 Yun-Choi H S, Pyo M K, Chang K C, Lee D H. The effects of higenamine on LPS-induced experimental disseminated intravascular coagulation (DIC) in rats.  Planta Med. 2002;  68 326-29
  • 15 Lee C H, Jeong T S, Choi Y K, Hyun B H, Oh G T, Kim E H, Kim J R, Han J I, Bok S H. Anti-atherogenic effect of citrus flavonoids, naringin and naringenin, associated with hepatic ACAT and aortic VCAM-1 and MCP-1 in high cholesterol-fed rabbits.  Biochem Biophys Res Commun. 2001;  284 681-8
  • 16 Kim H K, Cheon B S, Kim Y H, Kim S Y, Kim H P. Effects of naturally occurring flavonoids on nitric oxide production in the macrophage cell line RAW 264.7 and their structure-activity relationships.  Biochem Pharmacol. 1999;  58 759-65
  • 17 Wadsworth T L, McDonald T L, Koop D R. Effects of Ginkgo biloba extract (EGb 761) and quercetin on lipopolysaccharide-induced signaling pathways involved in the release of tumor necrosis factor-alpha.  Biochem Pharmacol. 2001;  62 963-74
  • 18 Xagorari A, Roussos C, Papapetropoulos A. Inhibition of LPS-stimulated pathways in macrophages by the flavonoid luteolin.  Br J Pharmacol. 2002;  136 1058-64
  • 19 Van Dien M, Takahashi K, Mu M M, Koide N, Sugiyama T, Mori I, Yoshida T, Yokochi T. Protective effect of wogonin on endotoxin-induced lethal shock in D-galactosamine-sensitized mice.  Microbiol Immunol. 2001;  45 751-6
  • 20 Kotanidou A, Xagorari A, Bagli E, Kitsanta P, Fotsis T, Papapetropoulos A, Roussos C. Luteolin reduces lipopolysaccharide-induced lethal toxicity and expression of proinflammatory molecules in mice.  Am J Respir Crit Care Med. 2002;  165 818-23

Dr. Yoshio Kumazawa

Department of Biosciences

School of Science

Kitasato University

1-15-1 Kitasato

Sagamihara

Kanagawa 228-8555

Japan

Phone: +81-42-778-9534

Fax: +81-42-778-9534

Email: kumazawa@jet.sci.kitasato-u.ac.jp