title: Inhibitory effect of naringin on lipopolysaccharide (LPS)-induced endotoxin shock in mice and nitric oxide production in RAW 264.7 macrophages.
abstract: Lipopolysaccharide (LPS) has been known to induce endotoxin shock via production of inflammatory modulators such as tumor necrosis factor alpha (TNF-alpha), or nitric oxide (NO). In this study, we have examined the effect of naringin (NG), one of the flavonoids, on LPS-induced endotoxin shock in mice and NO production in RAW 264.7 macrophages. For intraperitoneal (i.p., 20 mg/kg) injection of LPS at 48 h, the survival rate of mice administered with LPS alone (n=10) or pretreated with NG at 10, 30 and 60 mg/kg (i.p.) group (n=10) was 0% or 10%, 50% and 70%, respectively. NG dose-dependently suppressed LPS-induced production of TNF-alpha. LPS-induced production of NO at 6 h (125.89+/-16.35 microM), as measured by nitrite formation, was significantly reduced by NG at 30 or 60 mg/kg for 49.49+/-4.81 or 27.91+/-1.81 microM (P<0.01 vs. LPS alone), respectively. To further examine the mechanism by which NG suppresses LPS-induced endotoxin shock, we used an in vitro model, RAW 264.7 mouse macrophage cells. NG (1 mM) suppressed LPS (0.01, 0.1 or 1 microg/ml)-induced production of NO and the expression of inflammatory gene products such as inducible NO synthase (iNOS), TNF-alpha, inducible cyclooxygenase (COX-2) and interleukin-6 (IL-6) as determined by RT-PCR assay. NG was found to have blocked the LPS-induced transcriptional activity of NF-kappaB in electrophoretic mobility shift assay and reporter assay. These findings suggest that suppression of the LPS-induced mortality and production of NO by NG is due to inhibition of the activation of NF-kappaB.
authors.affiliation: Department of Pharmacology and Toxicology, Cancer Research Institute, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan. syu-kan@tohoku-pharm.ac.jp
authors.forename: Syu-Ichi
authors.initials: S
authors.lastname: Kanno
authors.forename: Ai
authors.initials: A
authors.lastname: Shouji
authors.forename: Ayako
authors.initials: A
authors.lastname: Tomizawa
authors.forename: Takako
authors.initials: T
authors.lastname: Hiura
authors.forename: Yuu
authors.initials: Y
authors.lastname: Osanai
authors.forename: Mayuko
authors.initials: M
authors.lastname: Ujibe
authors.forename: Yutaro
authors.initials: Y
authors.lastname: Obara
authors.forename: Norimichi
authors.initials: N
authors.lastname: Nakahata
authors.forename: Masaaki
authors.initials: M
authors.lastname: Ishikawa
mesh_terms: D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004926:Escherichia coli / Q000276:immunology; D044950:Flavanones / Q000494:pharmacology*; D007274:Injections, Intraperitoneal; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012772:Shock, Septic / Q000188:drug therapy / Q000401:mortality / Q000517:prevention & control*; D015996:Survival Rate; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D044950:Flavanones; D015850:Interleukin-6; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D051546:Cyclooxygenase 2; C005274:naringin