S-Space College of Medicine/School of Medicine (의과대학/대학원) Pharmacology (약리학전공) Journal Papers (저널논문_약리학전공)
Anti-inflammatory effects of 8-hydroxy-2'-deoxyguanosine on lipopolysaccharide-induced inflammation via Rac suppression in Balb/c mice
- Choi, Seongwon; Choi, Hyun-Ho; Lee, Sun-Hye; Ko, Seong-Hee; You, Ho-Jin; Ye, Sang-Kyu; Chung, Myung-Hee
- Issue Date
- Free Radic Biol Med. 2007 Dec 15;43(12):1594-603. Epub 2007 Sep 6.
- Animals; Anti-Inflammatory Agents, Non-Steroidal/pharmacology; Cytokines/blood; Deoxyguanosine/*analogs & derivatives/pharmacology; Free Radicals/metabolism; Inflammation/chemically induced/metabolism/*prevention & control; JNK Mitogen-Activated Protein Kinases/metabolism; Lipopolysaccharides/toxicity; Lung/drug effects/metabolism/pathology; Male; Mice; Mice, Inbred BALB C; NF-kappa B p50 Subunit/metabolism; Neutrophils/drug effects/pathology; Peroxidase/metabolism; rac GTP-Binding Proteins/*antagonists & inhibitors
- Recently, we observed that 8-hydroxyguanosine triphosphate and 8-hydroxy-2'-deoxyguanosine (oh(8)dG) inactivate Rac and consequently down-regulate the Rac-linked NADPH oxidase, iNOS, and Cox2. Based on these observations, we tested whether oh(8)dG has anti-inflammatory activity in vivo in lipopolysaccharide (LPS)-treated mice. LPS (1 mg/kg, ip)-treated mice exhibit marked inflammatory responses, including increases in proinflammatory cytokines (TNF-alpha, IL-6, IL-18, and IL-12p70) in serum and infiltration of neutrophils, increased translocation of NF-kappaB p50 from the cytosol to the nucleus, and phosphorylation of c-Jun in lung tissues. Mice were pretreated with oh(8)dG (up to 60 mg/kg, ip) 4 h before LPS injection, and this pretreatment dose-dependently inhibited the inflammatory responses; the inhibitions observed with 60 mg/kg oh(8)dG were statistically significant. At the same time, oh(8)dG pretreatment inactivated Rac in lung tissues. Oh(8)dG pretreatment (50 mg/kg, ip) also significantly protected against LPS-induced septic death. Furthermore, oh(8)dG was more effective than acetyl salicylic acid in inhibiting these inflammatory responses. 8-Hydroxyguanosine also had some effect but was much weaker than oh(8)dG. The effects of normal nucleosides (dG, G, and A) were negligible or not significant. These results support an anti-inflammatory activity for oh(8)dG, which could be ascribed to its Rac-inactivating action.
- 0891-5849 (Print)
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