Anti-inflammatory effects of 8-hydroxy-2'-deoxyguanosine on lipopolysaccharide-induced inflammation via Rac suppression in Balb/c mice.

Abstract 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-α, IL-6, IL-18, and IL-12p70) in serum and infiltration of neutrophils, increased translocation of NF-κB 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.