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

Cited 21 time in Web of Science Cited 23 time in Scopus
Authors
Choi, Seongwon; Choi, Hyun-Ho; Lee, Sun-Hye; Ko, Seong-Hee; You, Ho-Jin; Ye, Sang-Kyu; Chung, Myung-Hee
Issue Date
2007-11-27
Publisher
Elsevier
Citation
Free Radic Biol Med. 2007 Dec 15;43(12):1594-603. Epub 2007 Sep 6.
Keywords
AnimalsAnti-Inflammatory Agents, Non-Steroidal/pharmacologyCytokines/bloodDeoxyguanosine/*analogs & derivatives/pharmacologyFree Radicals/metabolismInflammation/chemically induced/metabolism/*prevention & controlJNK Mitogen-Activated Protein Kinases/metabolismLipopolysaccharides/toxicityLung/drug effects/metabolism/pathologyMaleMiceMice, Inbred BALB CNF-kappa B p50 Subunit/metabolismNeutrophils/drug effects/pathologyPeroxidase/metabolismrac GTP-Binding Proteins/*antagonists & inhibitors
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-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.
ISSN
0891-5849 (Print)
Language
English
URI
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18037125

http://hdl.handle.net/10371/29411
DOI
https://doi.org/10.1016/j.freeradbiomed.2007.08.022
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College of Medicine/School of Medicine (의과대학/대학원)Pharmacology (약리학전공)Journal Papers (저널논문_약리학전공)
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