Potent anti-inflammatory effects of two quinolinedione compounds, OQ1 and OQ21, mediated by dual inhibition of inducible NO synthase and cyclooxygenase-2
- Authors
- Lim, Kyung-Min; Lee, Joo-Young; Lee, Song-Mi; Bae, Ok-Nam; Noh, Ji-Yoon; Kim, Eun-Jin; Chung, Seung-Min; Chung, Jin-Ho
- Issue Date
- Jan-2009
- Publisher
- Wiley-Blackwell
- Keywords
- iNOS; cyclooxygenase-2; anti-inflammatory agent; inflammation; TPA-induced mouse ear oedema; quinolinedione
- Citation
- British Journal of Pharmacology, v.156, no.2, pp.328 - 337
- Indexed
- SCIE
SCOPUS
- Journal Title
- British Journal of Pharmacology
- Volume
- 156
- Number
- 2
- Start Page
- 328
- End Page
- 337
- URI
- https://scholarworks.bwise.kr/erica/handle/2021.sw.erica/41464
- DOI
- 10.1111/j.1476-5381.2008.00028.x
- ISSN
- 0007-1188
- Abstract
- Inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) have been suggested as key components in various inflammatory diseases. Here we examined the effects of new quinolinedione derivatives, 6-(4-fluorophenyl)-amino-5,8-quinolinedione (OQ1) and 6-(2,3,4-trifluorophenyl)-amino-5,8-quinolinedione (OQ21) on activity and expression of iNOS and COX-2 to explore their anti-inflammatory properties. The effects of OQ1 and OQ21 were assessed on lipopolysaccharide (LPS)-induced iNOS and COX-2 in murine macrophage cell line (RAW264.7), along with isolated enzyme assays to measure enzyme inhibition. Nuclear factor-kappa B (NF kappa B) activation pathways were investigated to elucidate mechanisms underlying OQ-mediated suppression of the expression of iNOS and COX-2. In vivo anti-inflammatory activities of OQ compounds were evaluated in mouse ear oedema, induced by topical 12-O-tetradecanoylphorbol-13-acetate (TPA). LPS-induced NO production in RAW264.7 cells was inhibited by OQ1 and OQ21 through the attenuation of iNOS expression as well as iNOS activity. Down-regulation of iNOS followed blocking of NF kappa B activation, as assessed by inhibitory kappa B degradation and electrophoretic mobility shift assay for NF kappa B. Synthesis and accumulation of prostaglandin E-2 were also suppressed by OQ1 and OQ21. LPS-induced COX-2 expression and cellular COX-2 activities were attenuated by OQ1 and OQ21. Consistent with these results, OQ1 showed potent anti-inflammatory effects in mouse ear oedema induced by TPA. The novel quinolinedione derivatives, OQ1 and OQ21, showed potent anti-inflammatory activity through dual inhibitory effects on iNOS and COX-2, suggesting that OQ derivatives might provide a new therapeutic modality for chronic inflammatory diseases, refractory to conventional drug therapies.
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