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Potent anti-inflammatory effects of two quinolinedione compounds, OQ1 and OQ21, mediated by dual inhibition of inducible NO synthase and cyclooxygenase-2

Title
Potent anti-inflammatory effects of two quinolinedione compounds, OQ1 and OQ21, mediated by dual inhibition of inducible NO synthase and cyclooxygenase-2
Author
배옥남
Keywords
iNOS; cyclooxygenase-2; anti-inflammatory agent; inflammation; TPA-induced mouse ear oedema; quinolinedione
Issue Date
2009-01
Publisher
WILEY-BLACKWELL PUBLISHING
Citation
BRITISH JOURNAL OF PHARMACOLOGY, v. 156, No. 2, Page. 328-337
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.
URI
https://bpspubs.onlinelibrary.wiley.com/doi/abs/10.1111/j.1476-5381.2008.00028.xhttp://repository.hanyang.ac.kr/handle/20.500.11754/103869
ISSN
0007-1188
DOI
10.1111/j.1476-5381.2008.00028.x
Appears in Collections:
COLLEGE OF PHARMACY[E](약학대학) > PHARMACY(약학과) > Articles
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