bay-11-7082 and Edema

To develop new anti-inflammatory agents with improved pharmaceutical profiles, a series of new phenyl-pyrazoline-coumarin derivatives (4a∼4m) were designed and synthesized. Compounds 4a and 4b were determined by X-ray crystallography. All of the compounds have been screened for their anti-inflammatory activity characterized by evaluating their inhibition against LPS-induced IL-6 release. Among them, compound 4m showed the highest anti-inflammatory activity with inhibiting IL-6, TNF-α and nitric oxide (NO) production lipopolysaccharide (LPS)-stimulated. The further study showed that title compound 4m could significantly suppress expressions of nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) and the productions of IL-6, TNF-α, NO through NF-κB/MAPK signaling pathway. The anti-inflammatory activity of compound 4m was determined by carrageenan induced paw edema. Furthermore in vivo evaluation results indicated that compound 4m could inhibit AA-induced rat ankle joints.

Topics: Animals; Ankle Joint; Anti-Inflammatory Agents, Non-Steroidal; Carrageenan; Cell Survival; Cells, Cultured; Coumarins; Crystallography, X-Ray; Dose-Response Relationship, Drug; Edema; Interleukin-6; Lipopolysaccharides; Male; Mice; Models, Molecular; Molecular Structure; Nitric Oxide; Pyrazoles; Rats; Rats, Sprague-Dawley; RAW 264.7 Cells; Structure-Activity Relationship; Tumor Necrosis Factor-alpha

Dodonaea polyandra is a medicinal plant used traditionally by the Kuuku I'yu (Northern Kaanju) indigenous people of Cape York Peninsula, Australia. The most potent of the diterpenoids previously identified from this plant, polyandric acid A (1), has been examined for inhibition of pro-inflammatory cytokine production and other inflammatory mediators using well-established acute and chronic mouse ear edema models and in vitro cellular models. Topical application of 1 significantly inhibited interleukin-1β production in mouse ear tissue in an acute model. In a chronic skin inflammation model, a marked reduction in ear thickness, associated with significant reduction in myeloperoxidase accumulation, was observed. Treatment of primary neonatal human keratinocytes with 1 followed by activation with phorbol ester/ionomycin showed a significant reduction in IL-6 secretion. The present study provides evidence that the anti-inflammatory properties of 1 are due to inhibition of pro-inflammatory cytokines associated with skin inflammation and may be useful in applications for skin inflammatory conditions including psoriasis and dermatitis.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Australia; Cytokines; Disease Models, Animal; Diterpenes, Clerodane; Ear; Edema; Interleukin-1beta; Interleukin-6; Lipopolysaccharides; Macrophages; Mice; Mice, Inbred BALB C; Molecular Structure; Nitric Oxide; Peroxidase; Plants, Medicinal; Psoriasis; Sapindaceae; Skin; Tetradecanoylphorbol Acetate; Tumor Necrosis Factor-alpha