Evaluation of the cutaneous anti-inflammatory activity of azaspiranes

Abstract.

Objective and Design: The ability of azaspiranes to modulate the acute inflammatory response in models of skin inflammation was examined.¶Material: The in vivo experiments involved the use of 5–6 age-matched male Balb/c inbred mice (22–25 g) per treatment group and a control group of 8–10 animals. In vitro mechanistic studies used RBL-1 and U937 cells lines and freshly isolated human monocytes.¶Treatment: Arachidonic acid (AA) (2 mg/20 ul in acetone) or PMA (phorbol myristate acetate) (4 ug/20 ul) were applied topically. SK&F 106615 and SK&F 106610 were administered topically either dissolved in acetone or dimethylacetamide just after the application of the irritant. Isolated cells were treated with the compounds dissolved in DMSO.¶Methods: The thickness and influx of neutrophils into the treated ears was measured as was the effects of the azaspiranes on 5-lipoxygenase activity, cyclooxygenase activity, prostaglandin and leukotriene synthesis, and the activation of the transcription factor NF-κB.¶Results: SK&F 106615 and SK&F 106610 significantly reduced inflammation in the AA- and PMA-induced inflammation models (p < 0.05) with ED₅₀'s of 179 and 120 mg/ear for edema and myeloperoxidase, respectively. The compounds did not inhibit eicosanoid biosynthesis, have a direct effect on 5-lipoxygenase or cyclooxygenase enzymes, or inhibit NF-κB.¶Conclusions: The potent anti-inflammatory and immunomodulatory activities of the azaspiranes observed in these and other studies appear to be mediated by a novel mechanism.