Antiinflammatory activity of topical auranofin in arachidonic acid- and phorbol ester-induced inflammation in mice

The antiarthritic, organogold compound auranofin was evaluated for its antiinflammatory activity in murine models of cutaneous inflammation. Initial studies involved the use of arachidonic acid‐induced inflammation, an evanescent response characterized by edema and neutrophil infiltration mediated, at least in part, by leukotrienes. The edema and myeloperoxidase (MPO) activity induced by application of arachidonic acid was assayed from the inflamed ears. After application of auranofin (1 mg or 1.47 m̈mol/ear in solution), inhibition of the MPO response was observed but little inhibition of the edematous response occurred. The application of 50 m̈l of 2% auranofin ointment (∼ 1.47 m̈mol/ear) administered after arachidonic acid resulted in the inhibition of both the edematous (54%) and the MPO (50%) components of the inflammatory response to arachidonic acid. It was found that auranofin in vitro weakly inhibited MPO activity, suggesting that inhibition of MPO‐derived oxidants might contribute to the antiinflammatory activity. In order to characterize further this antiinflammatory activity, the effect of auranofin on the response to the cutaneous application of phorbol ester (PMA) was studied. This psoriaform lesion involves intense infiltration of neurotrophils, microabcess formation and epidermal cell proliferation. The ear thickness and the MPO response were measured at 4 h after PMA application. In this model, auranofin in solution displayed marked, dose‐related antiinflammatory activity. The ED50s were calculated to be 0.12 (0.18 m̈mol) and 0.14 mg (0.21 m̈mol)/ear, respectively. An investigation of the antiinflammatory activity of the ointment was limited to the edematous response because of interference with the MPO analysis; however, potent antiinflammatory activity of the auranofin ointment proved to be dose‐related with an ED50 of 0.3% (0.22 m̈mol) at 2 h and 0.6% (0.44 m̈mol) at 4 h after PMA. In addition, if the response was allowed to proceed for 2 h before the application of ointment, further progression of the inflammation was essentially abolished. Despite strong inhibition of the inflammatory response, no significant alteration of PMA‐induced increased DNA content was demonstrable. Overall, the completeness of inhibition and potency observed with auranofin suggest that it may be of utility in the treatment of inflammatory diseases of the skin. ©1995 Wiley‐Liss, Inc.