ANTIINFLAMMATORY ACTIVITY OF TOPICAL AURANOFIN IN ARACHIDONIC ACID-INDUCED 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 inflamma tion, an evanescent response characterized by edema and neutrophil inf iltration mediated, at least in part, by leukotrienes. The edema and m yeloperoxidase (MPO) activity induced by application of arachidonic ac id was assayed from the inflamed ears. After application of auranofin (1 mg or 1.47 mu mol/ear in solution), inhibition of the MPO response was observed but little inhibition of the edematous response occurred. The application of 50 mu l of 2% auranofin ointment (similar to 1.47 mu mol/ear) administered after arachidonic acid resulted in the inhibi tion of both the edematous (54%) and the MPO (50%) components of the i nflammatory 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 p horbol ester (PMA) was studied. This psoriaform lesion involves intens e infiltration of neurotrophils, microabcess formation and epidermal c ell proliferation. The ear thickness and the MPO response were measure d at 4 h after PMA application. In this model, auranofin in solution d isplayed marked, dose-related antiinflammatory activity. The ED(50)s w ere calculated to be 0.12 (0.18 mu mol) and 0.14 mg (0.21 mu mol)/ear, respectively. An investigation of the antiinflammatory activity of th e ointment was limited to the edematous response because of interferen ce with the MPO analysis; however, potent antiinflammatory activity of the auranofin ointment proved to be dose-related with an ED,, of 0.3% (0.22 mu mol) at 2 h and 0.6% (0.44 mu mol) at 4 h after PMA. In addi tion, if the response was allowed to proceed for 2 h before the applic ation of ointment, further progression of the inflammation was essenti ally abolished. Despite strong inhibition of the inflammatory response , no significant alteration of PMA-induced increased DNA content was d emonstrable. Overall, the completeness of inhibition and potency obser ved with auranofin suggest that it may be of utility in the treatment of inflammatory diseases of the skin. (C) 1995 Wiley-Liss, Inc.