Topical application of the adenosine A2A receptor agonist CGS‐21680 prevents phorbol‐induced epidermal hyperplasia and inflammation in mice

The nucleoside adenosine is a known regulator of immunity and inflammation that mediates, at least in part, the anti‐inflammatory effect of methotrexate, an immunosuppressive agent widely used to treat autoimmune inflammatory diseases. Adenosine A_2A receptors play a key role in the inhibition of the inflammatory process besides promoting wound healing. Therefore, we aimed to determine the topical effect of a selective agonist, CGS‐21680, on a murine model of skin hyperplasia with a marked inflammatory component. Pretreatment with either CGS‐21680 (5 μg per site) or the reference agent dexamethasone (200 μg/site) prevented the epidermal hyperplasia and inflammatory response induced by topical application of 12‐O‐tetradecanoylphorbol‐13‐acetate (TPA, 2 nmol/site) for three consecutive days. The histological analysis showed that both CGS‐21680 and dexamethasone produced a marked reduction of inflammatory cell infiltrate, which correlated with diminished myeloperoxidase (MPO) activity in skin homogenates. Both treatments reduced the levels of the chemotactic mediators LTB₄ and CXCL‐1, and the inflammatory cytokine TNF‐α, through the suppression of NFκB phosphorylation. The immunohistochemical analysis of the hyperproliferative markers cytokeratin 6 (CK6) and Ki67 revealed that while both agents inhibit the number of proliferating cells in the epidermis, CGS‐21680 treatment promoted dermal fibroblasts proliferation. Consistently, increased collagen deposition in dermis was observed in tissue sections from agonist‐treated mice. Our results showed that CGS 21680 efficiently prevents phorbol‐induced epidermal hyperplasia and inflammation in mice without the deleterious atrophic effect of topical corticosteroids.