title: Topical application of the adenosine A2A receptor agonist CGS-21680 prevents phorbol-induced epidermal hyperplasia and inflammation in mice.
abstract: 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 A2A 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.
authors.affiliation: Departament of Pharmacology, Faculty of Pharmacy, University of Valencia, Valencia, Spain; Center of Molecular Recognition and Technological Development (IDM), Valencia, Spain.
authors.forename: Jorge
authors.initials: J
authors.lastname: Arasa
authors.forename: Patricio
authors.initials: P
authors.lastname: Martos
authors.forename: María Carmen
authors.initials: MC
authors.lastname: Terencio
authors.forename: Francisca
authors.initials: F
authors.lastname: Valcuende-Cavero
authors.forename: María Carmen
authors.initials: MC
authors.lastname: Montesinos
mesh_terms: D000241:Adenosine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D058908:Adenosine A2 Receptor Agonists / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use*; D000287:Administration, Topical; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D049109:Cell Proliferation; D003094:Collagen / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D003907:Dexamethasone / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D004817:Epidermis / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D005260:Female; D006965:Hyperplasia / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control; D007249:Inflammation / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D009195:Peroxidase / Q000378:metabolism; D010627:Phenethylamines / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use*; D012871:Skin Diseases / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D013755:Tetradecanoylphorbol Acetate / Q000009:adverse effects
chemical_list: D058908:Adenosine A2 Receptor Agonists; D000893:Anti-Inflammatory Agents; D016207:Cytokines; D010627:Phenethylamines; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; D003907:Dexamethasone; D003094:Collagen; D009195:Peroxidase; D000241:Adenosine; D013755:Tetradecanoylphorbol Acetate
keywords: NFκB; adenosine receptor; animal model; cytokines; epidermal hyperplasia; psoriasis