E6201, a Novel Kinase Inhibitor of Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase Kinase-1 and Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase Kinase Kinase-1: In Vivo Effects on Cutaneous Inflammatory Responses by Topical Administration
| Autor: | Yoko Inoue, Kenzo Muramoto, Naoto Ishii, Yuan John Wang, Kenichi Chiba, Takao Omae, Yoshikazu Kuboi, Masaki Goto, Hiroshi Shirota, Fabian Gusovsky |
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| Rok vydání: | 2010 |
| Předmět: |
Male
Croton Oil Administration Topical T-Lymphocytes T cell MAP Kinase Kinase Kinase 1 Pharmacology Ornithine Decarboxylase Interleukin-23 Proinflammatory cytokine Lactones Mice In vivo Animals Psoriasis Medicine Croton oil Protein Kinase Inhibitors Peroxidase Skin Mitogen-Activated Protein Kinase 1 Mice Inbred BALB C Hyperplasia biology Kinase business.industry Interleukin-17 Interleukin Biological activity Antineoplastic Agents Phytogenic medicine.anatomical_structure Biochemistry Mitogen-activated protein kinase biology.protein Tetradecanoylphorbol Acetate Molecular Medicine Dinitrofluorobenzene Indicators and Reagents Drug Eruptions Diterpenes business |
| Zdroj: | Journal of Pharmacology and Experimental Therapeutics. 335:23-31 |
| ISSN: | 1521-0103 0022-3565 |
| DOI: | 10.1124/jpet.110.168583 |
| Popis: | E6201 [(3S,4R,5Z,8S,9S,11E)-14-(ethylamino)-8,9,16-trihydroxy-3,4-dimethyl-3,4,9,10-tetrahydro-1H-2-benzoxacyclotetradecine-1,7(8H)-dione)] is a novel anti-inflammatory agent that has potent inhibitory effects on the production of proinflammatory cytokines from leukocytes and antiproliferative activity on keratinocytes. To characterize the in vivo pharmacological activity of E6201, topically administered E6201 was evaluated in several different animal models of dermatitis. E6201 formulated as an ointment or cream showed dose-dependent inhibition of croton oil-induced acute edema formation and neutrophil infiltration into mouse skin. In addition, E6201 cream inhibited the 1-fluoro-2,4-dinitrobenzene-induced contact hypersensitivity reaction mediated by T cells in mice. In this model, E6201 cream also suppressed the migration of neutrophils and lymphocytes into the inflammatory site. Pretreatment with E6201 cream attenuated phorbol-12 myristate 13-acetate-induced ornithine decarboxylase activity, a marker of proliferation in epidermis. Furthermore, E6201 ointment showed inhibitory effects on both mezerein-induced and interleukin (IL)-23-induced epidermal hyperplasia. E6201 also suppressed T cell receptor-stimulated IL-17 production from human T cells. These results indicate that topically administered E6201 may be a useful agent for the prevention and treatment of cutaneous inflammatory and hyperproliferative diseases such as psoriasis. |
| Databáze: | OpenAIRE |
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