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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
- Source :
- Journal of Pharmacology and Experimental Therapeutics. 335:23-31
- Publication Year :
- 2010
- Publisher :
- American Society for Pharmacology & Experimental Therapeutics (ASPET), 2010.
-
Abstract
- 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.
- Subjects :
- 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
Subjects
Details
- ISSN :
- 15210103 and 00223565
- Volume :
- 335
- Database :
- OpenAIRE
- Journal :
- Journal of Pharmacology and Experimental Therapeutics
- Accession number :
- edsair.doi.dedup.....fce83e2cbb82babfc06e29212c39626f