ASB16165, a phosphodiesterase 7A inhibitor, reduces cutaneous TNF-alpha level and ameliorates skin edema in phorbol ester 12-O-tetradecanoylphorbol-13-acetate-induced skin inflammation model in mice.

Abstract

Possible role of phosphodiesterase 7A (PDE7A) in skin inflammation was examined using ASB16165, a specific inhibitor for PDE7A. Epicutaneous application of phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) to mouse ear resulted in induction of skin edema, and topical treatment with ASB16165 inhibited the induction of skin edema in a dose-dependent manner. The TPA challenge also increased the level of TNF-alpha at the application site, and the ASB16165 treatment reduced the TNF-alpha level in the skin. In addition, ASB16165 suppressed the production of TNF-alpha by human keratinocytes stimulated in vitro with TPA and calcium ionophore. Forskolin, an activator of adenylyl cyclase, as well as dibutyryl cAMP also showed inhibitory effect on the TNF-alpha production in the cells, suggesting involvement of cAMP in TNF-alpha generation. These results demonstrate that PDE7A might regulate TNF-alpha production in keratinocytes in a cAMP-dependent fashion. As immunostaining analysis revealed that PDE7A is expressed in the epidermis and TNF-alpha is known to contribute to the TPA-induced edema, it is possible that the inhibitory effect of ASB16165 on skin edema in mouse TPA-induced dermatitis model is mediated by suppression of TNF-alpha production. This is the first report suggesting the association of PDE7A with the function of keratinocytes. ASB16165 will be useful as an agent for skin inflammation in which TNF-alpha plays a pathogenic role (e.g. psoriasis).

• Authors: Kumiko Kadoshima-Yamaoka, Megumi Goto, Masao Murakawa, Ryosuke Yoshioka, Yoshitaka Tanaka, Hidekazu Inoue, Hidenobu Murafuji, Satomi Kanki, Yasuhiro Hayashi, Kazuhiro Nagahira, Atsuto Ogata, Takashi Nakatsuka, Yoshiaki Fukuda
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 613 Issue 1-3 Pg. 163-6 (Jun 24 2009) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 19379723 (Publication Type: Journal Article)

Chemical References

• 1-cyclohexyl-N-(6-(4-hydroxy-1-piperidinyl)-3-pyridinyl)-3-methyl-1H-thieno(2,3-c)pyrazole-5-carboxamide
• Enzyme Inhibitors
• Pyrazoles
• Thiophenes
• Tumor Necrosis Factor-alpha
• Cyclic Nucleotide Phosphodiesterases, Type 7
• Pde7a protein, mouse
• Tetradecanoylphorbol Acetate

Topics

• Animals
• Cyclic Nucleotide Phosphodiesterases, Type 7 (antagonists & inhibitors)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Edema (drug therapy, metabolism)
• Enzyme Inhibitors (pharmacology, therapeutic use)
• Epidermis (drug effects, metabolism)
• Female
• Gene Expression Regulation (drug effects)
• Humans
• Inflammation (chemically induced, drug therapy, metabolism, pathology)
• Keratinocytes (drug effects, metabolism)
• Mice
• Mice, Inbred BALB C
• Pyrazoles (pharmacology, therapeutic use)
• Skin (drug effects, metabolism, pathology)
• Tetradecanoylphorbol Acetate (toxicity)
• Thiophenes (pharmacology, therapeutic use)
• Tumor Necrosis Factor-alpha (biosynthesis, metabolism)