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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

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

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, etc.

Eur J Pharmacol. 2009 Jun 24;613(1-3):163-6.

PMID: 19379723

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).

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR4245722	PDE7A active mouse			Price

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