Phosphodiesterase 7A inhibitor ASB16165 impairs proliferation of keratinocytes in vitro and in vivo.
Excessive proliferation of epidermal keratinocytes is a typical aspect of chronic skin diseases such as psoriasis. In the present study, the effect of phosphodiesterase 7A (PDE7A) inhibitor ASB16165 on proliferation of keratinocytes was investigated to examine the role of PDE7A in keratinocyte proliferation and the possible therapeutic relevance of PDE7A inhibition in psoriasis. Topical application of ASB16165 inhibited the increase of thickness of skin as well as epidermis in a skin inflammation model induced by repeated painting of 12-O-tetradecanoylphorbol-13-acetate (TPA) in a concentration-dependent manner. The ASB16165 treatment also suppressed the increase in the number of Ki67-positive keratinocytes in the model, showing the disturbance of keratinocyte proliferation by the treatment. In addition, both ASB16165 and dibutyryl cAMP significantly decreased the proliferation of human keratinocytes in vitro, suggesting that PDE7A participates in keratinocyte proliferation probably by controlling intracellular cAMP, while the contribution of other mechanism(s) is not completely denied. The findings in the present study indicate that the effect of ASB16165 on skin and epidermal hyperplasia in the TPA-induced skin inflammation is mediated, at least in part, by the inhibition of keratinocyte proliferation. The inhibitors for PDE7A including ASB16165 might be useful for the treatment of psoriasis.
Goto
Megumi
M
Biomedical Research Laboratories, Asubio Pharma Co., Limited, Osaka, Japan.
Kadoshima-Yamaoka
Kumiko
K
Murakawa
Masao
M
Yoshioka
Ryosuke
R
Tanaka
Yoshitaka
Y
Inoue
Hidekazu
H
Murafuji
Hidenobu
H
Kanki
Satomi
S
Hayashi
Yasuhiro
Y
Nagahira
Kazuhiro
K
Ogata
Atsuto
A
Nakatsuka
Takashi
T
Fukuda
Yoshiaki
Y
D000279:Administration, Cutaneous; D000818:Animals; D003994:Bucladesine / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D054708:Cyclic Nucleotide Phosphodiesterases, Type 7 / Q000037:antagonists & inhibitors*; D004195:Disease Models, Animal; D004817:Epidermis / Q000187:drug effects* / Q000473:pathology; D005260:Female; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D011565:Psoriasis / Q000139:chemically induced / Q000188:drug therapy*; D011720:Pyrazoles / Q000008:administration & dosage / Q000494:pharmacology*; D012867:Skin / Q000187:drug effects* / Q000473:pathology; D013755:Tetradecanoylphorbol Acetate; D013876:Thiophenes / Q000008:administration & dosage / Q000494:pharmacology*
C539237:1-cyclohexyl-N-(6-(4-hydroxy-1-piperidinyl)-3-pyridinyl)-3-methyl-1H-thieno(2,3-c)pyrazole-5-carboxamide; D010726:Phosphodiesterase Inhibitors; D011720:Pyrazoles; D013876:Thiophenes; D003994:Bucladesine; D054708:Cyclic Nucleotide Phosphodiesterases, Type 7; D013755:Tetradecanoylphorbol Acetate