The anti-pruritic efficacy of TS-022, a prostanoid DP1 receptor agonist, is dependent on the endogenous prostaglandin D2 level in the skin of NC/Nga mice.
TS-022 is a prostanoid DP(1) receptor agonist, originally developed as a novel anti-pruritic drug for atopic dermatitis. The drug has been shown to suppress scratching and improve the skin inflammation in the NC/Nga (NC) mouse, a model of atopic dermatitis. Corticosteroids are commonly used as effective agents for the treatment of atopic dermatitis. We examined the anti-pruritic efficacy of TS-022 in NC mice cohabited with skin-lesioned NC mice, which showed spontaneous scratching without skin lesions in the early phase and chronic itching with severe dermatitis in the late phase, in comparison with that of dexamethasone. We have previously reported that prostaglandin D(2) might have a physiological role in the inhibition of pruritus. While after 2 weeks of cohabitation with skin-lesioned NC mice (early phase of dermatitis, characterized by the appearance of spontaneous scratching), topically applied TS-022 exhibited a weak anti-pruritic effect in the NC mice, after 6 weeks of cohabitation (late phase, characterized by both chronic scratching and dermatitis), the drug exerted potent anti-pruritic activity. In contrast, dexamethasone exerted potent anti-pruritic effect in both the early and late phases. Indomethacin aggravated the scratching in the early phase, but had no effect in the late phase. The skin prostaglandin D(2) level was significantly increased in the early phase, to subsequently declined and return to the basal level in the late phase. The cutaneous ability for prostaglandin D(2) production following topical application of arachidonic acid or mechanical scratching was decreased in the late phase. Moreover, the expression level of the prostanoid DP(1) receptor in the skin was increased in the late phase. These findings suggest that the potent anti-pruritic activity of TS-022 in the late phase might be attributable to the decrease of endogenous prostaglandin D(2) production and increase of prostanoid DP(1) receptor expression.
Sugimoto
Masanori
M
Department of Pharmacology, Medicinal Research Laboratories, Taisho Pharmaceutical Co., Ltd., 1-403 Yoshino-cho, Kita-ku, Saitama 331-9530, Japan. masanori.sugimoto@po.rd.taisho.co.jp
Arai
Iwao
I
Futaki
Nobuko
N
Hashimoto
Yuki
Y
Sakurai
Takanobu
T
Honma
Yusuke
Y
Nakaike
Shiro
S
D000085:Acetates / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D000982:Antipruritics / Q000494:pharmacology* / Q000627:therapeutic use; D016718:Arachidonic Acid; D003510:Cyclohexanes / Q000494:pharmacology* / Q000627:therapeutic use; D003876:Dermatitis, Atopic / Q000188:drug therapy*; D003907:Dexamethasone / Q000627:therapeutic use; D005786:Gene Expression Regulation; D008297:Male; D051379:Mice; D015230:Prostaglandin D2 / Q000378:metabolism*; D011537:Pruritus / Q000188:drug therapy; D011982:Receptors, Prostaglandin / Q000819:agonists* / Q000187:drug effects / Q000378:metabolism; D012867:Skin / Q000187:drug effects / Q000503:physiopathology; D013438:Sulfhydryl Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D014870:Water Loss, Insensible
C518544:(4-((1R, 2S, 3R, 5R)-5-Chloro-2-((S)-3-cyclohexyl-3-hydroxyprop-1-ynyl)-3-hydroxycyclopentyl) butylthio) acetic acid monohydrate; D000085:Acetates; D000893:Anti-Inflammatory Agents; D000982:Antipruritics; D003510:Cyclohexanes; D011982:Receptors, Prostaglandin; D013438:Sulfhydryl Compounds; C501562:prostanoid D receptor 1, human; D016718:Arachidonic Acid; D003907:Dexamethasone; D015230:Prostaglandin D2