Suppressive effect of topically applied CX-659S, a novel diaminouracil derivative, on the contact hypersensitivity reaction in various animal models.
BACKGROUND
The T-cell-mediated contact hypersensitivity reaction (CHR) is thought to be involved in the pathogenesis of clinical cutaneous disorders including atopic dermatitis. A novel diaminouracil derivative, CX-659S, has been reported to have an inhibitory activity against picryl chloride (PC)-induced CHR when administered either orally or percutaneously. The inhibitory effect of topical CX-659S was assessed in three CHR models in the present study. In addition, to elucidate the mechanism of action of this compound, we examined the effect of CX-659S on the expression of messenger RNAs for proinflammatory cytokines after elicitation in PC models.


METHODS
For the in vivo evaluation of the efficacy of CX-659S, we used PC- or oxazolone-induced CHR in mice and 2,4-dinitrochlorobenzene (DNCB)-induced CHR in guinea pigs. CX-659S was topically applied immediately after the hapten challenge in each model. To assess the effect on gene expression of cytokines, we used the reverse transcriptase-polymerase chain reaction (RT-PCR), a semiquantitative technique with specific primers.


RESULTS
Topical CX-659S dose-dependently inhibited ear swelling at 24 h after the challenge in the two mouse models. This inhibitory effect was histologically confirmed in the PC model. Topically applied CX-659S also inhibited erythema and edema formation 24 h after challenge in the guinea pig model. CX-659S inhibited the expression of mRNA for proinflammatory cytokines IL-1 beta and TNF-alpha in vivo.


CONCLUSIONS
Topically applied CX-659S showed significant inhibitory activities against CHR models both in mice and in guinea pigs. Inhibition profiles of CX-659S toward mRNA expression for proinflammatory cytokines corroborated these findings. CX-659S thus could be a useful therapeutic agent for allergic cutaneous disorders such as allergic contact dermatitis and atopic dermatitis.
Goto
Y
Y
Pharmaceutical and Biotechnology Laboratory, Japan Energy Corporation, Toda-shi, Saitama, Japan.
Inoue
Y
Y
Tsuchiya
M
M
Isobe
M
M
Ueno
T
T
Uchi
H
H
Furue
M
M
Hayashi
H
H
D000287:Administration, Topical; D000818:Animals; D001483:Base Sequence; D017931:DNA Primers / Q000235:genetics; D003877:Dermatitis, Contact / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D004137:Dinitrochlorobenzene / Q000276:immunology / Q000633:toxicity; D004195:Disease Models, Animal; D006168:Guinea Pigs; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D007375:Interleukin-1 / Q000235:genetics; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010081:Oxazolone / Q000276:immunology / Q000633:toxicity; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D014498:Uracil / Q000008:administration & dosage* / Q000031:analogs & derivatives
D017931:DNA Primers; D004137:Dinitrochlorobenzene; D007166:Immunosuppressive Agents; D007375:Interleukin-1; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D010081:Oxazolone; D014498:Uracil; C418807:CX 659S