Protective and curative effects of topically applied CX-659S, a novel diaminouracil derivative, on chronic picryl chloride-induced contact hypersensitivity responses.
BACKGROUND
CX-659S, a newly discovered anti-inflammatory compound, exerts inhibitory effects against acute contact hypersensitivity responses (CHRs) induced by picryl chloride (PC), oxazolone and dinitrochlorobenzene. The murine model of chronic CHR induced by repeated application of PC is known to mimic many, if not all, events occurring within the lesional skin of patients with atopic dermatitis (AD).


OBJECTIVE
To investigate the ability of CX-659S to inhibit PC-induced chronic CHR in mice.


METHODS
The protective and curative effects of CX-659S were tested on PC-treated ears of BALB/c mice, and were compared with those of prednisolone. Effects were quantified by measurements of ear thickness, serum IgE and cytokine mRNA expression.


RESULTS
Both protectively applied and curatively applied CX-659S significantly inhibited increases in ear thickness and total serum IgE. Inhibition was dose-dependent. Although protectively applied prednisolone showed similar activities to CX-659S against chronic CHR, curatively applied prednisolone did not affect the serum IgE level despite inhibiting increases in ear thickness and inflammatory cell infiltration. Consistent with these results, CX-659S reduced mRNA expression of interleukin (IL)-4 and IL-10 but not of interferon (IFN)-gamma, whereas prednisolone inhibited not only mRNA expression of IL-4 and IL-10 but also that of IFN-gamma in the ear lesion. In contrast to prednisolone, CX-659S did not show any side-effect such as atrophy, alopecia or telangiectasia.


CONCLUSIONS
CX-659S is the first promising compound having inhibitory activities against chronic CHR accompanied by a diminishing effect on elevated serum IgE, without any other side-effect. Therefore, CX-659S may be a promising candidate for management of patients with recurring AD who require long-term therapy.
D000287:Administration, Topical; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D002908:Chronic Disease; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D017449:Dermatitis, Allergic Contact / Q000188:drug therapy* / Q000209:etiology / Q000276:immunology / Q000517:prevention & control; D005786:Gene Expression Regulation / Q000187:drug effects; D005938:Glucocorticoids; D007073:Immunoglobulin E / Q000097:blood; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010853:Picryl Chloride; D011239:Prednisolone / Q000627:therapeutic use; D012333:RNA, Messenger / Q000235:genetics; D014498:Uracil / Q000031:analogs & derivatives* / Q000627:therapeutic use*
D000893:Anti-Inflammatory Agents; D016207:Cytokines; D005938:Glucocorticoids; D012333:RNA, Messenger; D007073:Immunoglobulin E; D014498:Uracil; D011239:Prednisolone; C418807:CX 659S; D010853:Picryl Chloride