title: Efficacy of combined peroxisome proliferator-activated receptor-α ligand and glucocorticoid therapy in a murine model of atopic dermatitis.
abstract: Although topical glucocorticoids (GCs) show potent anti-inflammatory activity in inflamed skin, they can also exert numerous harmful effects on epidermal structure and function. In contrast, topical applications of ligands of peroxisome proliferator-activated receptor-α (PPARα) not only reduce inflammation but also improve cutaneous barrier homeostasis. Therefore, we examined whether sequential topical GCs followed by topical Wy14643 (a ligand of PPARα) might be more effective than either alone for atopic dermatitis (AD) in a hapten (oxazolone (Ox))-induced murine model with multiple features of AD (Ox-AD). Despite expected anti-inflammatory benefits, topical GC alone induced (i) epidermal thinning; (ii) reduced expression of involucrin, loricrin, and filaggrin; and (iii) allowed outside-to-inside penetration of an epicutaneous tracer. Although Wy14643 alone yielded significant therapeutic benefits in mice with mild or moderate Ox-AD, it was less effective in severe Ox-AD. Yet, topical application of Wy14643 after GC was not only significantly effective comparable with GC alone, but it also prevented GC-induced structural and functional abnormalities in permeability barrier homeostasis. Moreover, rebound flares were largely absent after sequential treatment with GC and Wy14643. Together, these results show that GC and PPARα ligand therapy together is not only effective but also prevents development of GC-induced side effects, including rebound flares, in murine AD.
authors.affiliation: Department of Dermatology, Faculty of Medicine, Oita University, Yufu-shi, Oita, Japan. HATANO@oita-u.ac.jp
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Hatano
authors.forename: Peter M
authors.initials: PM
authors.lastname: Elias
authors.forename: Debra
authors.initials: D
authors.lastname: Crumrine
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Feingold
authors.forename: Kazumoto
authors.initials: K
authors.lastname: Katagiri
authors.forename: Sakuhei
authors.initials: S
authors.lastname: Fujiwara
mesh_terms: D000276:Adjuvants, Immunologic / Q000633:toxicity; D000818:Animals; D002990:Clobetasol / Q000494:pharmacology*; D003876:Dermatitis, Atopic / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology; D004195:Disease Models, Animal; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004817:Epidermis / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D005260:Female; D005938:Glucocorticoids / Q000494:pharmacology; D006241:Haptens / Q000633:toxicity; D051379:Mice; D008812:Mice, Hairless; D009284:Naphthols; D010081:Oxazolone / Q000633:toxicity; D047493:PPAR alpha / Q000819:agonists* / Q000378:metabolism*; D020025:Peroxisome Proliferators / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology*; D055502:Secondary Prevention; D014227:Triazines
chemical_list: C409762:2-(3-aminophenol)-6-(4-amino-1-naphthol)-4-chloro-triazine; D000276:Adjuvants, Immunologic; D005938:Glucocorticoids; D006241:Haptens; D009284:Naphthols; D047493:PPAR alpha; D020025:Peroxisome Proliferators; D011743:Pyrimidines; D014227:Triazines; D010081:Oxazolone; C006253:pirinixic acid; D002990:Clobetasol