title: Pseudoceramide stimulates peroxisome proliferator-activated receptor-α expression in a murine model of atopic dermatitis: molecular basis underlying the anti-inflammatory effect and the preventive effect against steroid-induced barrier impairment.
abstract: Topical pseudoceramides are successfully used in skin barrier repair therapy for atopic dermatitis (AD) and demonstrated to reduce the adverse effects of topical glucocorticoids (GC). However, the molecular mechanisms involved are not fully understood. We investigated whether PC-9S (myristoyl/palmitoyloxostearamide/arachamide MEA, Neopharm, Daejeon, Korea), one of the synthetic pseudoceramides, could stimulate peroxisome proliferator-activated receptor (PPAR)α expression in a hapten [oxazolone (oxa)]-induced AD murine model (oxa-AD mice) and subsequently improved permeability barrier, reduced inflammation, and increased antimicrobial peptides (AMPs) expression. Normal hairless mice and oxa-AD mice were topically treated twice daily with either PC-9S-containing physiologic lipid mixture (PLM), vehicle (PLM), or PPARα agonist for 4 days. Topical PC-9S significantly increased PPARα expression in mouse epidermis in vivo and in oxa-AD mice skin comparable with PPARα agonist. Topical PC-9S-containing PLM significantly reduced basal trans-epidermal water loss (TEWL), surface pH, and mast cell infiltrates and prevented the decline of AMPs expression in oxa-AD mice, which were abrogated by PPARα antagonist. Then, oxa-AD mice were treated with super-potent topical GC twice daily for 4 days with or without PC-9S co-applications. Co-treatment with PC-9S-containing PLM suppressed GC-induced increase in basal TEWL, epidermal thinning, reduced loricrin expression, and impaired barrier recovery and these effects were attenuated by PPARα antagonist. Collectively, our findings suggest that pseudoceramide PC-9S-induced stimulation of PPARα expression provides a new mechanism by which pseudoceramides show anti-inflammatory property, improve the permeability and antimicrobial barrier function, and prevent the negative effects of topical GC.
authors.affiliation: Department of Dermatology, Yonsei University College of Medicine, Gangnam Severance Hospital, 712 Eonjuro, Gangnam-gu, Seoul, 135-720, Korea.
authors.forename: Sang Eun
authors.initials: SE
authors.lastname: Lee
authors.affiliation: Department of Dermatology, Yonsei University College of Medicine, Gangnam Severance Hospital, 712 Eonjuro, Gangnam-gu, Seoul, 135-720, Korea.
authors.forename: Min Kyung
authors.initials: MK
authors.lastname: Jung
authors.affiliation: Department of Dermatology, Yonsei University College of Medicine, Gangnam Severance Hospital, 712 Eonjuro, Gangnam-gu, Seoul, 135-720, Korea.
authors.forename: Seung Joon
authors.initials: SJ
authors.lastname: Oh
authors.affiliation: Research Division, Neopharm Co., Ltd, Daejeon, Korea.
authors.forename: Se Kyoo
authors.initials: SK
authors.lastname: Jeong
authors.affiliation: Department of Dermatology, Yonsei University College of Medicine, Gangnam Severance Hospital, 712 Eonjuro, Gangnam-gu, Seoul, 135-720, Korea. ydshderm@yuhs.ac.
authors.forename: Seung Hun
authors.initials: SH
authors.lastname: Lee
mesh_terms: D000287:Administration, Topical; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D001095:Arachidonic Acids / Q000627:therapeutic use*; D002518:Ceramides / Q000627:therapeutic use*; D003876:Dermatitis, Atopic / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D005938:Glucocorticoids / Q000009:adverse effects; D007249:Inflammation; D008565:Membrane Proteins / Q000096:biosynthesis; D051379:Mice; D008812:Mice, Hairless; D010081:Oxazolone / Q000494:pharmacology; D047493:PPAR alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D012867:Skin / Q000378:metabolism / Q000473:pathology; D013229:Stearic Acids / Q000627:therapeutic use*; D019108:Tight Junctions / Q000187:drug effects*
chemical_list: D000893:Anti-Inflammatory Agents; D001095:Arachidonic Acids; D002518:Ceramides; D005938:Glucocorticoids; D008565:Membrane Proteins; D047493:PPAR alpha; D013229:Stearic Acids; C064554:loricrin; D010081:Oxazolone
keywords: Atopic dermatitis; Glucocorticoid; Peroxisome proliferator-activated receptor-α; Pseudoceramide