title: Integrating targeted gene expression and a skin model system to identify functional inhibitors of the UV activated p38 MAP kinase.
abstract: The stress-activated p38α MAP Kinase is an integral and critical component of the UV-induced inflammatory response. Despite the advances in recent years in the development of p38 kinase inhibitors, validation of these compounds in the diseased models remains limited. Based on the pharmacological profile of p38α inhibitor lead compound, SB203580, we synthesized a series of pyrrole-derivatives. Using UV-irradiated human skin punch-biopsies and cell cultures, we identified and validated the inhibitory activity of the derivatives by quantitatively measuring their effect on the expression of p38α target genes using real-time PCR. This approach not only identified pyrrole-2 as a unique derivative of this series that specifically inhibited the UV-activated p38α kinase, but also documented the skin permeation, bioavailability and reversible properties of this derivative in a 3D structure. The successful skin permeation of pyrrole-2 and its impact on AREG, COX-2 and MMP-9 gene expression demonstrates its potential use in modulating inflammatory processes in the skin. This study underscored the importance of using adapted biological models to identify accurate bioactive compounds.
authors.affiliation: CNRS UMR6290, Institut de Génétique et Développement de Rennes, France. mgaliber@univ-rennes1.fr and University of Rennes1, France and University of Cape Town, Department of Human Biology, Cape Town, South Africa.
authors.forename: Amaal
authors.initials: A
authors.lastname: Abrahams
authors.affiliation: CNRS UMR6290, Institut de Génétique et Développement de Rennes, France. mgaliber@univ-rennes1.fr and University of Rennes1, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Mouchet
authors.affiliation: University of Rennes1, France and CNRS UMR6226, Sciences Chimiques de Rennes, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Gouault
authors.affiliation: University of Rennes1, France and CNRS UMR6226, Sciences Chimiques de Rennes, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Lohézic Le Dévéhat
authors.affiliation: University of Rennes1, France and CNRS UMR6226, Sciences Chimiques de Rennes, France.
authors.forename: Myriam
authors.initials: M
authors.lastname: Le Roch
authors.affiliation: University of Rennes1, France and CNRS UMR6226, Sciences Chimiques de Rennes, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Rouaud
authors.affiliation: CNRS UMR6290, Institut de Génétique et Développement de Rennes, France. mgaliber@univ-rennes1.fr and University of Rennes1, France.
authors.forename: David
authors.initials: D
authors.lastname: Gilot
authors.affiliation: CNRS UMR6290, Institut de Génétique et Développement de Rennes, France. mgaliber@univ-rennes1.fr and University of Rennes1, France and CHU-Pontchaillou, Rennes, France.
authors.forename: Marie-Dominique
authors.initials: MD
authors.lastname: Galibert
mesh_terms: D066258:Amphiregulin / Q000235:genetics; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects*; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000235:genetics; D008954:Models, Biological; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011758:Pyrroles / Q000737:chemistry / Q000494:pharmacology; D060888:Real-Time Polymerase Chain Reaction; D012867:Skin / Q000201:enzymology*; D014466:Ultraviolet Rays; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: C587848:AREG protein, human; D066258:Amphiregulin; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D051546:Cyclooxygenase 2; D048051:p38 Mitogen-Activated Protein Kinases; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9