title: A trifluoromethyl analogue of celecoxib exerts beneficial effects in neuroinflammation.
abstract: Celecoxib is a selective cyclooxygenase-2 (COX2) inhibitor. We have previously shown that celecoxib inhibits experimental autoimmune encephalomyelitis (EAE) in COX-2-deficient mice, suggestive for a mode of action involving COX2-independent pathways. In the present study, we tested the effect of a trifluoromethyl analogue of celecoxib (TFM-C) with 205-fold lower COX-2 inhibitory activity in two models of neuroinflammation, i.e. cerebellar organotypic cultures challenged with LPS and the EAE mouse model for multiple sclerosis. TFM-C inhibited secretion of IL-1β, IL-12 and IL-17, enhanced that of TNF-α and RANTES, reduced neuronal axonal damage and protected from oxidative stress in the organotypic model. TFM-C blocked TNF-α release in microglial cells through a process involving intracellular retention, but induced TNF-α secretion in primary astrocyte cultures. Finally, we demonstrate that TFM-C and celecoxib ameliorated EAE with equal potency. This coincided with reduced secretion of IL-17 and IFN-γ by MOG-reactive T-cells and of IL-23 and inflammatory cytokines by bone marrow-derived dendritic cells. Our study reveals that non-coxib analogues of celecoxib may have translational value in the treatment of neuro-inflammatory conditions.
authors.affiliation: Neurogenomiks Laboratory, University of Basque Country (UPV/ EHU), Zamudio, Spain ; Achucarro Basque Center for Neuroscience, Zamudio, Spain.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Di Penta
authors.affiliation: Department of Immunology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan ; Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Asako
authors.initials: A
authors.lastname: Chiba
authors.affiliation: Neurogenomiks Laboratory, University of Basque Country (UPV/ EHU), Zamudio, Spain ; Achucarro Basque Center for Neuroscience, Zamudio, Spain ; IKERBASQUE, Basque Foundation for Science, Bilbao, Spain.
authors.forename: Iraide
authors.initials: I
authors.lastname: Alloza
authors.affiliation: Neurotek Laboratory, University of Basque Country (UPV/EHU), Zamudio, Spain.
authors.forename: Ane
authors.initials: A
authors.lastname: Wyssenbach
authors.affiliation: Department of Immunology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Yamamura
authors.affiliation: Center of Neuroimmunology, Institute of Biomedical Research August Pi Sunyer (IDIBAPS) - Hospital Clinic of Barcelona, Barcelona, Spain.
authors.forename: Pablo
authors.initials: P
authors.lastname: Villoslada
authors.affiliation: Department of Immunology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan ; Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Sachiko
authors.initials: S
authors.lastname: Miyake
authors.affiliation: Neurogenomiks Laboratory, University of Basque Country (UPV/ EHU), Zamudio, Spain ; Achucarro Basque Center for Neuroscience, Zamudio, Spain ; IKERBASQUE, Basque Foundation for Science, Bilbao, Spain.
authors.forename: Koen
authors.initials: K
authors.lastname: Vandenbroeck
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism* / Q000473:pathology; D001369:Axons / Q000378:metabolism* / Q000473:pathology; D000068579:Celecoxib; D002478:Cells, Cultured; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D008070:Lipopolysaccharides / Q000633:toxicity; D051379:Mice; D009103:Multiple Sclerosis / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011720:Pyrazoles / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D016207:Cytokines; D008070:Lipopolysaccharides; D011720:Pyrazoles; D013449:Sulfonamides; D000068579:Celecoxib