A Trifluoromethyl Analogue of Celecoxib Exerts Beneficial Effects in Neuroinflammation

• Published in: PloS one Vol. 8; no. 12; p. e83119
• Main Authors: Di Penta, Alessandra, Chiba, Asako, Alloza, Iraide, Wyssenbach, Ane, Yamamura, Takashi, Villoslada, Pablo, Miyake, Sachiko, Vandenbroeck, Koen
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 11.12.2013; Public Library of Science (PLoS)
• Subjects: Analogs; Angiogenesis inhibitors; Animal models; Animals; Arthritis; Astrocytes - metabolism; Astrocytes - pathology; Axons - metabolism; Axons - pathology; Blood platelets; Blood-brain barrier; Bone marrow; Brain research; Celecoxib; Cells, Cultured; Cerebellum; COX-2 inhibitors; Cyclooxygenase 2 Inhibitors - pharmacology; Cyclooxygenase-2; Cytokines; Cytokines - metabolism; Dendritic cells; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental - drug therapy; Encephalomyelitis, Autoimmune, Experimental - metabolism; Encephalomyelitis, Autoimmune, Experimental - pathology; Experimental allergic encephalomyelitis; Experiments; Immunology; Inflammation; Inflammation - chemically induced; Inflammation - metabolism; Inflammation - pathology; Inflammatory diseases; Interferon; Interleukin 12; Interleukin 17; Interleukin 23; Laboratories; Lipopolysaccharides; Lipopolysaccharides - toxicity; Lymphocytes T; Mice; Microglia; Microglial cells; Mode of action; Multiple sclerosis; Multiple Sclerosis - chemically induced; Multiple Sclerosis - drug therapy; Multiple Sclerosis - metabolism; Multiple Sclerosis - pathology; Neurology; Neurosciences; Oligodendrocyte-myelin glycoprotein; Oxidative stress; Pathogenesis; Proteins; Psychiatry; Pyrazoles - pharmacology; RANTES; Rodents; Signal transduction; Sulfonamides - pharmacology; Thrombosis; Tumor necrosis factor; Tumor necrosis factor-TNF; γ-Interferon; Japan; Spain
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0083119

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.