A Trifluoromethyl Analogue of Celecoxib Exerts Beneficial Effects in Neuroinflammation

作者：Di Penta Alessandra; Chiba Asako; Alloza Iraide; Wyssenbach Ane; Yamamura Takashi; Villoslada Pablo; Miyake Sachiko; Vandenbroeck Koen^*

来源：PLos One, 2013, 8(12): UNSP e83119.

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-1 beta, IL-12 and IL-17, enhanced that of TNF-alpha and RANTES, reduced neuronal axonal damage and protected from oxidative stress in the organotypic model. TFM-C blocked TNF-alpha release in microglial cells through a process involving intracellular retention, but induced TNF-alpha 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-Y 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 neuroinflammatory conditions.

• 出版日期2013-12-11