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.
Highlights
Nonsteroidal anti-inflammatory drugs are indicated for the treatment of a variety of chronic inflammatory diseases and act by inhibiting prostaglandin H synthase
The effect of trifluoromethyl analogue of celecoxib (TFM-C) on cytokine release was assessed in a model of neuroinflammation consisting of mice cerebellar organotypic cultures stimulated with LPS, by means of a multiplex ELISA-based Q-Plex assay system
We have tested a non-coxib analogue of celecoxib, TFM-C, both in a model of neuroinflammation consisting of organotypic cultures challenged with LPS [32] and in EAE
Summary
Nonsteroidal anti-inflammatory drugs are indicated for the treatment of a variety of chronic inflammatory diseases and act by inhibiting prostaglandin H synthase ( known as cyclooxygenase, COX). We found that celecoxib in contrast to other COX-2 inhibitors such as nimesulid, prevented EAE by inhibiting the infiltration of inflammatory cells into the central nervous system, MOGspecific Th1 cytokine production and expression of adhesion molecules and MCP-1 [16]. This protective effect was not mediated via COX2 inhibition since it was observed in COX2-deficient mice [16]. We hypothesized that TFM-C may constitute a new drug candidate that retains the beneficial effects of celecoxib in the EAE model while its much decreased COX2 inhibitory activity would render it less adverse in terms of cardiovascular risk. We have analyzed the effect of TFM-C on cytokine secretion, demyelination, and axonal damage in mice cerebellar organotypic cultures, a model of neuroinflammation, and assessed its activity in the EAE model
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
