The effects of etifoxine on the NLRP3 inflammasome and its relevance in elucidating the pathophysiology of multiple sclerosis

Osmond, Jordan Marian (2021) The effects of etifoxine on the NLRP3 inflammasome and its relevance in elucidating the pathophysiology of multiple sclerosis. Masters thesis, Memorial University of Newfoundland.

[English] PDF - Accepted Version Available under License - The author retains copyright ownership and moral rights in this thesis. Neither the thesis nor substantial extracts from it may be printed or otherwise reproduced without the author's permission. Download (3MB)

Abstract

Multiple sclerosis (MS) is a chronic neuroinflammatory disease that is characterized by immune-mediated demyelination within the central nervous system. Nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activation has been previously reported as a possible pathophysiological contributor to microglial activation and oligodendroglial loss in MS, particularly in progressive forms of the disease. Herein, it is demonstrated that etifoxine, a translocator protein (TSPO) ligand, attenuates the clinical symptoms in a mouse model of MS and significantly inhibits NLRP3 inflammasome activation in human and murine myeloid-derived cells in vitro by decreasing inflammasome-associated genes and inflammatory cytokine production. These anti-inflammatory effects of etifoxine were mediated independently of its previously described mechanisms related to engagement with TSPO and the GABAA receptor. Furthermore, we observed a similar anti-inflammatory effect of etifoxine on MS patient-derived monocytes, which provides clinical relevance for the investigation of etifoxine as a potential therapeutic in progressive MS. Lastly, through the use of a gene array, we identified multiple signalling pathways in order to elucidate a novel mechanism whereby etifoxine may be inhibiting NLRP3 inflammasome activation.

Actions (login required)

View Item