UBC Theses and Dissertations
Novel monoamine oxidase B inhibitor downregulation of lipopolysaccharide-induced pro-inflammatory cytokines Tra, Michelle
Oral inflammatory diseases (e.g. periodontitis) and gastrointestinal inflammatory bowel diseases (e.g. Crohn’s disease and ulcerative colitis) are characterized by an imbalance in secretion of pro- and anti-inflammatory cytokines leading to inflammation and epithelial and endothelial cell barrier disruption. Monoamine oxidase (MAO) B, a pro-oxidative enzyme, is induced in epithelial cells of a rat periodontal disease model and topical application of a known MAO inhibitor reduced disease (Ekuni et al., 2009). MAO B inhibitors also reduced TNFα secretion in epithelial cells and decreased endothelial cell hyperpermeability associated with inflammation (Tharakan et al., 2010; Whaley et al., 2009). MAO B inhibitors, such as deprenyl, decrease inflammation, however the mechanism by which this occurs is poorly understood. The Putnins laboratory with collaborators have developed reversible and selective MAO B inhibitors derived from deprenyl that do not cross the BBB. These non-BBB permeable novel inhibitors were developed to reduce CNS-based negative side effects, however, their anti-inflammatory effects have yet to be investigated. Lipopolysaccharide (LPS) is a component of the gram-negative bacterial membrane and is a key mediator of inflammation. The aim of this study is to determine if four novel MAO B inhibitors alter LPS-induced pro-inflammatory cytokine expression in intestinal endothelial and epithelial cells using in vitro cell culture modeling. The two cell lines expressed MAO B but not MAO A protein and the novel MAO B inhibitors did not reduce cell viability nor induce cytotoxicity or apoptosis. However, one compound demonstrated anti-apoptotic effects in intestinal epithelial cells. The novel MAO B inhibitors reduced LPS-induced protein secretion and gene expression of IL-8, IL-6 and TNFα, pro-inflammatory cytokines commonly seen in mucosal inflammatory diseases. Ultimately, this project aims to provide in vitro evidence for the therapeutic potential of novel MAO B inhibitors for the treatment of LPS-induced pro-inflammatory cytokines. Reduction of pro-inflammatory cytokine secretion and gene expression by novel MAO B inhibitors may pose an effective clinical approach to treat a variety of mucosal inflammatory diseases.
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