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Novel monoamine oxidase B inhibitor downregulation of lipopolysaccharide-induced pro-inflammatory cytokines

University of British Columbia

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.

Text

2016-07-31

Attribution-NonCommercial-NoDerivs 2.5 Canada

http://hdl.handle.net/2429/54106

Craniofacial Science

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/2.5/ca/