Anti-Inflammatory Effects of Inhibiting the Amine Oxidase Activity of Semicarbazide-Sensitive Amine Oxidase

摘要

Human semicarbazide-sensitive amine oxidase (SSAO) or vascular adhesion protein-1 (VAP-1) is a copper-containing amine oxidase (AOC3,EC 1.4.3.6) that has both enzymatic and adhesive function.SSAO catalyzes the oxidative deamination of primary amines,resulting in the formation of the corresponding aldehyde and release of hydrogen peroxide and ammonia.Membrane-bound SSAO is an inflammation-inducible endothe-lial cell adhesion molecule that mediates the interaction between leukocytes and activated endothelial cells in inflamed vessels.Both the direct adhesive and enzymatic functions seem to be involved in the adhesion cascade.LJP 1207 [N'-(2-phenyl-allyl)-hydrazine hydrochloride] is a potent (human SSAO IC_(50)=17 nM),selective,and orally available SSAO inhibitor that blocks both the enzymatic and adhesion functions of SSAONAP-1.In a mouse model of ulcerative colitis,LJP 1207 significantly reduces mortality,loss of body weight,and colonic cytokine levels.Quantitative histopathological assessment of colitis activity in this model showed a highly significant suppression of inflammation,injury,and ulceration scores in the animals treated with the SSAOANAP-1 inhibitor.LJP 1207 also reduced serum levels of tumor necrosis factor-alpha and in-terleukin 6 in lipopolysaccharide (LPS)-challenged mice and prolonged survival post-LPS-induced endotoxemia.Therapeutic and prophylactic administration of LJP 1207 in the rat car-rageenan footpad model also markedly inhibited swelling and inflammation.Overall,the data suggest that small molecule SSAONAP-1 inhibitors may provide clinical benefit in the treatment of acute and chronic inflammatory diseases.