RT Journal Article
SR Electronic
T1 Anti-Inflammatory Effects of Inhibiting the Amine Oxidase Activity of Semicarbazide-Sensitive Amine Oxidase
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 553
OP 562
DO 10.1124/jpet.105.089649
VO 315
IS 2
A1 Luisa M. Salter-Cid
A1 Eric Wang
A1 Anne M. O'Rourke
A1 Andrew Miller
A1 Hongfeng Gao
A1 Li Huang
A1 Arnie Garcia
A1 Matthew D. Linnik
YR 2005
UL http://jpet.aspetjournals.org/content/315/2/553.abstract
AB 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 endothelial 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 IC50 = 17 nM), selective, and orally available SSAO inhibitor that blocks both the enzymatic and adhesion functions of SSAO/VAP-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 SSAO/VAP-1 inhibitor. LJP 1207 also reduced serum levels of tumor necrosis factor-α and interleukin 6 in lipopolysaccharide (LPS)-challenged mice and prolonged survival post-LPS-induced endotoxemia. Therapeutic and prophylactic administration of LJP 1207 in the rat carrageenan footpad model also markedly inhibited swelling and inflammation. Overall, the data suggest that small molecule SSAO/VAP-1 inhibitors may provide clinical benefit in the treatment of acute and chronic inflammatory diseases. The American Society for Pharmacology and Experimental Therapeutics