elsibucol and Inflammation

Elsibucol is a metabolically stable derivative of probucol with antioxidant, anti-inflammatory and antiproliferative properties. Here we investigated the effect of elsibucol on the development of atherosclerosis following arterial injury in hypercholesterolemic rabbits.. New Zealand White rabbits were fed a high cholesterol diet that was supplemented or not with 0.5% elsibucol, 1% elsibucol or 1% probucol. An angioplasty of the iliac artery was performed after 3 weeks of diet. We found that treatment with elsibucol significantly decreases blood total cholesterol, LDLc and triglyceride levels. This is associated with a significant 46% reduction of neointimal hyperplasia following arterial injury. Interestingly, the effect of elsibucol on cholesterol levels and neointimal formation appears to be more pronounced than that of probucol. In vitro, elsibucol reduces vascular smooth muscle cell proliferation without affecting cell viability. In vivo, treatment with elsibucol is associated with a significant reduction of cellular proliferation (PCNA immunostaining), oxidative stress (nitrotyrosine immunostaining), VCAM-1 expression and macrophage infiltration in injured arteries. Despite its potent effect on neointimal hyperplasia, elsibucol does not prevent endothelial healing (Evans blue staining) following arterial injury.. In hypercholesterolemic animals, elsibucol inhibits atherosclerosis and preserves endothelial healing following arterial injury. The mechanisms involved include lowering of blood cholesterol levels together with a reduction of oxidative stress and inflammation in injured arteries.

Topics: Animals; Antioxidants; Arteries; Atherosclerosis; Butyrates; Carotid Arteries; Cell Proliferation; Cell Survival; Cholesterol; Cholesterol, LDL; Endothelium, Vascular; Hypercholesterolemia; Iliac Artery; Immunohistochemistry; Inflammation; Male; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Neointima; Oxidative Stress; Phenols; Rabbits; Vascular Diseases

Vascular cell adhesion molecule-1 (VCAM-1) mediates recruitment of leukocytes to endothelial cells and is implicated in many inflammatory conditions. Since part of the signal transduction pathway that regulates the activation of VCAM-1 expression is redox-sensitive, compounds with antioxidant properties may have inhibitory effects on VCAM-1 expression. Novel phenolic compounds have been designed and synthesized starting from probucol (1). Many of these compounds demonstrated potent inhibitory effects on cytokine-induced VCAM-1 expression and displayed potent antioxidant effects in vitro. Some of these derivatives (4o, 4p, 4w, and 4x) inhibited lipopolysaccharide (LPS)-induced secretion of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), and IL-6 from human peripheral blood mononuclear cells (hPBMCs) in a concentration-dependent manner in vitro and showed antiinflammatory effects in an animal model. Compounds 4ad and 4ae are currently in clinical trials for the treatment of rheumatoid arthritis (RA) and prevention of chronic organ transplant rejection, respectively.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Anticholesteremic Agents; Antioxidants; Cells, Cultured; Cholesterol, HDL; Cholesterol, LDL; Chronic Disease; Cricetinae; Depression, Chemical; Endothelial Cells; Endothelium, Vascular; Humans; Inflammation; Interleukin-1; Interleukin-6; Male; Mice; Mice, Inbred BALB C; Phenols; Probucol; Structure-Activity Relationship; Sulfides; Tumor Necrosis Factor-alpha; Vascular Cell Adhesion Molecule-1