Antioxidative acylCoA cholesterol: acyl transferase inhibitor Avasimibe reduces the impact of a high cholesterol diet on brain lipid peroxidation in mice

High fat/high cholesterol diets and oxidative stress in Western countries are risk factors for age related diseases such as Alzheimer’s Disease (AD). Exercise and cholesterol-lowering drugs are being considered as potential therapies for AD. Diet-induced hypercholesterolemia has been used here as a model to assess the relationship between steatosis (hepatic dysfunction) and oxidative damage associated with neurodegeneration induced by vitamin E alterations. In mice fed a high cholesterol diet there was an increase in brain free cholesterol content and an increase in neuronal cholesterol oxidation (as assessed by 24S-hydroxycholesterol levels). The high fat and high cholesterol (HFHC) diet altered phosphatidylinositol turnover and levels of certain phospholipid classes in mouse brain membranes. The anti-oxidative acylCoA cholesterol transferase (ACAT) inhibitor Avasimibe was administered orally to mice. Avasimibe could be detected in the plasma but not in the brain and was found to inhibit ACAT activity in the periphery only, yet was associated with therapeutic improvements in neuronal cholesterol oxidation and membrane phospholipid composition. The HFHC diet induced steatosis (fatty liver) and treatment with Avasimibe reduced brain lipid peroxidation, reduced liver and brain cholesterol and triglyceride accumulation, and was associated with a reduction in hepatic and intestinal secretion of apoB cholesterol-containing lipoproteins. Avasimibe appears to improve diet-induced brain oxidative stress and vitamin E transport reducing brain cholesterol oxidation and phospholipase activity, thus preventing lipid peroxidation and possibly reducing neurodegeneration.