Dysfunction of the blood-brain barrier (BBB) is an early pathological feature of vascular dementia and Alzheimer's disease (AD) and is triggered by inflammatory stimuli. Probucol is a lipid-lowering agent with potent anti-oxidant properties once commonly used for the treatment of cardiovascular disease. Probucol therapy was found to stabilize cognitive symptoms in elderly AD patients, whereas in amyloid transgenic mice probucol was shown to attenuate amyloidosis. However, the mechanisms underlying the effects of probucol have note been determined. In the present study we investigated whether probucol can prevent BBB disturbances induced by chronic ingestion of proinflammatory diets enriched with either 20% (w/w) saturated fats (SFA) or 1% (w/w) cholesterol. Mice were fed the diets for 12 weeks before they were killed and BBB integrity was measured. Mice maintained on either the SFA- or cholesterol-supplemented diets were found to have a 30- and sevenfold greater likelihood of BBB dysfunction, respectively, as determined by the parenchymal extravasation of plasma-derived immunoglobulins and endogenous lipoprotein enrichment with β-amyloid. In contrast, mice fed the SFA- or cholesterol-enriched diets that also contained 1% (w/w) probucol showed no evidence of BBB disturbance. The parenchymal expression of glial fibrillary acidic protein, a marker of cerebrovascular inflammation, was significantly greater in mice fed the SFA-enriched diet. Plasma lipid, β-amyloid and apolipoprotein B levels were not increased by feeding of the SFA- or cholesterol-enriched diets. However, mice fed the SFA- or cholesterol-enriched diets did exhibit increased plasma non-esterified fatty acid levels that were not reduced by probucol. The data suggest that probucol prevents disturbances of BBB induced by chronic ingestion of diets enriched in SFA or cholesterol by suppressing inflammatory pathways rather than by modulating plasma lipid homeostasis.
Faculty of Health Sciences, School of Public Health, Curtin Health Innovation Research Institute Biosciences Research Precinct, Curtin University, Bentley, WA, Australia., , , ,