Homocysteine has anti-inflammatory properties in a hypercholesterolemic rat model in vivo

Inflammation is a hallmark in many neurodegenerative diseases like Alzheimer's disease or vascular dementia. Cholesterol and homocysteine are both vascular risk factors which have been associated with dementia, inflammation and blood–brain barrier dysfunction. In previous studies we found that hypercholesterolemia but not hyperhomocysteinemia induced inflammation in rats in vivo. The aim of the present study was to investigate the effect of a combined treatment of Sprague Dawley rats with cholesterol and homocysteine for 5 months on spatial learning and memory, blood–brain barrier integrity and inflammation. Cholesterol treated rats showed severe learning deficits, while rats treated with cholesterol and homocysteine (Mix) counteracted the cholesterol-induced inflammation and partly the cortical blood–brain barrier disruptions, although cognition was still impaired. To study the potential protective effect of homocysteine, inflammation was induced in organotypic rat brain cortex slices and primary microglial cells by treatment with different inflammatory stimuli (e.g. lipopolysaccharide or tissue plasminogen activator). Tissue plasminogen activator-induced inflammation was counteracted by homocysteine. In conclusion, our data demonstrate that homocysteine significantly ameliorates cholesterol-induced inflammation and blood–brain barrier disruption but not the memory impairment, possibly involving a tissue plasminogen activator-related mechanism.