Abstract
Contradictory results have been reported about the effects of liver diseases on the blood-brain barrier (BBB) permeability to markers. For instance, both an increase and no change in the BBB permeability to BBB markers sodium fluorescein and Evans blue have been reported in experimental cholestasis induced by bile duct ligation (BDL) in rats. These contradictory effects might be due to inherent limitations of these markers and/or methodological issues. Here, we investigated the time course of the impact of BDL in rats on BBB permeability using a recently developed stable isotope labeled marker [(13)C]sucrose, which is expected to be devoid of limitations of other markers, such as sodium fluorescein. At various times (five days, two weeks, and four weeks) after BDL or sham surgery, the brain uptake clearance (K(in)) of [(13)C]sucrose was estimated using quantitation of the marker in plasma, blood, and brain by a specific LC-MS/MS analytical method. BDL caused substantial increases in the plasma concentrations of liver biochemical markers (bilirubin, total bile acids, ammonia, and cholesterol) and reduced liver cytochrome P450 content and metabolic activities. However, compared with the sham group, the plasma or blood AUC, brain concentrations, and K(in) of [(13)C]sucrose in BDL animals remained unchanged at all the studied times. Additionally, we observed a negative correlation between the sucrose K(in) and plasma total bile acids concentrations in the BDL animals. It is concluded that cholestatic liver disease, induced by BDL surgery in rats, does not significantly affect the BBB permeability to sucrose up to 4 weeks after the surgery.