Abstract
The brain is protected by the blood brain barrier (BBB), which becomes leaky during obstructive cholestasis via an unknown mechanism. A common feature of cholestasis is increased serum bile acids, which can signal via the membrane bound receptor, TGR5. Our aim was to determine the effects of bile acids in the permeability of the BBB during the course of cholestasis. After bile duct ligation (BDL) in the rat, serum bile acid concentrations increased which was paralleled by increased BBB permeability as shown by an Evan's blue exclusion assay. In vitro, there was increased permeability of a monolayer of rat brain microvessel endothelial cells (RBMEC) after treatment with serum from BDL animals compared to controls and also after treatment with cholic acid (CA), deoxycholate (DCA) and chenodeoxycholate (CDCA), but not after ursodeoxycholate (UDCA). In parallel, the TGR5 agonist betulinic acid also increased permeability in vitro. Analysis of RBMECs treated with CA, CDCA, DCA, and betulinic acid all exhibited a disorganized cytoskeleton (demonstrated by F‐Actin staining) and an altered distribution of the tight junction proteins ZO‐1 and ZO‐2. Our data suggests that the increased circulating serum bile acids contribute to the increased permeability of the BBB seen during obstructive cholestasis. This is possibly via a mechanism involving TGR5 activation and subsequent disruption of the tight junctions.
Published Version
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