BLOOD-BRAIN-BARRIER PERMEABILITY IS MARKEDLY DECREASED IN CHOLESTASISIN THE RAT

The blood-brain-barrier plays an essential role in regulating the entr ance of substances into the brain. To date, permeability of the blood- brain barrier has not been studied in models of cholestatic liver inju ry, although levels of substances known to enhance vascular permeabili ty (bile acids, substance P, histamine) are elevated in cholestasis. T wo rat models of cholestasis were studied: bile duct resection (5 days after surgery) and alpha-naphthylhisothiocyanate treatment (45 mg/kg/ day for 7 days). The mean value for whole brain blood-to-brain transfe r constant in bile duct resection rats was about 50% less than corresp onding values in sham-operated and unoperated control rats (p less-tha n-or-equal-to 0.05, respectively). Reductions in blood-to-brain transf er constant of similar magnitude were found in the caudate nuclei, cor texes and hippocampi of bile duct-resected rats. Blood-to-brain transf er constant values in alpha-naphthylisothiocyanate-treated rats were a lso about 50% less in whole brain and specific brain regions than corr esponding control values. A precedent for a decrease in blood-to-brain transfer constant is the dexamethasone-treated rat, in which the phen omenon has been attributed to a decrease in cerebral capillary endothe lial cell membrane fluidity. We confirmed that blood-to-brain transfer constant values are reduced by about 50% in dexamethasone-treated rat s. A decrease in membrane fluidity affords a rational explanation for a decrease in blood-to-brain transfer constant in cholestasis as a con sequence of the dynamic equilibrium between elevated plasma levels of cholesterol in cholestasis and cell membranes exposed to the circulati on.