Appearance of middle molecular substances in serum associated with increased permeability of blood-brain barrier in experimental models of acute hepatic failure.

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Recent studies from our laboratory have revealed that HPLC peak areas of middle molecular substances (MMS) significantly increased both in serum and in cerebrospinal fluid (CSF) of patients with acute hepatic failure (AHF), and that some portions of MMS inhibited in vitro the activity of rat brain microsomal Na+, K+-ATPase. The present study was conducted to further elucidate the changes of MMS levels in sera and to investigate functional integrity of blood-brain barrier (BBB) in rat-and dog-AHF models, with special respect to the pathogenesis of hepatic encephalopathy and brain edema (BE).<BR>HPLC analysis of sera obtained from AHF models showed marked increaSes of several MMS peaks (in particular, below 4, 000 daltons) in parallel with developing grades of hepatic coma. Since HPLC peak areas of these MMS showed significant positive correlations with plasma levels of methionine and aromatic amino acids in AHF models, it is conceivable that serum levels of MMS are relevant to the extent of massive hepatic necrosis. In addition, AHF models showed the elevation of brain water contents and gradual increaSe of permeability of BBB to inulin (approximately 5, 200 daltons), sucrose and L-glucose which are reported to be impossible to transport acrosS the BBB in physiological conditions.<BR>These results strongly suggest that, in AHF models, increased MMS in circulation enter the brain across the "leaky" BBB and are presumably involved in the development of BE by interfering the function of sodium pump located along the cell membrane.

Appearance of middle molecular substances in serum associated with increased permeability of blood-brain barrier in experimental models of acute hepatic failure.

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