The role of diazepam-binding inhibitor (DBI) in the pathogenesis of hepatic encephalopathy will be studied in humans and animals. Recent theories on the neurochemical etiology for hepatic encephalopathy have suggested activation of inhibitory neurotransmitter GABA systems. GABA receptor sites are known to be modulated by benzodiazepines. Furthermore, hepatic encephalopathy can be ameliorated in animals and humans by the administration of benzodiazepine antagonists. The neuropeptide DBI is an endogenous allosteric modulator of BABA systems at the benezodiazepine receptor. These experiments will examine, in animals and humans, whether DBI metabolism is altered in hepatic encephalopathy and how these changes correlate with clinical indices of encephalopathy. In preliminary experiments cerebrospinal fluid DBI was found to be markedly elevated in patients with hepatic encephalopathy and was normal in non-encephalopathic patients with liver disease. A primary goal of the proposed experiments will be to quantify DBI in the CSF of patients with hepatic as well as non- hepatic encephalopathy and to correlate these changes with other clinical abnormalities. Since data acquisition from humans is limited, a major goal of this proposal will be the utilization and analysis of animal models of encephalopathy. Central nervous system DBI will be quantified in various animal models of acute and chronic hepatic encephalopathy as well as animal models of non-hepatic encephalopathy. Experiments are planned to quantify the content of mRNA for DBI in various brain regions to add the understanding of its synthesis. Furthermore, to test the hypothesis that DBI or its metabolites may be responsible for hepatic encephalopathy, the neuropeptide will be administered to the CNS of animals. Finally, the effectiveness and specificity of benzodiazepine antagonists in the reversal of hepatic encephalopathy will be examined in the proposed series of experiments. Understanding of role of DBI in the pathogenesis of hepatic encephalopathy may lead to important pharmacological therapies in this disease.
