The Role of Natural Benzodiazepines Receptor Ligands in Hepatic Encephalopathy

Abstract

The hypothesis that agonist ligands of the central benzodiazepine (BZ) receptor contribute to the manifestations of hepatic encephalopathy (HE) by enhancing the action of GABA was originally suggested by anecdotal observations of ameliorations of HE following administration of a BZ receptor antagonist. The term natural BZs has been introduced for BZ receptor ligands which have been demonstrated in brain, cerebrospinal fluid, and plasma of normal animals and humans and which cannot be attributed to ingestion of pharmaceutical BZs. Possible sources of natural BZs or their precursors include the food cycle and intestinal bacteria, but probably not mammalian tissues. In liver failure, mean levels of natural BZ agonist ligands are increased in both animal models and humans and correlate with the severity of HE; the levels associated with HE are sufficient to induce at least mild neuroinhibitory behavioral effects. Flumazenil is the only BZ receptor antagonist currently available for clinical use. Intravenously administered flumazenil has been shown to induce ameliorations of HE in large proportions of patients with acute or chronic liver failure. Its beneficial effects on HE are limited by its weak partial agonist properties and, because of rapid metabolism, the transience of its effects. Reports of lack of effects of flumazenil on HE may be attributable to studying inappropriate animal models and/or complex encephalopathic states rather than HE uncomplicated by other encephalopathies. Other experimental BZ receptor antagonists with partial inverse agonist properties have been reported to be more effective than flumazenil in ameliorating HE in animal models. The contribution of BZ receptor antagonists on the management of HE may be enhanced further by (1) assessing the efficacy of an oral preparation of flumazenil on chronic portal-systemic encephalopathy; (2) conducting preliminary clinical trials of the efficacy of BZ antagonists with partial inverse agonists properties on HE; and (3) developing new BZ antagonists with properties superior to those of flumazenil, such as milder partial agonist properties and slower metabolism.KeywordsNatural benzodiazepineBenzodiazepine receptorBenzodiazepine agonistHepatic encephalopathyGamma-aminobutyric acidBenzodiazepine antagonistFlumazenil