STUDIES OF RELATING TO THE PATHOGENESIS OF HEPATIC ENCEPHALOPATHY

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The abnormal pattern of visual evoked responses (VERs) in animals with hepatic encephalopathy (HE) due to fulminant hepatic failure (FHF) resembles that associated with encephalopathy induced by drugs which promote GABA-ergic neurotransmission, including benzodiazepines (BZs). These findings suggest that the pattern of neuronal activity in HE may resemble that associated with activation of the GABA inhibitory neurotransmitter system. Furthermore, rabbits with HE due to FHF exhibit increased resistance to the convulsive effects of the GABA receptor antagonist, bicuculline. Ameliorations of HE (both clinical and electrophysiologic (VER waveform)) have been induced in animals with FHF by BZ receptor antagonists. Furthermore, spontaneous in vitro activity of Purkinje neurons from rabbits in HE due to FHF exhibited increased sensitivity to depression by agonists of the GABA/BZ receptor complex, including a BZ, and, in contrast to control neurons, exhibited excitation when exposed to BZ receptor antagonists. These findings suggest that in HE due to FHF: (i) There is increased GABA-ergic tone; (ii) Blockading of BZ receptors can ameliorate HE; (iii) BZ receptor antagonists may be of value in the management of HE; and (iv) An endogenous BZ receptor agonist may contribute to HE. Such a ligand is being isolated from supernatants of brain obtained from models of HE.