STUDIES OF RELATING TO THE PATHOGENESIS OF HEPATIC ENCEPHALOPATHY

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The abnormal pattern of visual evoked responses (VERs) in rabbits with hepatic encephalopathy (HE) due to fulminant hepatic failure (FHF) resembles that associated with coma induced by a barbiturate, a benzodiazepine or a yield-amino-butyric acid (GABA) agonist. As these drugs induce neural inhibition by interacting with binding sites on the GABA receptor complex on postsynaptic neural membranes, these findings suggest that the pattern of neuronal activity in HE may resemble that associated with activation of the GABA inhibitory neurotransmitter system. Outside the CNS the main source of GABA is gut bacteria and the main site of its catabolism is the liver. When FHF was induced in rabbits the onset of HE was preceded by an increase in the plasma levels of GABA and by a nonspecific increase in the permeability of the blood brain barrier (BBB) to a nonmetabolized isomer of GABA. To take account of the rapid metabolism of GABA a modified Oldendorf technique, which employed the use of a vascular marker, has been used to demonstrate that the brain uptake index for GABA itself is increases in HE. FHF was associated with significant increased in the densities of brain receptors for the inhibitory amino acid neurotransmitters, and for benzodiazepines (BZ), with significant decreases in the densities of brain receptors for the excitatory amino acid neurotransmitters, and with changes in the composition of neural membranes. Both a GABA receptor antagonist and a BZ receptor antagonist induced an amelioration of HE due to FHF both clinically and electrophysiologically (VER pattern). These findings suggest that in acute liver failure: (i) plasma GABA gains access to the brain through a permeable BBB; (ii) the brain may be less sensitive to excitatory amino acid neurotransmitters and more sensitive to inhibitory amino acid neurotransmitters and to BZ and (iii) an endogenous BZ ligand may contribute to the neural inhibition of HE by augmenting GABAergic tone.