Hepatic encephalopathy: Lack of changes of γ-aminobutyric acid content in plasma and cerebrospinal fluid

Moroni, Flavio; Riggio, Oliviero; Carlà, Vincenzo; Festuccia, Vittorio; Ghinelli, F; Marino, Ignazio R.; Merli, Manuela; Natali, Laura; Pedretti, Giorgio; Fiaccadori, F; Capocaccia, L.

doi:10.1002/hep.1840070504

Cited by 36 publications

(9 citation statements)

References 32 publications

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“…Other reports suggested increased GABA or GABA-like activity in the brain, cerebrospinal fluid or plasma of human patients (16) and animals with HE (17,18). Again, these findings could not be confirmed by others (4, 19,20). More recently, evidence for increased concentrations of diazepam, N-desmethyldiazepam and other substances with benzodiazepine-like activity in the brain and cerebrospinal fluid of TAA-treated rats (6, 7), galactosamine-treated rabbits (8,21) and human subjects (9) with FLF has accumulated.…”

Section: Discussioncontrasting

confidence: 50%

Increased benzodiazepine-like activity is neither necessary nor sufficient to explain acute hepatic encephalopathy in the thioacetamide-treated rat

et al. 1993

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Increased levels of natural benzodiazepine receptor agonists, produced in the body (endogenous) or ingested with food (exogenous) have been proposed as one of the factors causing hepatic encephalopathy in both experimental animals and human subjects. However, the divergent response of hepatic encephalopathy to benzodiazepine antagonists sheds doubt on this attractive hypothesis. Acute liver failure was induced in male Sprague-Dawley rats (n = 17) with intraperitoneal thioacetamide (600 mg/kg/day for 3 days) while 14 control rats received vehicle only. Acute liver failure developed in all treated rats (AST: 1,898 +/- 1,359 IU/L vs. controls, 45 +/- 5 IU/L, p < 0.005; bilirubin: 36 +/- 27 mumol/L vs. controls, 1.5 +/- 0.5 mumol/L, p < 0.005; centrizonal necrosis) and grade 3 or 4 hepatic encephalopathy (neurologic assessment and activity monitoring). However, benzodiazepine receptor ligand activity, measured in the supernatant of whole-brain homogenates with a [3H]flumazenil binding competition assay, was clearly increased in only 1 of 17 rats with acute liver failure compared with controls (52.7 +/- 34.1 vs. 44.3 +/- 18.9 ng diazepam equivalents/gm; NS). To evaluate whether the reported increase in benzodiazepine receptor ligand activity could be due to prolonged residence of exogenous benzodiazepine-like substances, additional rats with acute liver failure and controls were treated with diazepam (five doses of 0.5 mg/kg at 12-hr intervals by gavage). Benzodiazepine receptor ligand activity was greater in animals with acute liver failure than in controls (223 +/- 65 vs. 103 +/- 23 ng diazepam equivalents/gm; p < 0.002) 1 to 3 hr after the last diazepam dose.(ABSTRACT TRUNCATED AT 250 WORDS)

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Section: Discussioncontrasting

confidence: 50%

Increased benzodiazepine-like activity is neither necessary nor sufficient to explain acute hepatic encephalopathy in the thioacetamide-treated rat

et al. 1993

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“…These findings extend those of previous reports in which both whole brain, 2,3 cerebrospinal fluid, 19 and microdialysate 4 concentrations of GABA were unchanged in this animal model of ALF. A lack of alterations of brain GABA have also been reported in hepatectomized rats 1 as well as in cerebrospinal fluid 32 or autopsied brain tissue 6 from patients who died in ALF.…”

Section: Discussionmentioning

confidence: 89%

Selective increase of brain lactate synthesis in experimental acute liver failure: Results of a [1H-13C] nuclear magnetic resonance study

2003

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Acute liver failure (ALF) results in alterations of energy metabolites and of glucose-derived amino acid neurotransmitters in brain. However, the dynamics of changes in glucose metabolism remain unclear. The present study was undertaken using 1 H and 13 C nuclear magnetic resonance (NMR) spectroscopy to determine the rates of incorporation of glucose into amino acids and lactate via cell-specific pathways in relation to the severity of encephalopathy and brain edema in rats with ALF because of hepatic devascularization. Early (precoma) stages of encephalopathy were accompanied by significant 2-to 4.5-fold (P < .001) increases of total brain glutamine and lactate concentrations. More severe (coma) stages of encephalopathy and brain edema led to a further significant increase in brain lactate but no such increase in glutamine. Furthermore, 13 C isotopomer analysis showed a selective increase of de novo synthesis of lactate from [1-13 C]glucose resulting in 2.5-fold increased fractional 13 C enrichments in lactate at coma stages. [2-13 C]glutamine, synthesized through the astrocytic enzyme pyruvate carboxylase, increased 10-fold at precoma stages but showed no further increase at coma stages of encephalopathy. 13 C-label incorporation into [4-13 C]glutamate, synthesized mainly through neuronal pyruvate dehydrogenase, was selectively reduced at coma stages, whereas brain GABA synthesis was unchanged at all time points. In conclusion, increased brain lactate synthesis and impaired glucose oxidative pathways rather than intracellular glutamine accumulation are the major cause of brain edema in ALF. Future NMR spectroscopic studies using stable isotopes and real-time measurements of metabolic rates could be valuable in the elucidation of the cerebral metabolic consequences of ALF in humans. (HEPATOLOGY 2003;37:420-428.) H epatic encephalopathy and brain edema are serious central nervous system complications of acute liver failure (ALF), which are accompanied by significant alterations of brain metabolites. For example, biochemical studies in brain tissue from animals with ALF resulting from hepatectomy, 1 hepatic devascularization, 2-4 or toxic liver injury 5 as well as autopsied brain tissue from patients with ALF 6 reveal significant increases in concentrations of glutamine and a concomitant reduction of glutamate. Several of these studies also show that brain lactate concentrations are elevated as a function of the deterioration of central nervous system function in ALF, a finding that has been attributed to decreased pyruvate oxidation because of ammonia exposure. 7 Although these biochemical studies provide important hints on metabolic derangements in ALF, they do not permit the elucidation of rates of synthesis/degradation of these metabolites, nor do they provide information on the cellular localization of the altered metabolism. The use of nuclear magnetic resonance (NMR) spectroscopy and stable isotope precursors provides an effective approach to the study of metabolic turnover in the brain. In particular, ...

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“…Support for an increased GABA-ergic tone during HE is found in, among other areas, the reported im-provements of HE after administration of benzodiazepine receptor antagonists or partial inverse agonists, observed in both humans and animals (Baraldi et al, 1984;Ferenci and Grimm, 1989;Bosman et al, 199 1). Whether this increased GABA-ergic tone during HE is due to increased cerebral GABA concentration, increased GABA release, altered receptor affinities, or increased levels of endogenous benzodiazepine receptor ligands is still a matter of debate (Baraldi et al, 1984;Ferenci et al, 1983Moroni et al, 1987;Mullen et al, 1990). In contrast, others did not observe any improvement of HE by administration of flumazenil in rabbits with acute ischemic liver failure (Van der Rijt et al, 1990) transmission might also contribute to the pathogenesis of HE (Buttenvorth et al, 1987).…”

mentioning

confidence: 99%

Amino Acid Release from Cerebral Cortex in Experimental Acute Liver Failure, Studied by In Vivo Cerebral Cortex Microdialysis

Bosman

Deutz

Maas

et al. 1992

Journal of Neurochemistry

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Both increased gamma-aminobutyric acid (GABA)-ergic and decreased glutamatergic neurotransmission have been suggested relative to the pathophysiology of hepatic encephalopathy. This proposed disturbance in neurotransmitter balance, however, is based mainly on brain tissue analysis. Because the approach of whole tissue analysis is of limited value with regard to in vivo neurotransmission, we have studied the extracellular concentrations in the cerebral cortex of several neuroactive amino acids by application of the in vivo microdialysis technique. During acute hepatic encephalopathy induced in rats by complete liver ischemia, increased extracellular concentrations of the neuroactive amino acids glutamate, taurine, and glycine were observed, whereas extracellular concentrations of aspartate and GABA were unaltered and glutamine decreased. It is therefore suggested that hepatic encephalopathy is associated with glycine potentiated glutamate neurotoxicity rather than with a shortage of the neurotransmitter glutamate. In addition, increased extracellular concentration of taurine might contribute to the disturbed neurotransmitter balance. The observation of decreasing glutamine concentrations, after an initial increase, points to a possible astrocytic dysfunction involved in the pathophysiology of hepatic encephalopathy.

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Hepatic encephalopathy: Lack of changes of γ-aminobutyric acid content in plasma and cerebrospinal fluid

Cited by 36 publications

References 32 publications

Increased benzodiazepine-like activity is neither necessary nor sufficient to explain acute hepatic encephalopathy in the thioacetamide-treated rat

Increased benzodiazepine-like activity is neither necessary nor sufficient to explain acute hepatic encephalopathy in the thioacetamide-treated rat

Selective increase of brain lactate synthesis in experimental acute liver failure: Results of a [1H-13C] nuclear magnetic resonance study

Amino Acid Release from Cerebral Cortex in Experimental Acute Liver Failure, Studied by In Vivo Cerebral Cortex Microdialysis

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