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

Abstract

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)

Indomethacin improves locomotor deficit and reduces brain concentrations of neuroinhibitory steroids in rats following portacaval anastomosis

“…Results of the present study demonstrated that such concentrations are sufficient to increase the binding of the GABA-A receptor agonist 3 H-muscimol to normal rat brain membranes, suggesting that the increased brain concentrations of these neurosteroids in PCA rats are of pathophysiological relevance. Previous studies showed that low nanomolar concentrations of allopregnanolone or THDOC increase the binding of 3 H-muscimol to normal rat brain cortical membranes, enhance muscimol-stimulated 36 Cl ) uptake in rat cerebral cortical synaptosomes, and increase GABA-activated chloride conductance in cultured neurons. [28][29][30][31] Moreover, the present study showed that brain extracts from PCA rats significantly increased the binding of 3 Hmuscimol compared to those from sham-operated controls.…”

“…relevance of these compounds in HE has been questioned. 35,36 There is an increasing body of evidence to suggest an involvement of neurosteroids in brain complications of liver diseases. We recently demonstrated that allopregnanolone is accumulated in brains of patients who died in hepatic coma.…”

The involvement of benzodiazepine receptor ligands in hepatic encephalopathy

“…1). As discussed (2,4) we may have slightly overestimated tissue levels of benzodiazepine-like activity in both HE and control rats. Because benzodiazepine-like activity was very similar, it is difficult to explain the differences between the results of Basile et al in 1990 (3) and those of Wilder et al in 1993 (2) by an inadequacy of the extraction procedure alone.…”

A new hepatic encephalopathy model to monitor the change of neural amino acids and astrocytes with behaviour disorder

“…Some experimental HE models that exhibited changes in neurotransmitters and receptors have been reported (1). For example, it has been reported that depression of consciousness and reduction of locomotor activity correlated with the activity of some neurotransmitters in a thioacetamide-induced ALF rat model (2)(3)(4). Furthermore, it has been shown that neural amino acids and N-methyl-D-aspartate receptors change in the rat brain concomitant with depression of consciousness in an ALF model induced by portacaval anastomosis followed 24 h later by hepatic artery ligation (5).…”