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

“…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. 35,36 There is an increasing body of evidence to suggest an involvement of neurosteroids in brain complications of liver diseases. Together, these findings demonstrate that brain accumulation of allopregnanolone and THDOC in PCA rats activates the GABA-A receptor complex, thus offering an explanation for the notion of Ôincreased GABAergic toneÕ in HE.…”

Pathogenesis of Hepatic Encephalopathy and Brain Edema in Acute Liver Failure

“…64 However, negative reports have subsequently appeared. 65,66 It has been suggested that the beneficial effects of flumazenil that appear to occur in a sub-group of patients may relate to allosteric effects on the neurosteroid modulatory site that is adjacent to the benzodiazepine site on the GABA-A receptor complex. 67 This hypothesis has not been tested in ALF.…”

Pathogenesis of Hepatic Encephalopathy: Potential Future Approaches

“…However, two laboratories, one in Mon treal [27,28] and another in Switzerland, have had difficulty in detecting BZs [29], What must be understood is that these com pounds are lipophilic and protein bound. Thus, extraction procedures to process the original matrix (sample) have to be designed to take these properties into account.…”

“…Of course, increases of brain GABA in critical brain subregions could arise in the CNS rather than be transported in from the blood. We noted in some simple experiments a number of years ago that slight 2-to 3-fold increases in 24 Dig Dis 1996:14<suppl I ): [20][21][22][23][24][25][26][27][28][29] Mulien/Kaminsky-Russ brain GABA occurred after induction of se vere hyperammonemia by urease administra tion. However, this field of research has be come somewhat dormant in the last few years.…”