Plasma gaba, gaba-like activity and the brain gaba-benzodiazepine receptor complex in rats with chronic hepatic encephalopathy

Abstract

Plasma gamma-aminobutyric acid (GABA)-like activity, plasma GABA and the brain GABA-benzodiazepine receptor complex were studied in rats with chronic hepatic encephalopathy. Portal vein ligation (after prior subcutaneous transposition of the spleen) results in complete portal bypass of splanchnic blood. In addition, significant hepatocellular damage was superimposed on this model of portosystemic shunting by ligation of the common bile duct. Plasma GABA-like activity (determined by radioreceptor assay) and true plasma GABA concentrations (determined by high-performance liquid chromatography) were found to be significantly increased in both portal vein-ligated and portal vein and bile duct-ligated rats, compared with controls. However, plasma GABA-like activity was consistently greater than the concentration of true GABA in the plasma of all rats. This suggested the presence of a GABA-like factor in plasma that can inhibit [3H]GABA binding, but is not GABA itself. The concentration of this GABA-like factor was significantly increased in the plasma of rats with chronic hepatic encephalopathy. Despite the significant increase in plasma GABA-like activity and plasma GABA concentrations, there was no alteration in the affinity or density of the physiologically relevant, low-affinity brain GABA binding site in the rats with portal vein ligation, with or without bile duct ligation. There was also no significant alteration in brain benzodiazepine binding in these rats. GABA enhancement of benzodiazepine binding was unchanged in the portal vein-ligated rats. However, the maximal enhancement of benzodiazepine binding was decreased in the rats with portal vein and bile duct ligation. There appears to be no substantial evidence that brain GABAergic neurotransmission is increased in these models of chronic hepatic encephalopathy.

Splenic transposition is superior to caudal shunt as a model of murine total hepatic ischemia

“…16 To assess the efficiency of splenic transposition, we performed a preliminary time-course response in 20 mice. Both an anatomic exploration of new vessel growth and a functional response to total hepatic ischemia and reperfusion injury were determined.…”

Marked Increases of Plasma Gamma-Aminobutyric Acid Concentrations in Cirrhotic Patients with Portacaval Shunts Are Not Associated with Alterations of Cerebral Functions

“…This correspondence is illustrated also by the present control levels of GABA, which are within the range of levels of GABA con sidered as normal [5, 26. 34], However, in case of decreased liver function, the radiore ceptor assay may overestimate true GABA concentrations in plasma samples [23,32], Thus, determination of GABA by the radio receptor assay in plasma samples from a patient with fulminant hepatic failure yielded too high values due to interference of other markedly elevated amino acids, espe cially glutamine, with the assay [23]. Similar ly.…”

“…The high activity of GABA-degrading en zyme in the liver certainly explains the very short half-life (10-20 min) of systemically administered GABA [12]. Inhibition of pe ripheral GABA-T by drugs, such as y-vinyl GABA, y-acetylenic GABA, amino-oxyacetic acid or valproic acid, has been shown to cause 2-to 6-fold increases of plasma GABA levels, determined by ion exchange fluorometry or radioreceptor assay in rats, dogs or humans [21,[28][29][30][31], Similarly, 3-to 5-fold increases of plasma GABA have been found after portosystemic shunting by portal vein ligation in rats, using HPLC for plasma GABA analysis [32], Thus, decreased liver function and/or portosystemic shunting in humans will result in reduced peripheral GABA degradation and thereby in marked increases of plasma GABA produced by pe ripheral tissues and gut bacteria [3,5,6], Plasma GABA increases which have been reported previously for patients with acute or chronic hepatocellular disease vary con siderably, which, at least in part, may be due to methodological differences. Singh et al [6], who used a spectrophotometric method for GABA analysis, reported an about 3-fold plasma GABA increase in 40 encephalopathic patients with fulminant hepatic failure.…”

Experimental models for hepatic encephalopathy

“…Multiple attempts were carry out to find a model using a biliary ligation based technique -easy to perform-able to develop episodes of unambiguous hepatic encephalopathy. In this sense, a model was described in which encephalopathy was manifested after a portacaval anastomosis in cirrhotic rats by bile duct ligation, although this model was not widely distributed, probably because of the high mortality of the surgical shunt in cirrhotic animals (11). It has recently been proposed a model that combines bile duct ligation with rats fed with ammonia enriched diet, which have been found to increase the ammonia levels in the blood and in the brain (8) but the presence of behavioral changes in these animals, suggesting the development of encephalopathy, has not been found yet.…”

“…Different works have been recently published using a complete biliary ligation in rats with previous PCS, which induced an acute or subacute cholestasis (11). This model has not been fully characterized and has the added difficulty of inducing a severe weight loss, probably caused by anorexia or malabsorption.…”