Beneficial effect of pharmacological modulation of the GABA A ‐benzodiazepine receptor on hepatic encephalopathy in the rat: Comparison with uremic encephalopathy

Hepatic encephalopathy is ameliorated by drugs acting on the central GABA A ‐benzodiazepine receptor complex. To investigate whether these effects are specific for hepatic encephalopathy or just reflect a nonspecific arousal reaction, various benzodiazepine antagonists like flumazenil or with inverse agonistic properties (Ro 15‐4513, Ro 15‐3505) were studied in uremic encephalopathy in rats after bilateral ureteral ligation (n = 20) and compared with hepatic encephalopathy caused by thioacetamide‐induced acute liver failure (n = 33). As soon as the animals developed clear signs of metabolic encephalopathy, their motor activity was recorded in an animal activity meter for 10 min. Furthermore, a composite score was calculated by grading various behavioral signs from 0 = absent to 3 = apparently normal. Rats were then injected with coded preparations of Ro 15‐4513 (0.5, 2.5 and 5 mg/kg body wt intraperitoneally), flumazenil (2.5, 10, 25 and 40 mg/kg), Ro 15‐3505 (10 mg/kg) or vehicle, and the measurements were repeated. The code was broken after the completion of the study. Pretreatment motor activity was decreased both in hepatic and uremic encephalopathy (20.7 ± 6.4 [S.E.M.] and 41.3 ± 37.1 movements/10 min). In hepatic encephalopathy motor activity and the composite score were improved both by 5 mg/kg Ro 15‐4513 (by 293%, p < 0.05) and by 10 mg/kg Ro 15‐3505 (by 509%, p > 0.01), whereas vehicle and flumazenil had no effects. In uremic encephalopathy neither drug was effective in improving the neurobehavioral status. These results indicate that the amelioration of neurobehavioral symptoms both by Ro 15‐4513 and Ro 15‐3505 seems to be specific for hepatic encephalopathy and is consistent with the hypothesis that hepatic encephalopathy is associated with an increased GABA‐ergic tone. (H EPATOLOGY 1991;14:963–968.)