Beneficial effect of pharmacological modulation of the GABAA-benzodiazepine receptor on hepatic encephalopathy in the rat: comparison with uremic encephalopathy.
Hepatic encephalopathy is ameliorated by drugs acting on the central GABAA-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 less than 0.05) and by 10 mg/kg Ro 15-3505 (by 509%, p greater than 0.01), whereas vehicle and flumazenil had no effects. In uremic encephalopathy neither drug was effective in improving the neurobehavioral status.(ABSTRACT TRUNCATED AT 250 WORDS)
Steindl
P
P
1st Department of Gastroenterology and Hepatology, University of Vienna, Austria.
Püspök
A
A
Druml
W
W
Ferenci
P
P
D000818:Animals; D001386:Azides / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D001569:Benzodiazepines / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D001570:Benzodiazepinones / Q000494:pharmacology*; D003128:Coma / Q000209:etiology* / Q000503:physiopathology; D005442:Flumazenil / Q000494:pharmacology*; D006501:Hepatic Encephalopathy / Q000503:physiopathology* / Q000523:psychology; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D011963:Receptors, GABA-A / Q000187:drug effects / Q000502:physiology*; D014511:Uremia / Q000150:complications*
D001386:Azides; D001570:Benzodiazepinones; D011963:Receptors, GABA-A; D001569:Benzodiazepines; D005442:Flumazenil; C040725:Ro 15-3505; C042957:Ro 15-4513