Acute liver failure and hyperammonemia increase peripheral-type benzodiazepine receptor binding and pregnenolone synthesis in mouse brain

• Published in: Brain research Vol. 705; no. 1; pp. 345 - 348
• Main Authors: Itzhak, Yossef, Roig-Cantisano, Ana, Dombro, Roy S., Norenberg, Michael D.
• Format: Journal Article
• Language: English
• Published: London Elsevier B.V 24-12-1995; Amsterdam Elsevier; New York, NY
• Subjects: Acetates - pharmacology; Ammonia; Ammonia - blood; Animals; Biological and medical sciences; Brain - metabolism; Brain - physiopathology; Disease Models, Animal; Gastroenterology. Liver. Pancreas. Abdomen; Hepatic encephalopathy; Hepatic Encephalopathy - chemically induced; Hepatic Encephalopathy - metabolism; Hepatic Encephalopathy - physiopathology; Liver Failure, Acute - metabolism; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Male; Medical sciences; Mice; Neurons - chemistry; Neurons - metabolism; Neurosteroid; Other diseases. Semiology; Peripheral benzodiazepine receptor; Pregnenolone; Pregnenolone - biosynthesis; Pregnenolone - metabolism; Receptors, GABA-A - metabolism; Thioacetamide; Thioacetamide - pharmacology; Ammonia; Thioacetamide; Peripheral benzodiazepine receptor; Neurosteroid; Hepatic encephalopathy; Pregnenolone; Animal model; Nervous system diseases; Rodentia; Central nervous system; Hyperammonemia; Hepatic disease; Biosynthesis; Cerebral disorder; Vertebrata; Liver failure; Mammalia; Mouse; Animal; Encephalopathy; Central nervous system disease; Digestive diseases; Brain (vertebrata)
• ISSN: 0006-8993; 1872-6240
• DOI: 10.1016/0006-8993(95)01244-3

We investigated the role of brain peripheral-type benzodiazepine receptors (PBRs) and pregnenolone (a product of PBRs activation) in hepatic encephalopathy (HE)/hyperammonemia. Administration of the hepatotoxin, thioacetamide, or ammonium acetate to mice for 3 days significantly increased the number of brain PBRs (138–146% of control) and the affinity of the ligands for these receptors (2-fold). The total content of pregnenolone and its rate of synthesis in brain of the experimental animals were significantly increased. Our results suggest a novel integrated mechanism by which ammonia-induced activation of PBRs leads to elevated levels of pregnenolone-derived neurosteroids which are known to enhance GABA-ergic neurotransmission. This mechanism may play a pivotal role in pathogenesis of HE.