Acute liver failure and hyperammonemia increase peripheral-type benzodiazepine receptor binding and pregnenolone synthesis in mouse brain.
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.
Itzhak
Y
Y
Department of Biochemistry, University of Miami, FL 33101, USA.
Roig-Cantisano
A
A
Dombro
R S
RS
Norenberg
M D
MD
D000085:Acetates / Q000494:pharmacology; D000641:Ammonia / Q000097:blood*; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000503:physiopathology*; D004195:Disease Models, Animal; D006501:Hepatic Encephalopathy / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D017114:Liver Failure, Acute / Q000378:metabolism*; D008297:Male; D051379:Mice; D009474:Neurons / Q000737:chemistry / Q000378:metabolism; D011284:Pregnenolone / Q000096:biosynthesis* / Q000378:metabolism; D011963:Receptors, GABA-A / Q000378:metabolism*; D013853:Thioacetamide / Q000494:pharmacology
D000085:Acetates; D011963:Receptors, GABA-A; D013853:Thioacetamide; D011284:Pregnenolone; D000641:Ammonia; C018824:ammonium acetate