The "peripheral-type" benzodiazepine (omega 3) receptor in hyperammonemic disorders.
Increased levels of brain ammonia occur in both congenital and acquired hyperammonemic syndromes including hepatic encephalopathy, fulminant hepatic failure, Reye's syndrome and congenital urea cycle disorders. In addition to its effect on neurotransmission and energy metabolism, ammonia modulates the expression of various genes including the astrocytic "peripheral-type" benzodiazepine (or omega 3) receptor (PTBR). Increased expression of the isoquinoline carboxamide binding protein (IBP), one of the components of the PTBR complex, is observed in brain and peripheral tissues following chronic liver failure as well as in cultured astrocytes exposed to ammonia. Increased densities of binding sites for the PTBR ligand [3H]-PK11195 are also observed in these conditions as well as in brains of animals with acute liver failure, congenital urea cycle disorders and in patients who died in hepatic coma. The precise role of PTBR in brain function has not yet fully elucidated, but among other functions, PTBR mediates the transport of cholesterol across the mitochondrial membrane and thus plays a key role in the biosynthesis of neurosteroids some of which modulate major neurotransmitter systems such as the gamma-aminobutyric acid (GABA(A)) and glutamate (N-methyl-D-aspartate (NMDA)) receptors. Activation of PTBR in chronic and acute hyperammonemia results in increased synthesis of neurosteroids which could lead to an imbalance between excitatory and inhibitory neurotransmission in the CNS. Preliminary reports suggest that positron emission tomography (PET) studies using [11C]-PK11195 may be useful for the assessment of the neurological consequences of chronic liver failure.
Desjardins
Paul
P
Neuroscience Research Unit, Hôpital Saint-Luc du Chum, University of Montreal, 1058 St-Denis Street, Que., H2X 3J4, Montreal, Canada.
Butterworth
Roger F
RF
D000641:Ammonia / Q000494:pharmacology; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D006801:Humans; D022124:Hyperammonemia / Q000378:metabolism*; D017093:Liver Failure / Q000378:metabolism; D008345:Manganese / Q000494:pharmacology; D018079:Receptors, GABA / Q000378:metabolism*
D002352:Carrier Proteins; D018079:Receptors, GABA; C499229:TSPO protein, human; D008345:Manganese; D000641:Ammonia