Chronic exposure of rat primary astrocyte cultures to manganese results inincreased binding sites for the 'peripheral-type' benzodiazepine receptor ligand H-3-PK 11195

Alterations of 'peripheral-type' benzodiazepine receptors (PTBRs) in brain are a feature of hepatic encephalopathy (HE). Although ammonia toxicity has been implicated in the disorder, recent findings suggest an accumulation o f manganese in the brains of cirrhotic patients dying in hepatic coma. In t his study, we examined the expression of PTBRs as well as the binding of th e selective PTBR ligand H-3-PK 11195 in cu Itu red astrocytes following chr onic exposure to manganese. When astrocytes were exposed to 100 mu M mangan ese for 1 week, a 57% increase in B-max for H-3-PK 11195 binding was detect ed (P < 0.01) with no change in the K-d value. However, an examination by R T-PCR of the expression of the isoquinoline-binding moiety of the PTBR comp lex in these cells revealed no change in PIER mRNA levels following mangane se treatment. These findings suggest that manganese up-regulates H-3-PK 111 95 binding sites by a process which does not involve a change in transcript ion. In view of the proposed role of astrocytic PTBRs in 'neurosteroid' syn thesis, manganese-induced increases of PTBRs could contribute to the pathog enesis of HE. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved.