EFFECT OF PERIPHERAL BENZODIAZEPINE RECEPTOR LIGANDS ON LIPOPOLYSACCHARIDE-INDUCED TUMOR-NECROSIS-FACTOR ACTIVITY IN THIOGLYCOLATE-TREATED MICE

To investigate the effect of peripheral and central benzodiazepine rec eptor ligands on lipopolysaccharide (LPS)-induced tumor necrosis facto r (TNF) activity in mouse macrophages, three types of ligands, 4'-chlo rodiazepam (pure peripheral), midazolam (mixed), and clonazepam (pure central), were compared. Midazolam and 4'-chlorodiazepam significantly suppressed LPS (1-mug/ml)-induced TNF activity in thioglycolate-elici ted mouse macrophages. In every concentration examined (0.001 to 100 m uM), 4'-chlorodiazepam was the most effective agent, clonazepam was th e least effective agent, and midazolam had an effect intermediate betw een those of the other two ligands. The peripheral benzodiazepine rece ptor ligands had a dose-dependent suppressive effect, and the 50% inhi bitory concentrations were 0.01 muM for 4'-chlorodiazepam and 5 muM fo r midazolam. Concomitant use of PK 11195 (10 muM), an antagonist of th e peripheral benzodiazepine receptor, reversed this suppressive effect with 4'-chlorodiazepam (10 muM) or midazolam (10 muM). PK 11195 showe d this antagonistic effect in a dose-dependent manner. Intravenous 4'- chlorodiazepam (5 mg/kg of body weight) significantly suppressed LPS ( 100-mug)-induced TNF activity of sera (2 h postchallenge with LPS) fro m thioglycolate-treated mice. The present findings suggest that the pe ripheral benzodiazepine receptor plays an important role in modulating LPS-induced TNF activity in mouse macrophages.