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 receptor ligands on lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF) activity in mouse macrophages, three types of ligands, 4'-chlorodiazepam (pure peripheral), midazolam (mixed), and clonazepam (pure central), were compared. Midazolam and 4'-chlorodiazepam significantly suppressed LPS (1-microgram/ml)-induced TNF activity in thioglycolate-elicited mouse macrophages. In every concentration examined (0.001 to 100 microM), 4'-chlorodiazepam was the most effective agent, clonazepam was the least effective agent, and midazolam had an effect intermediate between those of the other two ligands. The peripheral benzodiazepine receptor ligands had a dose-dependent suppressive effect, and the 50% inhibitory concentrations were 0.01 microM for 4'-chlorodiazepam and 5 microM for midazolam. Concomitant use of PK 11195 (10 microM), an antagonist of the peripheral benzodiazepine receptor, reversed this suppressive effect with 4'-chlorodiazepam (10 microM) or midazolam (10 microM). PK 11195 showed this antagonistic effect in a dose-dependent manner. Intravenous 4'-chlorodiazepam (5 mg/kg of body weight) significantly suppressed LPS (100-micrograms)-induced TNF activity of sera (2 h postchallenge with LPS) from thioglycolate-treated mice. The present findings suggest that the peripheral benzodiazepine receptor plays an important role in modulating LPS-induced TNF activity in mouse macrophages.
Department of Anesthesiology, School of Medicine, University of Occupational and Environmental Health, Fukuoka, Japan.
T
T
Matsumoto
M
M
Ogata
K
K
Koga
A
A
Shigematsu
D000818:Animals; D001570:Benzodiazepinones / Q000494:pharmacology; D002998:Clonazepam / Q000037:antagonists & inhibitors / Q000494:pharmacology; D058787:GABA-A Receptor Antagonists; D007546:Isoquinolines / Q000494:pharmacology; D008024:Ligands; D008070:Lipopolysaccharides / Q000494:pharmacology*; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008874:Midazolam / Q000494:pharmacology; D011963:Receptors, GABA-A / Q000187:drug effects*; D013864:Thioglycolates / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
D001570:Benzodiazepinones; D058787:GABA-A Receptor Antagonists; D007546:Isoquinolines; D008024:Ligands; D008070:Lipopolysaccharides; D011963:Receptors, GABA-A; D013864:Thioglycolates; D014409:Tumor Necrosis Factor-alpha; C028513:4'-chlorodiazepam; D002998:Clonazepam; D008874:Midazolam; C037850:PK 11195