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Effect of peripheral benzodiazepine receptor ligands on lipopolysaccharide-induced tumor necrosis factor activity in
1Department of Anesthesiology, School of Medicine, University of Occupational and Environmental Health, Fukuoka, Japan.
Abstract:
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.
Insights
Peripheral benzodiazepine receptor ligands, like 4'-chlorodiazepam, effectively suppress lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF) activity in mouse macrophages. This suggests a key role for peripheral receptors in modulating inflammatory responses.
Area of Science:
- Immunology
- Neuropharmacology
Background:
- Lipopolysaccharide (LPS) triggers inflammatory responses, including the production of tumor necrosis factor (TNF).
- Benzodiazepine receptor ligands are known to modulate various cellular functions.
Purpose of the Study:
- To investigate the differential effects of peripheral and central benzodiazepine receptor ligands on LPS-induced TNF activity in mouse macrophages.
- To determine the role of peripheral benzodiazepine receptors in modulating inflammatory responses.
Main Methods:
- Comparison of three benzodiazepine ligands: 4'-chlorodiazepam (peripheral), midazolam (mixed), and clonazepam (central).
- Assessment of LPS-induced TNF activity in thioglycolate-elicited mouse macrophages.
- In vitro and in vivo experiments using LPS challenge and benzodiazepine receptor ligands, including PK 11195 (peripheral antagonist).
Main Results:
- 4'-chlorodiazepam and midazolam significantly suppressed LPS-induced TNF activity.
- 4'-chlorodiazepam demonstrated the most potent suppressive effect in a dose-dependent manner.
- The suppressive effects of 4'-chlorodiazepam and midazolam were reversed by PK 11195, indicating peripheral receptor involvement.
- Intravenous 4'-chlorodiazepam administration reduced LPS-induced TNF activity in vivo.
Conclusions:
- Peripheral benzodiazepine receptor ligands play a significant role in modulating LPS-induced TNF activity.
- Targeting peripheral benzodiazepine receptors may offer a therapeutic strategy for inflammatory conditions.