Abstract
The in utero exposure of hamsters to low doses of diazepam results in impaired host defense against Mycobacterium bovis during adulthood. Delayed developmental immunotoxicity, however, represents a specific situation that might not be general. The present experiment was undertaken to investigate the effects of diazepam on hamster resistance to M. bovis using adult animals. The effects of diazepam treatment on serum cortisol levels were also studied. Adult hamsters (N = 10 for each group) were treated with diazepam (E1 = 1. 0, E2 = 2.0 or E3 = 3.0 mg kg-1 day-1 subcutaneously) or with control solution (C) for 30 days. Seven days after the beginning of the treatment, the animals received identical inoculum concentrations of M. bovis. Hamsters treated with the higher (2.0 and 3.0 mg kg-1 day-1) doses of diazepam exhibited: 1) increased granuloma areas in the liver (C = 1.81 +/- 1.39, E2 = 10.29 +/- 4.64 and E3 = 15.80 +/- 4.82) and lung (C = 0.54 +/- 0.55, E2 = 6.28 +/- 3.85 and E3 = 6.31 +/- 3.56) and 2) increased scores of M. bovis colony-forming units isolated from liver (C = 2.0, E2 = 3.0 and E3 = 3.5), lung (C = 1.0, E2 = 3.0 and E3 = 3.5) and spleen (C = 1.0, E2 = 2.5 and E3 = 4.0). These effects were dose dependent, and were not detected or were less severe in animals treated with the lowest (1.0 mg/kg) dose of diazepam as well as in those of the control group. Furthermore, diazepam treatment (3.0 mg kg-1 day-1 for 30 days) increased (E3 = 71.32 +/- 2.99; N = 10) the serum levels of cortisol compared to control hamsters (C = 22.61 +/- 2.75; N = 10). The present data, that demonstrate an impaired defense against M. bovis in adult hamsters treated with diazepam, were tentatively explained on the basis of a direct and/or indirect action of diazepam on the cytokine network. The effects may be related to stimulation of peripheral benzodiazepine receptor binding sites (PBR) by macrophages and/or lymphocytes, or they may be mediated by PBR stimulation of the adrenals.
Highlights
Several drugs and environmental chemicals are recognized today as potential immunotoxicants [1]
Hamsters treated with the higher (2.0 and 3.0 mg kg-1 day-1) doses of diazepam exhibited: 1) increased granuloma areas in the liver (C = 1.81 ± 1.39, E2 = 10.29 ± 4.64 and E3 = 15.80 ± 4.82) and lung (C = 0.54 ± 0.55, E2 = 6.28 ± 3.85 and E3 = 6.31 ± 3.56) and 2) increased scores of M. bovis colony-forming units isolated from liver (C = 2.0, E2 = 3.0 and E3 = 3.5), lung (C = 1.0, E2 = 3.0 and E3 = 3.5) and spleen (C = 1.0, E2 = 2.5 and E3 = 4.0)
Mortality was somewhat higher in hamsters treated with 3.0 mg kg-1 day-1 of diazepam (C = 0%, E1 = 0%, E2 = 0% and E3 = 20%) but the difference was not statistically significant
Summary
Several drugs and environmental chemicals are recognized today as potential immunotoxicants [1]. Benzodiazepines (BDZ) reduce anxiety and stress responses acting on high affinity receptor sites present in the central nervous system (CNS). Because of this, they are one of the most frequently prescribed classes of psychotropic drugs in Brazil, the United States and Europe and probably worldwide [2]. Delayed developmental immunotoxicity is not well understood and may be a situation that cannot be generalized in terms of age It consists of an unknown primary effect of a chemical during early ontogeny of the immune system and a recognized functional deficit observed later in life, in the complete absence of the drug or chemical. The effects of diazepam on immune function during early life might differ from those produced in adult organisms both in a qualitative and quantitative way
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