Abstract
The cholinergic nervous system has been demonstrated to attenuate the inflammatory response during sepsis via the inhibitory action of acetylcholine (ACh) on macrophages. These findings were largely based on experimental sepsis models using endotoxin as the inducing agent. Herein, however, we report that the specific inhibition of acetylcholinesterase (AChE) renders animals more resistant to infection by a virulent strain of Salmonella enterica serovar Typhimurium, a Gram-negative enteric pathogen. Inhibition of AChE was induced by a subchronic exposure to paraoxon, a potent anti-cholinesterase metabolite of the organophosphorous compound parathion. Our findings indicate that inhibition of AChE enhanced survival of infected mice in a dose-dependent fashion and this correlated with efficient control of bacterial proliferation in target organs. Immunologically, inhibition of AChE enabled the animals to mount a more effective inflammatory anti-microbial response, and to secrete higher levels of interleukin-12, a key T helper type 1-promoting cytokine. The ACh-induced enhancement in resistance to infection was abrogated by co-administration of an oxime which can reactivate AChE. Hence, in a model of Gram-negative bacterial infection, cholinergic stimulation is shown to enhance the anti-microbial immune response leading to effective control of bacterial proliferation and enhanced animal survival.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetylcholinesterase / metabolism
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Animals
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B-Lymphocytes / cytology
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Cell Count
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Cholinesterase Inhibitors / pharmacology*
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Cholinesterase Inhibitors / therapeutic use
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Cholinesterase Reactivators / pharmacology
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Concanavalin A / pharmacology
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Cytokines / blood
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Cytokines / metabolism
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Erythrocytes / drug effects
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Erythrocytes / metabolism
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GPI-Linked Proteins
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Immune System / drug effects*
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Immune System / immunology
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Lipopolysaccharides / pharmacology
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Lymph Nodes / microbiology
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Macrophages / cytology
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Macrophages / drug effects
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Macrophages / metabolism
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Male
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Mice
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Mice, Inbred BALB C
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Nitric Oxide / metabolism
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Oximes / pharmacology
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Paraoxon / pharmacology
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Paraoxon / therapeutic use
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Pyridinium Compounds / pharmacology
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Salmonella Infections / blood
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Salmonella Infections / drug therapy
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Salmonella Infections / microbiology*
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Salmonella Infections / prevention & control*
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Salmonella typhimurium* / pathogenicity
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Spleen / cytology
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Spleen / drug effects
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Spleen / microbiology
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Survival Analysis
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T-Lymphocytes / cytology
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T-Lymphocytes / drug effects
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T-Lymphocytes / metabolism
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Thymus Gland / drug effects
Substances
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4-(aminocarbonyl)-1-(3-(4-((E)-(hydroxyimino)methyl)pyridinium-1-yl)propyl)pyridinium dibromide
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Cholinesterase Inhibitors
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Cholinesterase Reactivators
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Cytokines
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GPI-Linked Proteins
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Lipopolysaccharides
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Oximes
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Pyridinium Compounds
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Concanavalin A
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Nitric Oxide
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Acetylcholinesterase
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Ache protein, mouse
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Paraoxon