Pharmacologic inhibition of cholinesterase improves survival in experimental sepsis

Introduction

Lethal sepsis occurs if an excessive inflammatory response evolves that cannot be controlled by physiological anti-inflammatory mechanisms. Vagus nerve stimulation showed improved survival in sepsis; however, this seems not to be feasible in septic patients. We therefore investigated the effect of activation of the cholinergic anti-inflammatory pathway by pharmacologic cholin-esterase inhibition on survival and inflammation in a septic mouse model.

Methods

To investigate the therapeutic effect of nicotine and physostigmine we performed cecal ligation and puncture (CLP) in female C57/B6 mice (each group n = 21). Substances were administered by intraperitoneal injection. Control groups received the same volume (50–180 μl) of LPS-free 0.9% NaCl (solvent). CLP was performed blinded to the identity of the treatment group. In addition to survival experiments we performed measurements of cytokines in plasma and the electrophoretic mobility shift assay (EMSA) for NF-κB in peritoneal skin, liver and kidneys.

Results

(1) Animals treated with nicotine (400 μg/kg) or physostigmine (80 μg/kg) survived significantly better than control mice (P < 0.05). There was no difference between the treatment groups. (2) Dose escalation of physostigmine was not superior to the normal dose. Survival in the high-dose group, however, was still significantly better than in the control group. (3) Proinflammatory cytokine levels of TNFα, IL-6 and IL-1β were significantly reduced in animals treated with physostigmine (P < 0.01). (4) Cholin-esterase inhibition with physostigmine in CLP reduced NF-κB activation in the peritoneum, kidney and liver compared with the control and sham-operated group (P < 0.01).

Conclusion

We show that pharmacological cholinesterase inhibition with physostigmine improves survival in experimental sepsis, most probably by activation of the cholinergic anti-inflammatory pathway. One possible mechanism is modulation of the NF-κB pathway. Therefore, cholinesterase inhibition may have important implications for treatment of sepsis.