Cholinesterase inhibitors improve survival in experimental sepsis: a new way to activate the cholinergic anti-inflammatory pathway.

Despite recent advances in intensive care treatment and the discovery of antibiotics, sepsis is the third leading cause of death in the developed world. The body’s first defense against invading pathogens or tissue injury is the innate immune system, but since excessive immune responses can be damaging, an anti-inflammatory mechanism (the so-called cholinergic anti-inflammatory pathway) functions to control the proinflammatory response and prevent injury. The cholinergic anti-inflammatory pathway is a neural mechanism that suppresses the innate inflammatory response and controls inflammation by inhibiting the release of pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-alpha, and other cytokine-producing cells to dampen inflammation. Systemic treatment with the cholinesterase inhibitor physostigmine and peripheric neostigmine can activate the cholinergic anti-inflammatory pathway. Therefore, peripheral stimulation of cholinergic receptors is sufficient to confer protection against experimental sepsis: It means that the additional central component of cholinesterase inhibition by physostigmine is not needed to achieve the observed activation of the anti-inflammatory pathway. As pointed out, cholinesterase inhibition significantly improves survival if administered directly after induction of sepsis, but when treatment was delayed no trend to a reduction in mortality could be achieved. This point appears to be relevant since therapeutic interventions are required within a short time following induction of sepsis, and it could be considered a weakness of the study.