Activation of the Cholinergic Antiinflammatory Pathway Reduces Ricin-Induced Mortality and Organ Failure in Mice

Abstract

Exposure to ricin, either by accident through ingestion of castor oil plant seeds or intentionally through its use as a bioweapon, invariably leads to multiple organ damage and death. Currently there is only a vaccine in advanced development to ricin, but no other antidote. Ricin causes systemic inflammation with increased proinflammatory cytokine release and subsequent multiple organ failure, particularly kidney and liver dysfunction. Activation of the cholinergic antiinflammatory pathway, specifically through the alpha7 nicotinic acetylcholine receptor (either indirectly through vagus nerve stimulation or directly through nicotine treatment) reduces proinflammatory gene expression. This activation also increases release of proinflammatory chemokines and cytokines, and has proven effective in a variety of inflammatory diseases. The aim of this study was to investigate whether nicotine treatment protected against ricin toxicity in mice. Male Balb/c mice exposed to ricin had increased serum levels of the inflammatory cytokine tumor necrosis factor-α and markers of both kidney (blood urea nitrogen, creatine) and liver (alanine tranaminase) dysfunction, with a subsequent increase in mortality. Nicotine administration 2 h after ricin injection significantly delayed and reduced ricin-induced mortality, an effect coupled with reduced serum levels of tumor necrosis factor-α and markers of kidney and liver dysfunction. Both the kidney and liver had markedly increased cellular oxidative stress following ricin exposure, an effect attenuated by nicotine administration. In conclusion, these data demonstrate that in cases of ricin poisoning, activation of the cholinergic antiinflammatory pathway may prove beneficial by reducing organ damage, delaying mortality, and allowing for a greater chance of survival.

Pharmacotherapy for Neurocognitive Disorders Based on the Hypothesis of Endogenous Appearance of Anticholinergic Activity

“…In AD, the cholinergic system is downregulated [1]; thus, inflammatory processes in both the central nervous system and peripheral tissues may be caused by downregulation of ACh [3]. NMDAR expression is also upregulated in central nervous system disorders, leading to hyperactivity of the inflammatory system [4].…”

Management of Castor Bean Seed-Associated Intraventricular Hemorrhage with Fresh Frozen Plasma: A Case Report

“…Mabley et al (2009) also showed that organ damage including kidney and liver failure could be diminished by activation of the cholinergic anti-inflammatory pathway using nicotine administration in mice (14). They showed that this management could delay mortality and increase survival rate (14). However, no certain antidote has been suggested to treat the patients.…”

Plasma Cholinesterase Activity in Alzheimer's Disease

“…pChE). Moreover, downregulation of acetylcholine (ACh) causes inflammatory hyperactivation of the CNS and peripheral nervous system [9,10]. Therefore, we speculated that this inflammatory hyperactivation appeared simultaneously in both systems.…”

“…Because ACh can suppress inflammation in both CNS and peripheral tissues [9,10], pChE hyperactivity also induces inflammatory hyperactivation via ACh downregulation. Therefore, pChE hyperactivation is not favorable in conditions such as AD, DM and LMD where inflammatory hyperactivation may be considered causative [11].…”