Activation of the cholinergic antiinflammatory pathway reduces ricin-induced mortality and organ failure in mice

Jon G. Mabley, Pal Packer, Csaba Szabo

Research output: Contribution to journalArticle

27 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)166-172
Number of pages7
JournalMolecular Medicine
Volume15
Issue number5-6
DOIs
StatePublished - May 2009

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Ricin
Cholinergic Agents
Anti-Inflammatory Agents
Mortality
Nicotine
Kidney
Cytokines
Liver Diseases
alpha7 Nicotinic Acetylcholine Receptor
Tumor Necrosis Factor-alpha
Ricinus
Vagus Nerve Stimulation
Antidotes
Multiple Organ Failure
Creatine
Liver
Blood Urea Nitrogen
Serum
Chemokines
Alanine

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Molecular Medicine
  • Genetics(clinical)

Cite this

Activation of the cholinergic antiinflammatory pathway reduces ricin-induced mortality and organ failure in mice. / Mabley, Jon G.; Packer, Pal; Szabo, Csaba.

In: Molecular Medicine, Vol. 15, No. 5-6, 05.2009, p. 166-172.

Research output: Contribution to journalArticle

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