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Open Access Highly Accessed Research article

Protection of early phase hepatic ischemia-reperfusion injury by cholinergic agonists

Elahé T Crockett1*, James J Galligan2, Bruce D Uhal1, Jack Harkema3, Robert Roth2 and Kinnari Pandya1

Author Affiliations

1 Departments of Physiology & Division of Human Pathology, College of Human Medicine, Michigan State University, East Lansing, USA

2 Department of Pharmacology, College of Human Medicine, Michigan State University, East Lansing, USA

3 Department of Pathology, College of Veterinary Medicine, Michigan State University, East Lansing, USA

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BMC Clinical Pathology 2006, 6:3  doi:10.1186/1472-6890-6-3

Published: 15 February 2006



Cytokine production is critical in ischemia/reperfusion (IR) injury. Acetylcholine binds to macrophages and inhibits cytokine synthesis, through the cholinergic anti-inflammatory pathway. This study examined the role of the cholinergic pathway in cytokine production and hepatic IR- injury.


Adult male mice underwent 90-min of partial liver ischemia followed by reperfusion. The AChR agonists (1,1-dimethyl-4-phenyl-L-pioperazinium-iodide [DMPP], and nicotine) or saline-vehicle were administered i.p. before ischemia. Plasma cytokine tumor necrosis factor (TNF)-α, macrophage inflammatory protein-2, and Interleukin-6 were measured. Liver injury was assessed by plasma alanine transaminase (ALT) and liver histopathology.


A reperfusion time-dependent hepatocellular injury occurred as was indicated by increased plasma-ALT and histopathology. The injury was associated with marked elevation of plasma cytokines/chemokines. Pre-ischemic treatment of mice with DMPP or nicotine significantly decreased plasma-ALT and cytokines after 3 h of reperfusion. After 6 h of reperfusion, the protective effect of DMPP decreased and reached a negligible level by 24 h of reperfusion, despite significantly low levels of plasma cytokines. Histopathology showed markedly diminished hepatocellular injury in DMPP- and nicotine-pretreated mice during the early-phase of hepatic-IR, which reached a level comparable to saline-treated mice at late-phase of IR.


Pharmacological modulation of the cholinergic pathway provides a means to modulate cytokine production and to delay IR-induced heaptocellular injury.