Central activation of the cholinergic anti-inflammatory pathway reduces surgical inflammation in experimental post-operative ileus.

Abstract

BACKGROUND AND PURPOSE:

Electrical stimulation of the vagus nerve reduces intestinal inflammation following mechanical handling, thereby shortening post-operative ileus in mice. Previous studies in a sepsis model showed that this cholinergic anti-inflammatory pathway can be activated pharmacologically by central administration of semapimod, an inhibitor of p38 mitogen-activated protein kinase. We therefore evaluated the effect of intracerebroventricular (i.c.v.) semapimod on intestinal inflammation and post-operative ileus in mice.

EXPERIMENTAL APPROACH:

Mice underwent a laparotomy or intestinal manipulation 1 h after i.c.v. pre-treatment with semapimod (1 µg·kg(-1) ) or saline. Drugs were administered through a cannula placed in the left lateral ventricle 1 week prior to experimentation. Twenty-four hours after surgery, gastric emptying was measured using scintigraphy, and the degree of intestinal inflammation was assessed. Finally, activation of brain regions was assessed using quantitative immunohistochemistry for c-fos.

KEY RESULTS:

Intestinal manipulation induced inflammation of the manipulated intestine and significantly delayed gastric emptying, 24 h after surgery in saline-treated animals. Semapimod significantly reduced this inflammation and improved gastric emptying. Vagotomy enhanced the inflammatory response induced by intestinal manipulation and abolished the anti-inflammatory effect of semapimod. Semapimod but not saline induced a significant increase in c-fos expression in the paraventricular nucleus, the nucleus of the solitary tract and the dorsal motor nucleus of the vagus nerve.

CONCLUSIONS AND IMPLICATIONS:

Our findings show that i.c.v. semapimod reduces manipulation-induced intestinal inflammation and prevented post-operative ileus. This anti-inflammatory effect depends on central activation of the vagus nerve.

• Authors: Fo The, C Cailotto, J van der Vliet, W J de Jonge, R J Bennink, R M Buijs, G E Boeckxstaens
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 163 Issue 5 Pg. 1007-16 (Jul 2011) ISSN: 1476-5381 [Electronic] England
• PMID: 21371006 (Publication Type: Journal Article)
• Copyright: © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Hydrazones
• Proto-Oncogene Proteins c-fos
• semapimod
• Acetylcholine

Topics

• Acetylcholine (agonists)
• Animals
• Anti-Inflammatory Agents, Non-Steroidal (administration & dosage, therapeutic use)
• Brain (drug effects, metabolism)
• Disease Models, Animal
• Enteritis (etiology, immunology, metabolism, prevention & control)
• Female
• Gastric Emptying (drug effects)
• Hydrazones (administration & dosage, therapeutic use)
• Ileus (etiology, immunology, metabolism, prevention & control)
• Injections, Intraventricular
• Mice
• Mice, Inbred BALB C
• Motor Neurons (drug effects, metabolism)
• Postoperative Complications (etiology, immunology, metabolism, prevention & control)
• Proto-Oncogene Proteins c-fos (biosynthesis)
• Vagotomy
• Vagus Nerve (drug effects, metabolism)