CPSI-121 pharmacologically prevents intestinal barrier dysfunction after cutaneous burn through a vagus nerve-dependent mechanism.

Abstract

BACKGROUND:

We have recently demonstrated the protective effects of electrical stimulation of the vagus nerve in prevention of gut injury after severe burn. Here we evaluate the potential for a pharmacologic agonist of the vagus nerve as an approach to regulate outcomes in preclinical models. We tested a new generation of guanylhydrazone-derived compounds, CPSI-121; a compound that may activate the parasympathetic nervous system through poorly understood mechanisms to determine whether we could prevent intestinal mucosal barrier breakdown.

METHODS:

Male balb/c mice were subjected to a full-thickness, 30% total body surface area steam burn, and the efficacy of CPSI-121 was tested against vagus nerve stimulation (VNS) postburn at 4 hours. Surgical vagotomy was used to disrupt the neuroenteric axis and gut injury prevention was assessed. Gut barrier dysfunction was quantified by permeability to 4-kDa fluorescein isothiocyanate-dextran. Gut injury was assessed by histologic evaluation. Tight junction protein expression (ZO-1 and occludin) was characterized by immunofluorescence and immunoblot.

RESULTS:

VNS and CPSI-121 administration significantly reduced the permeability to 4-kDa fluorescein isothiocyanate-dextran and maintained normal histology compared with burn. However, abdominal vagotomy eliminated the protective effects of both VNS and CPSI-121. ZO-1 and occludin expression was similar to sham in VNS and CPSI-121-treated burn animals, but significantly altered in burn-vagotomized animals. Splenectomy did not alter the effect of CPSI-121.

CONCLUSION:

Similar to direct electrical VNS, CPSI-121 effectively protects the intestinal mucosal barrier from breakdown after severe burn. We suggest that this could represent a noninvasive therapy to prevent end-organ dysfunction after trauma that would be administered during resuscitation.

• Authors: Michael Krzyzaniak, Yan Ortiz-Pomales, Nicole Lopez, Luiz Guilherme Reys, Gerald Cheadle, Paul Wolf, Brian Eliceiri, Vishal Bansal, Andrew Baird, Raul Coimbra
• Journal: The journal of trauma and acute care surgery (J Trauma Acute Care Surg) Vol. 72 Issue 2 Pg. 355-61; discussion 361-3 (Feb 2012) ISSN: 2163-0763 [Electronic] United States
• PMID: 22327977 (Publication Type: Journal Article)

Chemical References

• CPSI-121
• Hydrazones
• Membrane Proteins
• Occludin
• Ocln protein, mouse

Topics

• Analysis of Variance
• Animals
• Burns (metabolism, physiopathology)
• Hydrazones (pharmacology)
• Immunoblotting
• Intestinal Mucosa (metabolism, physiopathology)
• Male
• Membrane Proteins (metabolism)
• Mice
• Mice, Inbred BALB C
• Microscopy, Confocal
• Occludin
• Permeability (drug effects)
• Statistics, Nonparametric
• Vagus Nerve
• Vagus Nerve Stimulation