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.