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

Abstract

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. 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. 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. 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.