Abstract
Gastrointestinal dysmotility frequently occurs in cancer cachexia and may result from damage to enteric innervation caused by oxidative stress, especially due to glutathione depletion. We assessed the effect of dietary supplementation with 20 g/kg l-glutamine (a glutathione precursor) on the intrinsic innervation of the enteric nervous system in healthy and Walker 256 tumor-bearing Wistar rats during the development of experimental cachexia (14 days), in comparison with non-supplemented rats, by using immunohistochemical methods and Western blotting. The total neural population and cholinergic subpopulation densities in the myenteric plexus, as well as the total population and VIPergic subpopulation in the submucosal plexus of the jejunum and ileum, were reduced in cachectic rats, resulting in adaptive morphometric alterations and an increase in vasoactive intestinal peptide (VIP) and calcitonin gene-related peptide (CGRP) expression, suggesting a neuroplastic response. l-glutamine supplementation prevented decrease in myenteric neuronal density in the ileum, morphometric alterations in the neurons and nerve fibers (in both the plexuses of the jejunum and ileum), and the overexpression of VIP and CGRP. Cancer cachexia severely affected the intrinsic innervation of the jejunum and ileum to various degrees and this injury seems to be associated with adaptive neural plasticity. l-glutamine supplementation presented partial protective effects on the enteric innervation against cancer cachexia, possibly by attenuating oxidative stress.
Highlights
Most cancer patients (50–80%) develop cachexia, a frequent comorbidity of cancer that accounts for over 20% of deaths in the terminal stage and represents one of the most prevalentPLOS ONE | DOI:10.1371/journal.pone.0162998 September 16, 2016Cachexia and Enteric Nervous System
The animals were randomly assigned to four experimental groups with water and food available ad libitum (n = 8 per group): control (C); control supplemented with 2% L-glutamine (CG); Walker 256 tumor (TW); and Walker 256 tumor supplemented with 2% L-glutamine (TWG)
Values expressed as mean expressed as mean ± standard error of the mean (SEM) CI (%) =/(initial body mass + body mass gain of control)] × 100% [5] FI = g/100g weight body/day + represents positive weight variation * Indicates a significant difference when compared with C group (p < 0.05) by analysis of variance followed by Tukey's post hoc test ** Indicates a significant difference from TW group (p < 0.05) determined by ANOVA followed by Tukey's post hoc test # Indicates a significant difference from TW group (p < 0.05) according student t test doi:10.1371/journal.pone.0162998.t003
Summary
All procedures described in this study were performed in agreement with international ethical guidelines and were previously approved by the Ethics Committee in Animal Experimentation (CEAE) of the Universidade Estadual de Maringá –Parana—Brazil (UEM), under the protocol number 099/2012. For experimental tumor induction in the TW and TWG group animals, Walker 256 carcinosarcoma cells were suspended in 16.5 mM phosphate-buffered saline (PBS), pH 7.5, and subcutaneously injected into the right flank of each animal. All experimental procedures were performed starting on the 14th day after tumor cell inoculation. This period was chosen based on a 15-day survival time after Walker 256 tumor implantation [5, 26]
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