The beneficial influence of rhubarb on 5-fluorouracil-induced ileal mucositis and the combined role of aquaporin-4, tumour necrosis factor-α, nuclear factor-kappa B & matrix metalloproteinase-9 in rat model: histological study

Abstract

A 5-fluorouracil (5-FU) is used for cancer treatment despite its cytotoxic sequelae on healthy cells, especially the rapid proliferating ones. Intestinal mucositis is one of the most frequent chemotherapeutic debilitating sequelae. Rhubarb (Rh), an ancient herb, is known for its curing effect on gastrointestinal complications. This study aims to detect the role of aquaporin-4 (AQP-4), tumour necrosis factor-α (TNF-α), nuclear factor-kappa B (NF-κB), and matrix metalloproteinase-9 (MMP-9) in 5-FU-induced ileal histological and biochemical changes and the potential therapeutic effect of Rh water extract on these changes in rats. A 45 rats were divided into 3 groups; control, 5-FU (single intraperitoneal injection of 150 mg/kg/ rat) and Rh-treated (oral 20 mg/kg/day/rat for 8 days). The change in animals' weight, incidence of diarrhoea and AQP-4 and TNF-α values in ileal homogenates were measured. Ileal sections were subjected to hematoxylin and eosin stain, periodic acid Schiff (PAS)-reaction and MMP-9, NF-κB and AQP-4 immunohistochemical staining. A 5-FU group revealed marked ileal mucosal damage associated with a significant decrease in the mean body weight, AQP-4 level and area percent of PAS and AQP-4 positive reaction. Significant increase in the mean incidence of diarrhoea, TNF-α value and area percent of MMP-9 and NF-κB was detected. These changes were significantly corrected with Rh administration. A 5-FU resulted in severe ileal mucositis through TNF-α, NF-κB, MMP-9, and AQP-4 disturbances. Rh treatment was highly effective in preventing such mucositis.

Intestinal Mucositis Induced by 5- Fluorouracil and the Possible Protective Effect of Probiotics Containing Lactobacillus in Adult Male Albino Rats: Histological and Immunohistochemical Study

“…The mucosal damage in the present study was found to progress up to complete erosion of the mucosa. This was in agreement with other authors [ 28,29,30] .…”

Effect of the Cannabinoid Agonist WIN 55,212-2 on Neuropathic and Visceral Pain Induced by a Non-Diarrheagenic Dose of the Antitumoral Drug 5-Fluorouracil in the Rat

“…As previously reported, 5-FU at 150 mg/kg reduced body weight and food intake [38][39][40][41], but did not change water intake [38,42]. The body weight reduction could be explained, at least partially, by the associated reduction in food intake, but other factors could also be involved.…”

“…In fact, mucositis was associated with diarrhea in other studies using 5-FU at the same dose and route of administration, but with different sexes and/or strains of rats. Thus, compared with mucositis, diarrhea does not seem to be a robust finding, with some rat strains showing vulnerability (female Dark Agouti [40,41]; male Sprague-Dawley rats [42]) and others displaying relative resistance to its development (male Wistar rats: present results and [8]).…”

A Rat Model for Oral Mucositis Induced by a Single Administration of 5-Fluorouracil

“…A higher dose of 5-FU was administrated to induce CIOM than the dose used to induce intestinal mucositis in murine (13). Since a single IP injection of 150 mg/kg of 5-FU successfully induced intestinal mucositis in a previous study (15), we IP injected 5-FU with a higher single dosage of 160 mg/kg, 200 mg/kg, or 240 mg/kg after anesthetizing rats using isoflurane. The maximum volume of IP injection in rats is known to be 20 ml/kg (16,17).…”

“…There are technical considerations when developing CIOM in murine. A high-dose IP administration of 5-FU ranging from 100 to 500 mg/kg has been used for inducing CIOM in murine (15). Since the solubility of 5-FU at room temperature is about 12 mg/ml in water (14), more than 3 ml of 5-FU mixture administration is generally required for inducing CIOM in rats when considering rat's weight in the 7 th week (19).…”