Protective Effects of Alpha-Lipoic Acid against 5-Fluorouracil-Induced Gastrointestinal Mucositis in Rats

Abstract

Alpha-lipoic acid (ALA) is extensively utilized in multivitamin formulas and anti-aging products. The purpose of this study was to investigate the potential protective benefits of ALA on 5-fluorouracil (5-FU)-induced gastrointestinal mucositis in Wistar albino rats. Tissues from the stomach, small intestine, and large intestine were excised, and blood sera were obtained to identify biochemical indices such as TNF-α, IL-1β, MDA, GPx, SOD, MMP-1, -2, -8, and TIMP-1. A histopathological study was also performed. The results revealed mucositis-elevated TNF-, IL-1, MDA, MMP-1, -2, -8, and TIMP-1 levels in both tissues and sera, and these values dropped dramatically following ALA treatment. Reduced SOD and GPx activities in mucositis groups were reversed in ALA-treated groups. The damage produced by mucositis in the stomach and small intestine regressed in the ALA-treated group, according to histopathological evaluation. Consequently, the implementation of ALA supplementation in 5-FU therapy may act as a protective intervention for cancer patients with gastrointestinal mucositis. In light of the findings, ALA, a food-derived antioxidant with pleiotropic properties, may be an effective treatment for 5-FU-induced gastrointestinal mucositus, and prevent oxidative stress, inflammation, and tissue damage in cancer patients receiving 5-FU therapy.

Keywords: 5-fluorouracil; alpha-lipoic acid; gastrointestinal mucositis; inflammation; oxidative stress.

Figure 3

Histological view of HE stained stomach tissue for (a) the Control group, (b) the ALA group, (c) the Mucositis group, and (d) the Mucositis + ALA group. Bar = 100 µm; enlarged area Bar = 50 µm. (a) It is seen that epithelial cells and gland structures of the corpus-fundus region of the stomach of the control group are normal. (b) The stomach structure of the ALA-only group is similar to the control group. (c) Degeneration of gastric epithelial cells and edema (*) and enlargement of glands (arrows) are common in the Mucositis group. (d) It is seen that edema in the surface epithelial cells and enlargement of the glands decreased in the Mucositis + ALA group compared to the Mucositis group. In both the control and experimental groups, no structural alterations in the large intestine were seen. Visually normal simple layered columnar epithelial cells, goblet cells, and glands were observed (Figure 5a–d).

Figure 1

Comparisons of serum, stomach, small intestine, and large intestine concentrations of) TNF-α, IL-1β in the Control, ALA, Mucositis and Mucositis + ALA groups. * p < 0.05, ** p < 0.01, and *** p < 0.001 and **** p < 0.0001.

Figure 2

Comparisons of MDA levels and GPx and SOD activities in the stomach, small intestine, and large intestine in the Control, ALA, Mucositis and Mucositis + ALA groups. * p < 0.05, ** p < 0.01, and *** p < 0.001 and **** p < 0.0001. In Mucositis group rats, GPx levels in all tissues were significantly reduced compared to the Control, ALA and Mucositis + ALA groups (p < 0.05–0.0001). Also, in the stomach tissue, the GPx levels of animals in the ALA and Mucositis + ALA groups were shown to be significantly different to the Control group (p < 0.05).

Figure 4

The microscopic images of HE-stained slides of the small intestine tissue. Bar = 100 µm; enlarged area Bar = 50 µm. (a) The structure of the small intestine of the control group is shown; Villus (v) and Brunner’s glands (B). (b) The structure of the small intestine in the ALA-only group is similar to the control group. (c) Shedding of villi and irregularity in enterocytes are seen in the Mucositis group. (d) In the Mucositis + ALA group, it is seen that the villi structures are smooth.

Figure 5

The microscopic images of HE-stained slides of the large intestine tissue. Bar = 100 µm. (a) The image shows a large intestine of the control group. (b) The structure in the ALA-only group is similar to the control group. (c) Goblet cell density in the Mucositis group was similar to the control and ALA groups, no degeneration was observed in enterocytes. (d) The structure in the Mucositis + ALA group is similar to the control group.