Abstract
Background: Gastrointestinal mucositis occurs as a consequence of cytotoxic treatment. Quercetin (QCT) is a bioflavonoid that exerts significant antioxidant activity and anti-inflammatory as well as anti-malignancy properties. Objective: To evaluate the effects of oral QCT consumption in preventing intestinal mucosal damage and stimulating intestinal recovery following methotrexate (MTX)-induced intestinal damage in a rat model. Design: Male Sprague–Dawley rats were divided into four groups: Control Group A (CONTR) – rats were treated with 2 cc of saline given by gavage for 6 days. Group B (CONTR-QCT) – rats were treated with QCT (100 mg/kg in 2 ml saline) given by gavage 3 days before and 3 days after intraperitoneal (IP) injection of saline. Group C (MTX) – rats were injected a single dose (25 mg/kg) of MTX IP. Group D (MTX-QCT) rats were treated with QCT (similar to Group B) 3 days before and 3 days after IP MTX injection. Intestinal mucosal parameters (bowel and mucosal weight, mucosal DNA and protein content, and villus height and crypt depth), enterocytes proliferation, and enterocyte apoptosis degree were investigated at sacrifice on the 4th day after MTX or saline injection. Results: Administration of QCT to MTX-treated rats resulted in: (1) significant decrease in intestinal injury score, (2) significant increase in intestinal and mucosal weight in jejunum and ileum, (3) increase on the protein content of the ileum, (4) increase in the villus height in the ileum, (5) increase of crypt depth of jejunum and ileum, and (6) increase in cell proliferation in the jejunum and ileum compared to MTX-nontreated group. Conclusions: Administration of QCT prevents intestinal damage and improves intestinal recovery following MTX-induced intestinal damage in a rat. We surmise that the effect of QCT is based on induction of cell proliferation in the crypt rather than inhibition of apoptosis.
| Original language | American English |
|---|---|
| Article number | 1327 |
| Journal | Food and Nutrition Research |
| Volume | 62 |
| DOIs | |
| State | Published - 28 Mar 2018 |
Bibliographical note
Funding Information:In the current experiment, we investigated the effects of QCT on enterocyte turnover following MTX administration in in vivo rat model. Consistent with our previous experiments, treatment with MTX in the present study resulted in apparent intestinal damage. This conclusion is supported by the observed increase in injury score of MTX-treated rats compared to CONTR animals. MTX-treated rats presented with severe villous atrophy, epithelial flattening, and extensive crypt loss. In addition, treatment with MTX resulted in a significant mucosal hypoplasia. A decrease in bowel and mucosal weight, mucosal DNA and protein, and decrease in villus height support this conclusion. Parallel decreases in mucosal DNA and protein indicate that the smaller mucosal mass of MTX-treated animals can be attributed to cellular hypoplasia. MTX and its active metabolites block tetrahydrofolate synthesis by binding to the folic acid site on the enzyme dihydrofolate reductase. This action results in depletion of nucleotide precursors, and inhibition of DNA, RNA, protein synthesis, and cellular proliferation. Histologically, villus height decreased in response to MTX administration, suggesting decreased absorptive surface area; however, crypt depth decreased nonsignificantly. Analysis of epithelial proliferation 3 days after MTX administration, using BrdU incorporation as a marker, demonstrated an inhibition of DNA synthesis in the epithelium of the entire small intestine and concomitant decrease in the rates of cell proliferation. In addition, the proliferative zone in the crypts moved progressively upward toward the crypt-villus junction in MTX-treated rats. The mechanism responsible for this effect is poorly understood. Verburg and coworkers have shown in MTX-treated rats that BrdU-positive cells are not restricted to the crypts but are also found in up to one-third of the length of the villi due to migration of the cells (34).
Publisher Copyright:
© 2018 Igor Sukhotnik et al. T.
Keywords
- Chemotherapy
- Enterocyte apoptosis
- Enterocyte proliferation
- Methotrexate
- Mucositis
- Quercetin
