Protection from Radiation-induced Damage in Rat’s Ileum and Colon by Combined Regimens of Melatonin and Metformin: A Histopathological Study

Abstract

Background: Radiation-induced enteritis and proctitis are common side effects of abdominopelvic cancers among patients that undergo radiotherapy for prostate, colorectal or urinary cancers. Exposure of these tissues to high doses of radiation leads to damage to villous, inflammation, pain, ulcer and bleeding, which may cause malabsorption and gastrointestinal disorders. To date, several procedures such as pharmaceutical treatment have been proposed for protection and mitigation of gastrointestinal toxicity following radiotherapy. Aims: In the current study, we aimed to investigate the possible radioprotection of ileum and colon in rats using a combination of melatonin and metformin. Methods: In this experimental study, 30 male Wistar rats were randomly assigned to six groups: control, melatonin (100 mg/kg) treatment, melatonin (100 mg/kg) plus metformin (100 mg/kg) treatment, radiation (10 Gy to whole body) group, radiation + melatonin (100 mg/kg) treatment, and radiation + melatonin (100 mg/kg) plus metformin (100 mg/kg) treatment. After 3.5 days, rats were sacrificed and their ileum and colon tissues carefully removed. Histopathological evaluations were conducted on these tissue samples. Results: Histological evaluations reported moderate to severe damages to ileum and colon following whole body irradiation. Melatonin administration was able to protect the ileum remarkably, while the combination of melatonin and metformin was less effective. Interestingly, for the colon, melatonin was less effective while its combination with metformin was able to protect against radiation toxicity completely. Conclusion: For the ileum, melatonin was a more effective radioprotector compared to its combination with metformin. However, the combination of melatonin and metformin can be proposed as an ideal radioprotector for the colon.

Protective Effects of Melatonin and Misoprostol against Experimentally Induced Increases in Intestinal Permeability in Rats

“…However, other mechanisms of action have also been proposed. For instance, melatonin has been shown to be a potent scavenger of free radicals, and thus has protective effects on radiation-induced increases in intestinal permeability [ 13 , 29 , 30 , 31 ]. This process occurs both through direct detoxification of reactive oxygen and nitrogen species as well as by stimulating antioxidant enzymes and suppressing pro-oxidant enzymes [ 32 ].…”

Protective rules of natural antioxidants against gamma‐induced damage—A review

“…Another process through which IR stimulates toxicities is through systemic impacts, also called “nontargeted” impacts. It is a procedure wherein tissues or cells that do not directly intermingle with IR are stimulated with intricate radiation impacts comprising radio adaptive response, bystander impacts, and genomic instability (Najafi et al., 2019 ). Nonetheless, late impacts such as organ dysfunction, necrosis, death, and cancer might surface months to years after exposure (Peña et al., 2000 ).…”

“…Table 1 presents the antioxidant effect of Melatonin in in vitro test models and its capability to reduce the damaging impacts of gamma radiation by changing the histopathological and biochemical biomarkers of oxidative stress. According to the literature study, the administration of melatonin through oral gavage of male Wistar rats in a dose of 100 mg/kg in 24 hr and 30 min before exposing them to 10 Gy gamma rays and continued for 3 days after irradiation protects ileum against radiation toxicity, protects vessels and goblet cells, prevents infiltration of macrophages and lymphocytes or mucositis, stimulates antioxidant defense in cells, protects against radiation‐induced apoptosis, reduces inhibitory effect on radiation‐induced apoptosis, preserves villi length, and inhibits inflammation in the intestine (Najafi et al., 2019 ).…”

Metabolic Rewiring in Radiation Oncology Toward Improving the Therapeutic Ratio

“…Additionally, MLT downregulates NF-kB-signaling, mitigating an inflammatory response and enhances expression of DNA-repair genes contributing to genomic stability in normal cells (410)(411)(412). However, evidence implies that MLT combined with metformin exerted both synergizing and antagonizing effects in healthy rodents in a tissue-specific manner (94,413). Findings in xenografts suggested that MLT exerts tumor-sensitizing effects by reducing DNA repair and stimulating OXPHOS in malignant cells intensifying the oxidative stress.…”