title: Melatonin protects rats from radiotherapy-induced small intestine toxicity.
abstract: Radiotherapy-induced gut toxicity is among the most prevalent dose-limiting toxicities following radiotherapy. Prevention of radiation enteropathy requires protection of the small intestine. However, despite the prevalence and burden of this pathology, there are currently no effective treatments for radiotherapy-induced gut toxicity, and this pathology remains unclear. The present study aimed to investigate the changes induced in the rat small intestine after external irradiation of the tongue, and to explore the potential radio-protective effects of melatonin gel. Male Wistar rats were subjected to irradiation of their tongues with an X-Ray YXLON Y.Tu 320-D03 irradiator, receiving a dose of 7.5 Gy/day for 5 days. For 21 days post-irradiation, rats were treated with 45 mg/day melatonin gel or vehicle, by local application into their mouths. Our results showed that mitochondrial oxidative stress, bioenergetic impairment, and subsequent NLRP3 inflammasome activation were involved in the development of radiotherapy-induced gut toxicity. Oral treatment with melatonin gel had a protective effect in the small intestine, which was associated with mitochondrial protection and, consequently, with a reduced inflammatory response, blunting the NF-κB/NLRP3 inflammasome signaling activation. Thus, rats treated with melatonin gel showed reduced intestinal apoptosis, relieving mucosal dysfunction and facilitating intestinal mucosa recovery. Our findings suggest that oral treatment with melatonin gel may be a potential preventive therapy for radiotherapy-induced gut toxicity in cancer patients.
authors.affiliation: Instituto de Biotecnología, Centro de Investigación Biomédica, Universidad de Granada, Granada, Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Fernández-Gil
authors.affiliation: Department of Zoology and Entomology, Faculty of Science, Helwan University, Cairo, Egypt.
authors.forename: Ahmed E Abdel
authors.initials: AE
authors.lastname: Moneim
authors.affiliation: Instituto de Biotecnología, Centro de Investigación Biomédica, Universidad de Granada, Granada, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Ortiz
authors.affiliation: Instituto de Biotecnología, Centro de Investigación Biomédica, Universidad de Granada, Granada, Spain.
authors.forename: Ying-Qiang
authors.initials: YQ
authors.lastname: Shen
authors.affiliation: Neuroscience Research Group, Medical Research Institute, Faculty of Medicine, University of Antioquia, Medellin, Colombia.
authors.forename: Viviana
authors.initials: V
authors.lastname: Soto-Mercado
authors.affiliation: Neuroscience Research Group, Medical Research Institute, Faculty of Medicine, University of Antioquia, Medellin, Colombia.
authors.forename: Miguel
authors.initials: M
authors.lastname: Mendivil-Perez
authors.affiliation: Instituto de Biotecnología, Centro de Investigación Biomédica, Universidad de Granada, Granada, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Guerra-Librero
authors.affiliation: Instituto de Biotecnología, Centro de Investigación Biomédica, Universidad de Granada, Granada, Spain.|Departamento de Fisiología, Facultad de Medicina, Universidad de Granada, Granada, Spain.
authors.forename: Darío
authors.initials: D
authors.lastname: Acuña-Castroviejo
authors.affiliation: Instituto Cavanilles, Universidad de Valencia, Valencia, Spain.
authors.forename: María M
authors.initials: MM
authors.lastname: Molina-Navarro
authors.affiliation: Instituto Cavanilles, Universidad de Valencia, Valencia, Spain.
authors.forename: José M
authors.initials: JM
authors.lastname: García-Verdugo
authors.affiliation: Department of Anatomy and Embryology, Faculty of Veterinary Medicine, Sohag University, Sohag, Egypt.
authors.forename: Ramy K A
authors.initials: RK
authors.lastname: Sayed
authors.affiliation: Instituto de Biotecnología, Centro de Investigación Biomédica, Universidad de Granada, Granada, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Florido
authors.affiliation: Departamento de Bioestadística, Facultad de Medicina, Universidad de Granada, Granada, Spain.
authors.forename: Juan D
authors.initials: JD
authors.lastname: Luna
authors.affiliation: Instituto de Biotecnología, Centro de Investigación Biomédica, Universidad de Granada, Granada, Spain.|Departamento de Fisiología, Facultad de Medicina, Universidad de Granada, Granada, Spain.
authors.forename: Luis Carlos
authors.initials: LC
authors.lastname: López
authors.affiliation: Instituto de Biotecnología, Centro de Investigación Biomédica, Universidad de Granada, Granada, Spain.|Departamento de Fisiología, Facultad de Medicina, Universidad de Granada, Granada, Spain.
authors.forename: Germaine
authors.initials: G
authors.lastname: Escames
mesh_terms: D000818:Animals; D017209:Apoptosis; D004353:Drug Evaluation, Preclinical; D005782:Gels; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism / Q000473:pathology* / Q000528:radiation effects; D007421:Intestine, Small / Q000187:drug effects / Q000378:metabolism / Q000473:pathology* / Q000528:radiation effects; D008297:Male; D008550:Melatonin / Q000008:administration & dosage*; D016328:NF-kappa B / Q000378:metabolism; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000378:metabolism; D010085:Oxidative Phosphorylation; D018384:Oxidative Stress; D011833:Radiation Injuries, Experimental / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D011837:Radiation-Protective Agents / Q000008:administration & dosage*; D017208:Rats, Wistar; D014059:Tongue / Q000528:radiation effects
chemical_list: D005782:Gels; D016328:NF-kappa B; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C573346:Nlrp3 protein, rat; D011837:Radiation-Protective Agents; D008550:Melatonin