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