Objectives: 

Radiotherapy-induced oral mucositis is one of the main side-effects of the therapy in patients with cancer. The molecular mechanisms of the oral mucositis are currently unknown. It was reported that during cell stress, the free radicals produced by the mitochondria are responsible for the NLRP3 inflammasome activation, which in turn yield intracellular changes conducting to pro-inflammatory cytokines activation. During these responses, the NF-kB pathway is also activated, increasing the pro-inflammatory response. The objectives of this study were to analyze the molecular pathways involved in the development of oral mucositis, and to evaluate whether the antioxidant and anti-inflammatory actions of melatonin can prevent this pathology.

Materials: 

Male Wistar rats were subjected to irradiation. The radiation was administered using a Ray-X YXLON Y.Tu 320-D03 irradiator, and the rats received a dose of 7,5 Gy/day for 5 days in their tongues. Rats were treated with 45 mg /day melatonin or vehicel during 21 days post-irradiation, either by local application their mouths or by sc injection. Inflammatory reaction was determined with the measurements of NF-kB, iNOS/i-mtNOS, NLRP3, ASC, caspase-1, and proinflammatory cytokines. Apoptosis studies were also performed through the quantification of pro- and anti-apoptotic proteins. We analize macro and microscopy damage by histology and microscopy electronic. Pharmaceutical preparation of melatonin in gel is currently under patent.

Results: 

We observe an amelioration of the acute mucosal effects of radiotherapy with topical gel melatonin. Melatonin decrease the expression of NF-kB, iNOS/i-mtNOS, NLRP3, ASC, caspase-1, and proinflammatory cytokines, and we observe a decrease of fibrosis with melatonin.

Conclusions: 

Considering the low toxicity of melatonin even during long term makes possible its use, our results provide evidence for the therapeutic value of melatonin to prevent mucositis in cancer patients.

Supported in part by grants nordm; SAF2009-14037