1‐Palmitoyl‐2‐linoleoyl‐3‐acetyl‐rac‐glycerol Ameliorates Chemoradiation‐Induced Oral Mucositis

OBJECTIVE: This study was designed to investigate whether necroptosis is involved in the pathogenesis of chemoradiation-induced oral mucositis in a murine model and whether 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) ameliorates this disorder. MATERIALS AND METHODS: A chemoradiation-induced oral mucositis model was established by treating mice with concurrent 5-fluorouracil (100 mg/kg, i.p.) and head and neck X-irradiation (20 Gy). Phosphate-buffered saline or PLAG (100 mg/kg or 250 mg/kg, p.o.) was administered daily. Body weights were recorded daily, and mice were sacrificed on Day 9 for tongue tissue analysis. RESULTS: On Day 9, chemoradiotherapy-treated (ChemoRT) mice had tongue ulcerations and experienced significant weight loss (Day 0:26.18 +/- 1.41 g; Day 9:19.44 +/- 3.26 g). They also had elevated serum macrophage inhibitory protein 2 (MIP-2) (control: 5.57 +/- 3.49 pg/ml; ChemoRT: 130.14 +/- 114.54 pg/ml) and interleukin (IL)-6 (control: 198.25 +/- 16.91 pg/ml; ChemoRT: 467.25 +/- 108.12 pg/ml) levels. ChemoRT-treated mice who received PLAG exhibited no weight loss (Day 0:25.78 +/- 1.04 g; Day 9:26.46 +/- 1.68 g) and had lower serum MIP-2 (4.42 +/- 4.04 pg/ml) and IL-6 (205.75 +/- 30.41 pg/ml) levels than ChemoRT-treated mice who did not receive PLAG. Tongue tissues of mice who received PLAG also displayed lower phosphorylation levels of necroptotic signalling proteins. CONCLUSION: 1-Palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol mitigated chemoradiation-induced oral mucositis by modulating necroptosis.