Edaravone attenuates doxorubicin-induced oral mucosal injury via modulation of oxidative stress, inflammatory signaling, and the SIRT1/TLR4/NF-kB/ACE2 axis in rats.

BACKGROUND

Oral mucositis (OM) is a common complication of chemotherapy, particularly with anthracyclines like doxorubicin (DOX), which induce oxidative stress and inflammation. This study investigated the protective effects of edaravone (EDO), a free radical scavenger, against DOX-induced oral mucosal injury.

METHODS

Twenty-eight male Wistar rats were randomly divided into four groups (n = 7): Control, DOX (18 mg/kg, i.p., days 19-21), and two EDO + DOX groups (1 or 30 mg/kg EDO daily for 21 days). On day 22, tongue tissues and plasma were analyzed for oxidative stress markers (MDA, GSH, SOD, TAS, TOS) and cytokines (TNF-α, IL-6, IL-1β, IL-10). NF-κB, SIRT1, and TLR4 expression were assessed via immunohistochemistry and ELISA, while ACE2 expression was evaluated by immunohistochemistry.

RESULTS

DOX significantly upregulated ACE2 (p < 0.001), TLR4 (p < 0.001), NF-κB (p < 0.001), and proinflammatory cytokines in plasma and tongue tissue (TNF-α, IL-6, IL-1β; all p < 0.01), while reducing IL-10 (p < 0.001), GSH (p = 0.002), SOD (p = 0.001), and SIRT1 (p < 0.001). EDA treatment reduced ACE2 and TLR4 expression, with 30 mg/kg normalizing ACE2 (p = 0.978 vs. control). EDO restored antioxidant markers and significantly lowered MDA, TOS, cytokines, and NF-κB (all p < 0.05). Histological injury and inflammation scores also improved significantly (p < 0.001).

CONCLUSION

Edaravone effectively attenuates DOX-induced mucosal injury by modulating oxidative stress, inflammatory signaling, and TLR4/ACE2 pathways, suggesting therapeutic potential in mucosal protection.