Edaravone attenuates doxorubicin-induced oral mucosal injury via modulation of oxidative stress, inflammatory signaling, and the SIRT1/TLR4/NF-kB/ACE2 axis in rats
Makaleler > Tam Makale · 2025
Yazarlar: Mert ZEYTİNOĞLU, Aras Erdil, Sefa Çolak, Mustafa Sami Demirsoy, Ali Tuğrul Akin, Necla Değer, Derya Karabulut, Serdar Savaş Gül, Hatice Aygun, Oytun Erbaş
BMC Oral Health, Uluslararası, Wos, 2025, cilt 25, ss 1841-1841
DOI: 10.1186/s12903-025-07148-y
Özet
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. 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. 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). Edaravone effectively attenuates DOX-induced mucosal injury by modulating oxidative stress, inflammatory signaling, and TLR4/ACE2 pathways, suggesting therapeutic potential in mucosal protection. Doxorubicin induces mitochondrial ROS production, leading to oxidative stress (↑MDA, ↑TOS, ↓GSH, ↓SOD, ↓TAS). This redox imbalance downregulates SIRT1 and activates TLR4, both of which contribute to NF-κB signaling. As a result, proinflammatory cytokines (↑TNF-α, ↑IL-6, ↑IL-1β) are upregulated, while anti-inflammatory IL-10 is suppressed. This inflammatory cascade, in turn, promotes ACE2 overexpression in the tongue epithelium. Edaravone treatment mitigates these effects through ROS scavenging, restoration of SIRT1, and suppression of TLR4/NF-κB signaling, ultimately protecting the oral mucosa.