European journal of pharmacology · 2025
Therapeutic potential of oral edaravone in diabetic endothelial dysfunction through NF-κB and p38 pathway inhibition.
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Xu Yong-Xuan, Zhang Xiao-Yan, Wang Ling, Ma Hao-Cheng, Xue Si-Quan, Gu Juan-Hua, Zhou Xin-Fu, Zeng Yue-Qin, Luo Hai-Yun, Pu Li-Jin
Аннотация
OBJECTIVE: Diabetes mellitus is a chronic metabolic disorder frequently associated with endothelial dysfunction, a major contributor to cardiovascular complications. This study aimed to investigate the protective effects of oral edaravone (OED) on endothelial dysfunction in diabetic models and explore its underlying molecular mechanisms.
METHODS: Type 2 diabetes was induced in rat models using a high-fat diet combined with streptozotocin (STZ), followed by treatment with different doses of OED (1 mg/kg/day, 3 mg/kg/day, 10 mg/kg/day) for 12 weeks. In parallel, human coronary artery endothelial cells (HCAECs) exposed to high glucose/high fat (HG/HF, 25 mM/50 μM) conditions were treated with OED for 5 days.
RESULTS: OED treatment significantly reduced levels of total cholesterol (TC), triglycerides (TG), malondialdehyde (MDA), and reactive oxygen species (ROS), while enhancing superoxide dismutase (SOD) activity in both HCAECs under high glucose and high fat conditions and in diabetic rats. Furthermore, OED attenuated oxidative stress, inflammation, and macrophage infiltration in the vascular endothelium. Transcriptomic and bioinformatics analyses identified the involvement of the NF-κB and p38 MAPK signaling pathways. Notably, the therapeutic effects of OED were markedly diminished in vitro upon co-treatment with agonists of NF-κB and p38 MAPK, further supporting the regulatory role of these pathways in OED-mediated vascular protection.
CONCLUSION: OED significantly attenuates inflammation and oxidative stress-associated arterial endothelial dysfunction in diabetes by inhibiting the NF-κB and p38 MAPK signaling pathways. These findings highlight the therapeutic potential of OED for the prevention and treatment of diabetes-related vascular complications.
METHODS: Type 2 diabetes was induced in rat models using a high-fat diet combined with streptozotocin (STZ), followed by treatment with different doses of OED (1 mg/kg/day, 3 mg/kg/day, 10 mg/kg/day) for 12 weeks. In parallel, human coronary artery endothelial cells (HCAECs) exposed to high glucose/high fat (HG/HF, 25 mM/50 μM) conditions were treated with OED for 5 days.
RESULTS: OED treatment significantly reduced levels of total cholesterol (TC), triglycerides (TG), malondialdehyde (MDA), and reactive oxygen species (ROS), while enhancing superoxide dismutase (SOD) activity in both HCAECs under high glucose and high fat conditions and in diabetic rats. Furthermore, OED attenuated oxidative stress, inflammation, and macrophage infiltration in the vascular endothelium. Transcriptomic and bioinformatics analyses identified the involvement of the NF-κB and p38 MAPK signaling pathways. Notably, the therapeutic effects of OED were markedly diminished in vitro upon co-treatment with agonists of NF-κB and p38 MAPK, further supporting the regulatory role of these pathways in OED-mediated vascular protection.
CONCLUSION: OED significantly attenuates inflammation and oxidative stress-associated arterial endothelial dysfunction in diabetes by inhibiting the NF-κB and p38 MAPK signaling pathways. These findings highlight the therapeutic potential of OED for the prevention and treatment of diabetes-related vascular complications.