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  3. Therapeutic potential of oral edaravone in diabetic endothelial dysfunction through NF-κB and p38 pathway inhibition

Therapeutic potential of oral edaravone in diabetic endothelial dysfunction through NF-κB and p38 pathway inhibition

  • Eur J Pharmacol. 2026 Jan 20:1012:178500. doi: 10.1016/j.ejphar.2025.178500.
Yong-Xuan Xu 1,  Xiao-Yan Zhang 1,  Ling Wang 1,  Hao-Cheng Ma 1,  Si-Quan Xue 2,  Juan-Hua Gu 2,  Xin-Fu Zhou 3,  Yue-Qin Zeng 4,  Hai-Yun Luo 5,  Li-Jin Pu 6
Affiliations

Affiliations

  • 1 Department of Cardiology, First Affiliated Hospital and Faculty of Basic Medical Science, Kunming Medical University, Kunming, China.
  • 2 Yunnan Key Laboratory of Stem Cells and Regeneration Medicine, Biomedical Engineering Research Center, Kunming, China.
  • 3 Auzone Biotech, Shanghai, China; Health and Biomedical Innovation, Clinical and Health Sciences, University of South Australia, Adelaide, Australia.
  • 4 Yunnan Key Laboratory of Stem Cells and Regeneration Medicine, Biomedical Engineering Research Center, Kunming, China. Electronic address: [email protected].
  • 5 Department of Cardiology, First Affiliated Hospital and Faculty of Basic Medical Science, Kunming Medical University, Kunming, China. Electronic address: [email protected].
  • 6 Department of Cardiology, First Affiliated Hospital and Faculty of Basic Medical Science, Kunming Medical University, Kunming, China. Electronic address: [email protected].
PMID: 41421410 DOI: 10.1016/j.ejphar.2025.178500
Abstract

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.

Keywords

Endothelial dysfunction; NF-κB; Oral edaravone; Oxidative stress; p38 MAPK.

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