Edaravone Improves the Efficacy of Metformin Against Diabetic Nephropathy by Attenuating Inflammation, Oxidative Stress, and Apoptosis with Associated Modulation of MAPK/NF-κB1 and AKT/NRF2 Pathways in Rats

The present study investigated the protective effects of edaravone (EDA), metformin (Met), and their combined treatment against diabetic nephropathy (DN) in rats. Sixteen normal non-diabetic rats were allocated to the negative control (NC) and EDA-treated control (EDA10; 10 mg/kg/day) groups and received a standard diet throughout the study. Type 2 diabetes was induced by feeding male Wistar rats (n = 40) a high-fat diet (HFD) for four weeks followed by a single intraperitoneal injection of streptozotocin (STZ; 40 mg/kg). Of the 40 rats, 36 developed diabetes; 32 were subsequently maintained on the HFD for an additional four weeks to establish DN and were then randomly allocated into four equal diabetic groups (n = 8/group) for the 8-week therapeutic intervention as follows: untreated DN, DN treated with Met alone (300 mg/kg/day), and DN treated with Met combined with either 5 or 10 mg/kg/day EDA. The diabetic animals remained on the HFD throughout the intervention period. Blood, urine, and renal tissue were collected to assess glucose homeostasis along with renal function, histopathology, oxidative stress, antioxidant defense, inflammation, apoptosis, and selected molecular regulatory markers at both gene and protein levels. DN was associated with impaired glucose homeostasis together with marked renal dysfunction, histopathological injury, oxidative stress, inflammation, and apoptosis. While Met significantly ameliorated many of these abnormalities, co-administration of EDA produced additional improvements, with the greatest overall effects observed with the higher EDA dose. Correlation and Mantel network analyses showed stronger associations of Mapk1 expression with renal injury, inflammation, and oxidative stress markers in DN, whereas combined treatment was associated with stronger relationships between Akt1 and Hmox1 expression and the cytoprotective biomarkers. In conclusion, combined EDA and Met treatment produced greater overall renoprotective effects than Met monotherapy, with the higher EDA dose showing the strongest nephroprotection. Further studies are required to determine the mechanisms underlying EDA-associated renoprotection and their translational relevance in humans.