Investigations of AGEs’ inhibitory and nephroprotective potential of ursolic acid towards reduction of diabetic complications

• Published in: Journal of natural medicines 2022-03, Vol.76 (2), p.490-503
• Main Authors: Mazumder, Kishor, Biswas, Biswajit, Al Mamun, Abdullah, Billah, Hasan, Abid, Ahsan, Sarkar, Kishore Kumar, Saha, Bisti, Azom, Shorrowar, Kerr, Philip G.
• Format: Article
• Language: English
• Subjects: Acids; Advanced glycosylation end products; Alanine; Alanine transaminase; Alkaline phosphatase; Animals; Antidiabetics; Aspartate aminotransferase; Biomedical and Life Sciences; Biomedicine; Blood glucose; Bovine serum albumin; Complementary & Alternative Medicine; Computer applications; Creatinine; Crystal structure; Diabetes; Diabetes Complications - drug therapy; Diabetes mellitus; Diabetes Mellitus, Experimental - chemically induced; Fluorescence; Glucose; Glycation End Products, Advanced - metabolism; Glycosylation; Hemoglobin; Kidneys; Medicinal Chemistry; Metformin; Mice; Pharmacokinetics; Pharmacology/Toxicology; Pharmacy; Plant Sciences; Pyruvaldehyde; Receptor for Advanced Glycation End Products; Triterpenes - pharmacology; Triterpenes - therapeutic use; Uric acid; Ursolic Acid
• ISSN: 1340-3443; 1861-0293
• DOI: 10.1007/s11418-021-01602-1

In diabetes, interactions between AGEs (advanced glycation end products) and RAGEs (receptors of AGEs) are responsible for chronic complications and the current work reports the potential of ursolic acid as a RAGE inhibitor. The three-dimensional crystal structure of RAGE was first docked with target molecules by ‘AutodockVina’ using GROMOS 96 4381 parameters. Druggability and pharmacokinetic properties were calculated from the SwissADME server. In vitro bovine serum albumin (BSA)–glucose fluorescence and BSA–methylglyoxal fluorescence assays were also performed. Finally, alloxan-induced diabetic mice were administered ursolic acid and metformin standards (at 1, 50, 100 mg/kg) for 50 days. Blood glucose levels, several blood parameters, blood lipid profiles, supernatants of homogenized kidney and plasma of mice were examined. In the computational study, ursolic acid showed greater binding affinity (-7.5 kcal/mol) for RAGE with an ADMET profiles and lead-likeness compared to metformin as a standard antidiabetic. In the in vitro fluorescence assays, the IC 50 value for ursolic acid was much less than that of metformin standard. During the in vivo study, significant reduction in the levels of blood glucose, HbA 1C (glycated hemoglobin), creatinine, uric acid, BUN (blood urea nitrogen), AST (aspartate aminotransferase), ALT (alanine aminotransferase), ALP (alkaline phosphatase) were observed in the ursolic acid and metformin-treated mice. Substantial inhibition of AGEs’ formation in the plasma and kidney were also detected. Finally, the histopathological examinations of the kidney revealed reversal of cellular necrosis. Hence, ursolic acid is proved to be a potent AGE inhibitory agent in managing the diabetic complications. Graphical abstract