Dipeptidyl Peptidase-4 Inhibitor Sitagliptin Exhibits Antioxidant Mechanism for Abrogation of Cyclophosphamide-Induced Cardiac Damage and Oxidative Hepatorenal Toxicity in Rats.

Abstract

Cyclophosphamide (CYP) is a potent DNA-interactive anticancer drug; however, its clinical drawbacks are chiefly associated with induction of oxidative multi-organ toxicity. Sitagliptin (STG) is an antidiabetic dipeptidyl peptidase-4 inhibitor drug with antioxidant efficacy. Herein, we have explored whether STG could abrogate the CYP-induced oxidative stress-mediated cardiac and hepatorenal toxicities in male rats. Sitagliptin (20 mg/kg, o.p) was administered to rats for 5 consecutive days against organ toxicities induced by CYP (200 mg/kg, i.p) on day 5 only. CYP induced marked injuries in the liver, kidney and heart underscored by prominent increases in serum activities of ALT, AST, LDH, creatine kinase and levels of urea, uric acid and creatinine, while albumin level significantly decreased compared to normal control rats. Further, CYP considerably reduced the activities of SOD, CAT, GPx, and levels of GSH, whereas MDA level increased significantly in comparison to control rats. These biochemical alterations were confirmed by multiple histopathological lesions in the tissues. Interestingly, the STG pretreatment abrogated the biochemical and histopathological changes induced by CYP. These results provide first evidence that repurposing STG may protect the liver, kidney and heart from the oxidative deterioration associated with CYP chemotherapy.