The Protective Effects of Saxagliptin and Cilostazol in an Experimental Model of Cyclophosphamide‐Induced Nephrotoxicity in Rats: Targeting iNOS/<i>NF</i>‐<i>kB</i> and <i>Nrf‐2</i>/<i>HO‐1</i> Pathways

Cyclophosphamide (CYP) is an extensively used immunosuppressive drug and chemotherapeutic agent for various malignancies. Nevertheless, its use is limited due to adverse effects, including nephrotoxicity. Saxagliptin is a DPP4 inhibitor, while cilostazol serves as an antiplatelet agent. Their nephroprotective effects arise from antioxidant and anti-inflammatory properties. This study investigated the potential protective effects of Saxagliptin and Cilostazol in rats with kidney damage induced by CYP. Five equal groups of 50 male Wistar rats were randomly categorised as Group I (Control group), Group II: CYP untreated nephrotoxicity-induced group, Group III: Nephrotoxicity-induced group treated with saxagliptin, Group IV: Nephrotoxicity-induced group treated with cilostazol, and Group V: Nephrotoxicity-induced group treated with saxagliptin and cilostazol. Renal tissues and blood samples were collected for biochemical analysis of urea, creatinine, and acute kidney injury biomarkers, including Kim-1 and NGAL. Additionally, oxidative stress and inflammatory biomarkers such as GSH, MDA, TNF-α and IL-1β were assessed, along with gene expression of Nrf-2/HO-1 and NF-kB. Immunohistochemical analysis of iNOS, and histopathological study were also conducted. Saxagliptin and cilostazol ameliorated the nephrotoxicity induced by CYP, as indicated by improvements in urea, creatinine, and acute kidney injury biomarkers Kim-1 and NGAL. Furthermore, there was a decrease in oxidative stress via the upregulation of Nrf-2/HO-1, increased levels of GSH, downregulation of MDA and decreased inflammation via the downregulation of TNF-α, IL-1β and iNOS/NF-kB. The combination of saxagliptin and cilostazol demonstrated a significant improvement compared to using each agent individually. The combination of Saxagliptin/Cilostazol is superior to monotherapy by either of each alone in preventing CYP-induced nephrotoxicity.