The Nephroprotective Effects of Nebivolol Against Cyclophosphamide-Induced Toxicity Occur via Antioxidant and...

Cyclophosphamide is a chemotherapy drug used to treat various types of neoplasms and autoimmune diseases. During its hepatic metabolism, acrolein is formed, a toxic metabolite responsible for increasing oxidative stress in tissues such as the kidney. Acrolein-induced oxidative stress is characterized by the excessive formation of reactive oxygen species (ROS) and lipid peroxidation. Additionally, the release of pro-inflammatory cytokines leads to the accumulation of immune cells in the renal cortex. Therefore, cyclophosphamide-induced nephrotoxicity is a limiting factor in cancer treatment, creating a need to find nephroprotective agents that reduce renal oxidation and inflammation. Nebivolol is a third-generation β-blocker with established antioxidant effects. This study aimed to evaluate the cytoprotective properties of nebivolol in the renal cortex of mice exposed to cyclophosphamide. Male C57Bl/6 mice were intraperitoneally injected with a single dose of cyclophosphamide (300 mg/kg). Nebivolol (10 mg/kg/day) was administered by gavage for 5 days prior to cyclophosphamide injection. Nebivolol prevented the cyclophosphamide-induced increase in serum creatinine levels. The cyclophosphamide-induced increases in lipoperoxidation and NADPH oxidase-derived superoxide (O₂ ^{• -}) were mitigated by nebivolol. The anti-inflammatory effects of nebivolol included a reduction in the number of neutrophils and macrophages in the renal tissue of cyclophosphamide-treated animals. Finally, nebivolol prevented the cyclophosphamide-induced increase in metalloproteinase (MMP)-2 and MMP-9 activities. In summary, cyclophosphamide induces renal dysfunction through pro-oxidative and pro-inflammatory mechanisms. Nebivolol exerts nephroprotective effects via antioxidant and anti-inflammatory pathways, preventing cyclophosphamide-induced renal dysfunction. These beneficial effects suggest nebivolol could help prevent the renal toxicity associated with cyclophosphamide.