The Nephroprotective Effects of Nebivolol Against Cyclophosphamide‐Induced Toxicity Occur via Antioxidant and Anti‐Inflammatory Pathways
Alessandra O. Silva, João M. R. de Freitas, Cristopher M. Carvalho, Carolina M. T. Alvim, Gustavo F. Pimenta, Thales M. H. Dourado, Carolina de P. S. Jesus, Jéssyca M. Ribeiro, Jefferson Luiz Silva, Vânia Brazão, Carla S. Ceron, Carlos R. Tirapelli, Simone R. Potje, Gabriel T. do ValeABSTRACT
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 (O 2 • − ) 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.