Nebivolol Mitigates the Pro-Oxidative and Pro-Inflammatory Effects of Cyclophosphamide in the Heart

Abstract

Cyclophosphamide (CP) is an alkylating agent commonly used to treat malignant conditions. However, CP is associated with various adverse effects, one of which is cardiotoxicity. To minimize this toxicity, a common clinical strategy involves combining CP with a cytoprotective agent. One of the main causes of cardiac toxicity from CP is redox imbalance. Nebivolol, an antihypertensive medication that selectively targets β₁-adrenoceptors, has demonstrated cardioprotective effects in certain situations, partly due to its antioxidant properties. In this study, we evaluated whether nebivolol could reduce the harmful effects of CP on the heart. Male C57BL/6 mice were treated with nebivolol (10 mg/kg/day, administered by gavage for 5 days) and subsequently injected with either saline or a single dose of CP (300 mg/kg, via intraperitoneal injection). We assessed pro-oxidative and pro-inflammatory parameters in the left ventricle 24 h after the CP injection. Treatment with CP resulted in increased levels of superoxide (O₂^•−) derived from NADPH-oxidase, upregulation of NOX1 expression, and elevated hydrogen peroxide (H₂O₂) levels and lipoperoxidation. Pretreatment with nebivolol significantly mitigated these pro-oxidative effects. Moreover, nebivolol prevented the increase in COX2 expression induced by CP. Echocardiographic analyses indicated that, despite the molecular changes caused by CP, cardiac function was preserved in the CP-injected mice. In conclusion, nebivolol demonstrates cardioprotective effects against the toxicity of CP by reducing pro-oxidative and pro-inflammatory responses. Thus, nebivolol may represent a novel clinical approach for managing the cardiotoxic effects associated with CP.