Nebivolol protects against cyclophosphamide‐induced nephrotoxicity through modulation of oxidative stress, inflammation, and apoptosis

Abstract

The usefulness of cyclophosphamide (CP) in the treatment of multiple human malignancies and immunological diseases is hindered by the danger of developing nephrotoxicity. The toxic metabolites of CP are suggested to be responsible for oxidative stress resulted from the production of reactive oxygen species (ROS) and stimulation of lipid peroxidation. Nebivolol (NEB) is a third‐generation selective B1 adrenoceptor antagonist, but it has also various pharmacological properties such as anti‐inflammation, anti‐apoptotic, and antioxidant activities. Thus, the present study aims to explore the potential protective effect of NEB against CP‐induced nephrotoxicity. A cumulative dose of CP (75 mg/kg) was administered to albino rats by intraperitoneal injection. The protective effect of NEB was investigated by co‐administration of NEB (10 mg/kg orally daily). Administration of NEB with CP significantly improved renal functions and reduced the oxidative renal changes induced by CP injection. Co‐administration of NEB ameliorated apoptosis and inflammatory markers that were markedly exaggerated by CP. Our results indicated that NEB could be used as a protective agent against CP‐induced nephrotoxicity.

Effect of a Low Dose of Carvedilol on Cyclophosphamide-Induced Urinary Toxicity in Rats—A Comparison with Mesna

“…As expected, mesna significantly reversed the CPX-induced changes, which was confirmed in the kidney score. In contrast to nebivolol [83], carvedilol did not attenuate significantly histological changes caused by CPX in kidneys, except for decreasing incidents of interstitial hemorrhages. It seems, however, that the presence of kidney pathologies does not 100% correlate with kidney function, as carvedilol alleviates CPX-induced changes in serum potassium and creatinine concentrations, which can be interpreted as improvement of kidney function.…”

“…Additionally, in groups receiving CPX, different levels of the swelling tubules were noticed. Similarly, other authors described swelling of proximal convoluted tubules, inflammatory cells infiltration, tubular and glomeruli atrophy, tubular degeneration, and dilatation in Bowman's capsules [76][77][78][79]83]. In contrast to our study, Dobrek et al [47] did not reveal any significant pathology in the rat kidneys after the same intraperitoneal dose of CPX.…”

“…Despite so many published papers, we did not find anything about the action of carvedilol on CPX-induced increase in kidney IL-1β concentration or expression. In one very recently published study by Wanas et al [83], nebivolol, another third-generation beta adrenolytic, decreased the IL-1β level in rat kidneys. Renal toxicity of cyclophosphamide was confirmed by us in histological evaluation.…”

“…We cannot exclude that a longer treatment with a low dose of carvedilol is necessary for the full antioxidant effect to be revealed. Interleukin 1β is an important proinflammatory cytokine and its level is increased after CPX administration in serum [75,76], urinary bladder [69,82], kidney [75,83], and many other tissues [84]. Carvedilol is potent in decreasing IL-1β concentration or mRNA expression in the model of brain I/R injury [85], experimental myocardial infarction [63], drug-induced cardiotoxicity [23,57], diabetes [62], or even in the rat model of periodontitis [22].…”

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

“…More interestingly, the markers of renal and cardiac damage were also altered indicating CYP-induced cardiorenal injury in this study. However, studies have shown that CYP could damage the heart 23 , kidney 4 5 , testis 6 24 , and bladder 3 . In this study, CYP prominently increased levels of urea, creatinine as well as activities of cardiac CK and LDH ( Table 2 and Fig.…”