The Protective Effect of Piperine Against Nephrotoxicity Induced by Cyclophosphamide in Mice

Cyclophosphamide (CP) is an alkylating anticancer drug and one of the most successful drugs with a wide range of clinical activities. This drug has toxic effects on most organs, especially kidney tissue. Piperine, as a flavonoid, has antioxidant, anti-inflammatory, and anti-apoptotic properties. The purpose of the present study is to investigate the antioxidant effect of piperine (PIP) on nephrotoxicity following cyclophosphamide (CP) by tissue, serum, and histopathological biochemical evaluation.

In this experimental study, 48 adult male BALB/c mice aged 6-8 weeks and weighing 30-35 grams were divided into 6 groups, the control group (C), the group receiving cyclophosphamide (CP) with a dose of 200mg/kg, the group receiving piperine (Pip) with a dose of 5mg/kg, the group receiving piperine (Pip) with a dose of 10mg/kg, the group receiving cyclophosphamide and piperine at a dose of 5mg/kg (CP+Pip) and the group receiving cyclophosphamide and piperine with A dose of 10mg/kg (CP+Pip) was used. CP was administered on the third day of the study. Piperine was prescribed for 7 days in the form of pre-treatment and post-treatment. On the eighth day of the study, histochemical (GSH and MDA), histopathology, and serum biochemical evaluations were performed. Then, the data were analyzed with GraphPad Prism software one-way ANOVA and Tukey's post hoc tests.

CP induced oxidative stress with a significant decrease in GSH level (P<0.001) and increased MDA level (P<0.0001). On the other hand, administration of PIP with two doses of 5 and 10 mg/kg in mice receiving CP could significantly reduce the amount of MDA (respectively: P˂0.001, P˂0.001) and increase the amount of GSH compared to the mice that only received CP (respectively: P˂0.05, P˂0.05). In mice receiving CP, a significant increase (P<0.05) in the amount of urea and creatinine was shown compared to mice in the control group. In contrast, groups treated with piperine (5 and 10 mg/kg body weight) before and after CP administration significantly (P<0.0001) improved the kidney damage towards normalization compared to mice treated with CP alone and histopathological evaluation confirmed this finding. The effect of piperine was seen in a dose-dependent manner in this study. Thus, in the group treated with cyclophosphamide, the loss of epithelial cells and the widening of the lumen of the distal and proximal convoluted tubules, the contraction of the glomerular network, and the expansion of Bowman's capsule between the visceral and parietal layers were seen. The administration of piperine improved these changes, and the 5 mg/kg dose showed a more effective role.

The general results of the present study showed that before and after the administration of piperine in rats treated with CP, it reduces nephrotoxicity caused by CP and has a positive effect on improving kidney function in connection with its antioxidant effect. Piperine can be suggested as a potential candidate for cancer patients undergoing chemotherapy.