Protection from the Acute Cisplatin-Induced Nephrotoxicity by Simvastatin in Rats

Al-Thamir, S. N. K.,Al-Shalah, H. H., Bairam, A. F. H.
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Keywords : Acute Cisplatin,Nephrotoxicity,Simvastatin in Rats
Medical Journal of Babylon  9:1 , 2014 doi:1812-156X-9-1
Published :2012

Abstract

Background: The usefulness of cisplatin, a potent anti-tumor, is limited by its ability to induce nephrotoxicity. The cellular changes leading to this toxicity are suggested to be mediated by increased free radicals generation and lipid peroxidation. Aim of the study: To investigate the protective properties of simvastatin on cisplatin-induced nephrotoxicity in rats using biochemical and histopa- thological approaches. Material and methods: 35 healthy male Swiss albino rats were used. They were divided into 5 groups (7 animals in each group and all animals supplied with standard food during the experiment): control group (1 ml/kg of normal saline i.p. once daily for 14 days), cisplatin treated group (7.5 mg/kg, i.p. single dose), simvastatin treated group (1 mg/kg, i.p., once daily for 14 days), simvastatin (1 mg/kg) plus cisplatin treated group (i.p., once daily for 7 days before and after cisplatin injection), and simvastatin (2 mg/kg) plus cisplatin treated group (i.p., once daily for 7 days before and after cisplatin injection). Blood samples were collected and used to determine the serum urea, creatinine and total antioxidant status (TAS) levels. kidneys were removed and prepared for histopathological examinations. Results: In simvastatin plus cisplatin treated groups serum urea and creatinine were significantly lower than those of cisplatin-treated group, While serum TAS was increase. These changes occurred in a dose-dependant manner (simvastatin). Histopathological examinations showed a massive damage in the proximal tubules in cisplatin-treated group. No damage was observed in simvastatin treated groups. Conclusion: These data show that simvastatin can provide a protective effect against Acute cisplatin-induced nephrotoxicity. This protective effect of simvastatin may be related to the antioxidant status on the kidney.

Introduction

cisplatin is an antineoplastic drug, administered to cancer patients as a sterile solution. It is widely used for the treatment of several human malignancies (as standard component of treatment regimens) including head and neck cancers [1], testicular cancer [2], small-cell [3] and non-small cell lung cancer [4], ovarian cancer [5], cervical cancer [6] and bladder cancer [7]. The main dose-limiting side effect of cisplatin is nephrotoxicity [8] Cisplatin nephrotoxicity can present in a number of ways. However, the most serious and one of the more common presentations is the acute renal failure which occurs in 25–35% of patients [9]. Several investigators have hypothesized the oxidative stress mechanism of cisplatin induced nephrotoxicity that is related to depletion of the antioxidant defense system [10] and to inhibitory effect of cisplatin on antioxidant enzymes activities [11]. On the other hand, simvistatin which is a structural analogs of HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) can decreased oxidative stress as well as it has a reductase inhibitory effect [12].

Materials and methods

Cisplatin 50mg/dl vial (Ebewe pharma, Austria), Simvastatin 10 mg tablets (Actavis, Barnstable, United Kingdom). All other chemicals were of the highest available analytical grade. After 24hr from the last injection of all treatments, the rats were anesthetized with phenobarbital (50 mg/kg s.c.). Blood samples (3mls) were obtained from each rat by cardiac puncture using disposable syringe. Sera were obtained via centrifugation at 3000 rpm for 10 minutes and preserved at -20 °C until determination of parameters of serum urea, creatinine and TAS by commercially available colorimetric kits Rats abdomen was opened through a midline incision and the kidneys were quickly removed and fixed in 10% formalin for histopathological examination.
Statistical analysis of data: Statistical analyses were performed using SPSS
version 18 (GrraphPad, ISI software, Philadelphia, PA, USA, 1993)
computer program. Data are expressed as means ± standard deviation (M±SD). Multiple comparisons were done using one way ANOVA Bonferroni test. The (p<0.05) level of probability was chosen as a criterion for the lowest level of significance.


Results

Effects of cisplatin and simvastatin treatment on serum urea and creatinine concentrations : According to Figures 1 and 2, serum urea and creatinine levels were significantly (p<0.01) higher in cisplatin-treated group than the controls. Simvastatin produced a significant (p<0.01) and dose dependent reduction in the urea and creatinine concentrations when compared with the cisplatin treated group.

Discussions

Cisplatin is one of the most effective anticancer agents. It is used to treat solid tumors such as testicular, bladder, ovarian, breast and lung cancers [14]. The present study indicated that simvastatin dramatically protected the cisplatin-induced in vivo nephrotoxicity in rat. In the present study, a single dose of cisplatin (7.5 mg/kg, i.p.) induced nephrotoxicity as revealed from the increase in serum urea, creatinine levels and decrease serum TAS as well as by histopathological findings. These changes occurred acutely (24 hours) after cisplatin injection into rats. These results are consistent with those experimentally reported by [15,16]. The main mechanism of cisplatin induced nephrotoxicity is oxidative stress through lipid peroxidation and free radical generation in the tubular cells causing tubular cell necrosis as reported by [17]. The proposed mechanisms by which cisplatin causes oxidative stress are: a. Depletion of the antioxidant defense system [10]. b. Inhibitory effect of cisplatin on antioxidant enzymes activities as catalase (CAT), glutathione peroxidase (GSH-Px) and super oxide dismutase (SOD), [11]. The increase in free radical generation and the decrease in antioxidant defense system results in an increase in serum and renal lipid peroxidation that lead to decrease the level of TAS production in serum and renal tissue. The results of this study confirm the nephro-protective activity of simvastatin, When the rats received simvastatin (1mg and 2mg/kg for 14 days), 7 days before and 7 days after cisplatin injection, the serum urea, creatinine concentrations are significantly lower than that in cisplatin administered group, while the serum TAS is more than that in cisplatin administered group. These results are in agreement with [18, 19].

Conclusions

Simvastatin is able to protect the kidneys against cisplatin-induced acute renal failure. But, before a conclusive statement on potential usefulness of simvastatin as adjunct to the cisplatin therapy, there is a need for further studies including human trials

References

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