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      The Role of Magnesium Supplementation in Cisplatin-induced Nephrotoxicity in a Rat Model: No Nephroprotectant Effect

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          Abstract

          Objectives:

          Cisplatin (CP) is used as the commonest drug to treat solid tumors. It is accompanied by a nephrotoxicity side effect. The main objective of this study is to investigate the protective role of magnesium (Mg) supplementation in CP-induced nephrotoxicity in a rat model.

          Methods:

          Twenty-nine Wistar rats were randomly assigned to four groups (1–4). Groups 1–3 received 20, 80, and 200 mg/kg magnesium sulfate respectively, for 10 days, but on day 3, a single dose of CP (7 mg/kg, i.p.) was also injected. Group 4 (positive control group) received the same regimen of Groups 1–3 except saline instead magnesium sulfate. One week after CP administration, blood samples were obtained and all animals were killed for kidney histopathological investigations.

          Results:

          All CP-treated animals lost weight, and the percentage of weight loss in Group 1 (low dose Mg sulfate treated) was significantly higher compared with the positive control group (Group 4, P < 0.05). The increase in blood urea nitrogen (BUN) and creatinine (Cr) levels in serum in Group 1 were more than those in other groups ( P < 0.05). No statistical differences were observed in serum magnesium, nitrite, and total protein levels among the groups. The kidney tissue damage in Groups 1–3 was not significantly different when compared with Group 4. Moreover, the kidney and testis weights in Group 1 were significantly greater than those in the positive control group ( P < 0.05).

          Conclusion:

          Regarding the BUN and Cr levels in the serum, kidneys weight, and the histopathological study, the low dose of Mg supplementation intensifies kidney toxicity and renal dysfunction in CP-induced nephrotoxicity in the rat model. However, the protective role of Mg with moderate and high doses is not certain.

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          Most cited references46

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          Biochemical modulation of Cisplatin mechanisms of action: enhancement of antitumor activity and circumvention of drug resistance.

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            Cisplatin-induced nephrotoxicity is associated with oxidative stress, redox state unbalance, impairment of energetic metabolism and apoptosis in rat kidney mitochondria.

            The clinical use of cisplatin (cis-diamminedichloroplatinum II) is highly limited by its nephrotoxicity. The precise mechanisms involved in cisplatin-induced mitochondrial dysfunction in kidney have not been completely clarified. Therefore, we investigated in vivo the effects of cisplatin on mitochondrial bioenergetics, redox state, and oxidative stress as well as the occurrence of cell death by apoptosis in cisplatin-treated rat kidney. Adult male Wistar rats weighing 200-220 g were divided into two groups. The control group (n = 8) was treated only with an intraperitoneal (i.p.) injection of saline solution (1 ml per 100 g body weight), and the cisplatin group (n = 8) was given a single injection of cisplatin (10 mg/kg body weight, i.p.). Animals were sacrificed 72 h after the treatment. The cisplatin group presented acute renal failure characterized by increased plasmatic creatinine and urea levels. Mitochondrial dysfunction was evidenced by the decline in membrane electrochemical potential and the substantial decrease in mitochondrial calcium uptake. The mitochondrial antioxidant defense system was depleted, as shown by decreased GSH and NADPH levels, GSH/GSSG ratio, and increased GSSG level. Moreover, cisplatin induced oxidative damage to mitochondrial lipids, including cardiolipin, and oxidation of mitochondrial proteins, as demonstrated by the significant decrease of sulfhydryl protein concentrations and increased levels of carbonylated proteins. Additionally, aconitase activity, which is essential for mitochondrial function, was also found to be lower in the cisplatin group. Renal cell death via apoptosis was evidenced by the increased caspase-3 activity. Results show the central role of mitochondria and the intensification of apoptosis in cisplatin-induced acute renal failure, highlighting a number of steps that might be targeted to minimize cisplatin-induced nephrotoxicity.
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              Renal protection with magnesium subcarbonate and magnesium sulphate in patients with epithelial ovarian cancer after cisplatin and paclitaxel chemotherapy: a randomised phase II study.

              The aim of this study was to examine the effect of magnesium supplementation on nephrotoxicity accompanying standard cisplatin-based chemotherapy in patients with epithelial ovarian cancer (EOC). A double-blind, placebo-controlled, randomised study was conducted in which study arm magnesium sulphate (5 g) was administered before each course of standard chemotherapy with paclitaxel (135 mg/m(2)/24 h) plus cisplatin (75 mg/m(2)) every 3 weeks in patients with EOC. Magnesium subcarbonate (500 mg), three times per day orally, was administered during the treatment intervals. The control arm was administered a placebo instead of both magnesium salts. Magnesium serum levels (sMg) and GFR markers: serum levels of creatinine (sCr), Cockroft-Gault (ClCG) and Modification Diet of Renal Disease (MDRD) formulae were recorded before each cycle, and 3 weeks after the sixth course. 41 EOC patients were randomised and 40 were eligible. sMg varied significantly between the supplemented and placebo groups (p<0.0001). The control group showed a significantly greater decrease of GFR assessed by: sCr (p=0.0069), ClCG (p=0.0077) and MDRD (p=0.032) formulae compared with the magnesium supplemented group. These results demonstrate the nephroprotective effect of magnesium supplementation during chemotherapy with cisplatin.
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                Author and article information

                Journal
                Int J Prev Med
                Int J Prev Med
                IJPVM
                International Journal of Preventive Medicine
                Medknow Publications & Media Pvt Ltd (India )
                2008-7802
                2008-8213
                September 2012
                : 3
                : 9
                : 637-643
                Affiliations
                [1 ]Water and Electrolytes Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
                [2 ]Department of Internal Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
                [3 ]Kidney Diseases Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
                [4 ]Department of Physiology, Isfahan University of Medical Sciences, Isfahan, Iran
                [5 ]Department of Clinical Pathology, Isfahan University of Medical Sciences, Isfahan, Iran
                Author notes
                Correspondence to: Prof. Mehdi Nematbakhsh, Water and Electrolytes Research Center, Isfahan University of Medical Sciences, Isfahan, Iran. E-mail: nematbakhsh@ 123456med.mui.ac.ir
                Article
                IJPVM-3-637
                3445280
                23024853
                6810ddc6-9353-4cd0-b9d5-a08f41f7f527
                Copyright: © International Journal of Preventive Medicine

                This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 11 April 2012
                : 05 June 2012
                Categories
                Original Article

                Health & Social care
                cisplatin,magnesium,rat,nephrotoxicity
                Health & Social care
                cisplatin, magnesium, rat, nephrotoxicity

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