Pulmonary, Gastrointestinal and Urogenital Pharmacology
Abrogation of cisplatin-induced nephrotoxicity in mice by alpha lipoic acid through ameliorating oxidative stress and enhancing gene expression of antioxidant enzymes

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Abstract

Cisplatin is chemotherapeutic drug used in treatment of malignancies. However, its clinical utility is limited by nephrotoxicity. The purpose of present study is to investigate biochemical and molecular effects of alpha lipoic acid (ALA) to protect against cisplatin-induced nephrotoxicity in mice. Cisplatin (12 mg/kg/day) was administered i.p. for 4 days. Group of mice were given ALA (20 mg/kg/day) for 18 days. Another set were administered ALA for 4 days before and 14 days after cisplatin intoxication. The results obtained revealed that kidney/body weight ratio of cisplatin-treated mice was increased by + 40%. ALA intake declined the ratio by − 19%. Serum creatinine and urea levels were increased in cisplatin-treated mice by + 375% and + 69%, respectively. These changes were moved to normalcy upon ALA intake. Cisplatin treatment elevated malondialdehyde (MDA) by 27 fold and declined reduced glutathione (GSH) by − 49%. Cisplatin decreased catalase, superoxide dismutase (SOD) and glutathione peroxidase (GPx) enzymes by − 47%, − 49% and − 59%, respectively. ALA decreased the MDA by − 286% and increased the GSH, catalase, SOD and GPx levels by + 60%, + 81%, + 90% and + 38%, respectively. ALA increased mRNA expression of catalase, CuZn SOD and GPx genes near to normalcy compared to cisplatin-treated mice. Cisplatin-treated mice increased caspase-3-activity by + 223%, nitric oxide (NO) by + 74% and inducible nitric oxide synthase (iNOS) by 10 fold. ALA intake declined these changes by − 43%, −45% and − 73%, respectively. ALA may play renoprotective role on cisplatin-induced nephrotoxicity through antioxidant and antiapoptotic mechanisms combined with initiation of mRNA expression of antioxidant genes.

Introduction

Cisplatin and other platinum derivatives are among the most effective chemotherapeutic agents widely used in the treatment of a variety of malignancies, including head and neck, ovarian and testicular cancers (Badary et al., 2005, Rabik and Dolan, 2007). However, the full clinical utility of cisplatin is limited by its nephrotoxicity (Schrier, 2002). Approximately 28 to 36% of patients receiving an initial dose (50–100 mg/m2) of cisplatin develop acute renal failure. The vigorous hydration has not been effective in eliminating cisplatin toxicity. Also, the use of diuretics may complicate the electrolyte disturbance induced by cisplatin. The discontinuation of cisplatin remains the only option in cases of progressive renal failure (Lebwohl and Canetta, 1998).

The mechanism of cisplatin nephrotoxicity remains to be fully elucidated. In addition to direct tubular toxicity in the form of apoptosis and necrosis (Arany and Safirstein, 2003), vascular factors (Luke et al., 1992) and inflammation (Ramesh and Reeves, 2003) that have been implicated in the pathogenesis of cisplatin-mediated nephrotoxicity, several other studies have also demonstrated that cisplatin-induced oxidative stress is involved in the development of renal tubule injury (Chirino and Pedraza-Chaverri, 2009, Pabla and Dong, 2008). The involvement of oxidative stress is further supported by the fact that free radical scavengers and antioxidants prevented cisplatin-induced nephrotoxicity (Dickey et al., 2005, Gulec et al., 2006, Tsuruya et al., 2003, Weijl et al., 2004).

Alpha lipoic acid (ALA) has been proposed as therapeutic agent for treatment or prevention of several ailments such as diabetes, polyneuropathy, cataract, neurodegeneration and nephropathies (Alegre et al., 2010, Amudha et al., 2007a, Amudha et al., 2007b, Takaoka et al., 2002) due to its antioxidant properties (Winiarska et al., 2008). It was reported that, the dietetic supplementation with ALA prevents glomerular injury caused by diabetes mellitus (Takaoka et al., 2002) and protects against drug-induced nephrotoxicity (Abdel-Zaher et al., 2008). The efficacy of ALA has been attributed to the unique properties of lipoate/dihydrolipoate system to scavenger reactive oxygen species and to stimulate the synthesis of other antioxidants, as glutathione (Bilska et al., 2007).

This study was undertaken to gain insight and understand the biochemical and molecular effects of ALA to protect against the cisplatin-induced nephrotoxicity in mice.

Section snippets

Chemicals and kits

Cisplatin was purchased in the form of solution dissolved in dist. H2O under the trade name Platinol® (Bristol-Meyers Squibb Co., USA). ALA and DL-dithiotreitol (DTT) were purchased from Sigma-Aldrich Co., USA. The protein assay kit was purchased from Bio-Rad Laboratories, USA. The nitrate/nitrite assay kit purchased from Cayman Chemical Co., USA. The serum creatinine kit was purchased from Randox Laboratories Ltd., UK. The serum urea kit was purchased from Span Diagnostica Ltd., India. The

Serum enzymes and kidney/body weight ratio

The kidney/body weight ratio of cisplatin-treated mice was significantly increased by + 40% as compared to the normal control group. The ALA intake declined the ratio by − 19% as compared to cisplatin-treated mice (Fig. 1A). The serum creatinine and urea were significantly increased in cisplatin-treated mice by + 375% and + 69%, respectively as compared to the normal control group. The intake of ALA to the cisplatin-treated mice significantly ameliorated these changes and restored the serum

Discussion

It was evident that cisplatin nephrotoxicity occurs as a result of oxidative stress and increased generation of superoxide anion, hydrogen peroxide and hydroxyl radicals due to increased activity of NADPH oxidase, xanthine oxidase and adenosine deaminase (Chirino et al., 2008a, Gulec et al., 2006) that leads to decline in the activity of the antioxidant enzymes (catalase, SOD and GPx), depletion of both the GSH and protein thiols and enhancement of MDA production in renal tissue (Ali et al.,

Conclusion

The results of the present study indicate that, cisplatin induced a state nephrotoxicity through the generation of reactive oxygen and nitrogen species and enhancement the apoptosis as well as decline in the mRNA expression levels of antioxidant genes. ALA may play a renoprotective role on cisplatin-induced nephrotoxicity through antioxidant and antiapoptotic mechanisms concomitant with the initiation of the mRNA expression of antioxidant genes. This study provides persuasive evidence for ALA

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