Abstract. – BACKGROUND: The anticancer- drug cisplatin (CP) causes nephrotoxicity through different mechanisms, including generation of free radicals. Ellagic acid (EA) is a polyphenolic antiox- idant found in fruits and nuts. AIM: This study aimed to investigate the abili- ty of different doses of EA to ameliorate CP nephrotoxicity in rats. MATERIALS AND METHODS: Animals were randomly divided into six groups and treated with saline; CP alone (6 mg/kg); two doses of EA, both alone (10 and 30 mg/kg) or with CP. RESULTS: Treatment with CP alone reduced body weight, water intake, urine output, and renal total antioxidant and reduced glutathione (GSH) concentrations (p < 0.01). In addition, it increased relative kidney weight, plasma creatinine, and blood urea nitrogen (BUN) concentrations (p < 0.01). However, a dose of 30 mg/kg EA mitigated most of the CP-induced actions, but no effect was seen for the 10 mg/kg dose. Histopathologically, rats given CP+EA30 showed < 25% necrotic le- sions in the renal cortical area compared with > 60% in rats treated with CP alone. Molecular analy- sis showed that clusterin (Clu) mRNA and protein were expressed in all treated groups, meanwhile kidney injury molecule-1 (Kim-1) mRNA and pro- tein were only expressed in the CP and CP+EA treated rats. CONCLUSIONS: EA (30 mg/kg) ameliorated most of the physiological, histological, and bio- chemical markers of CP nephrotoxicity.The mol- ecular findings in this work did not completely tally with the conventional method used. The overexpression of the molecular markers may be related to the EA induced repair mechanism. Key Words: Ellagic acid, Cisplatin, Nephrotoxicity, Rats. Introduction Cisplatin (CP) or cis-diamminedichloroplat- inum II is an inorganic platinum-based antineo- European Review for Medical and Pharmacological Sciences Ellagic acid protects against cisplatin-induced nephrotoxicity in rats: a dose-dependent study N. AL-KHARUSI, H.A. BABIKER*, S. AL-SALAM**, M.I. WALY § , A. NEMMAR***, I. AL-LAWATI*, J. YASIN****, S. BEEGAM*, B.H. ALI* Department of Biochemistry and *Department of Pharmacology, College of Medicine and Health Sciences, § Department of Food Science and Nutrition, College of Agricultural and Marine Sciences, Sultan Qaboos University, Al Khod, Oman **Department of Pathology and ***Department of Physiology, ****Department of Internal Medicine; College of Medicine, UAE University, Al Ain, United Arab of Emirates Corresponding Author: Mostafa I. Waly, Ph.D.; e-mail: waly.mostafa@gmail.com 299 plastic drug used to treat solid tumors such as head and neck, testicular, ovarian, small cell and non-small cell cancers 1 . However, its effective- ness against tumors is limited by its neurotoxici- ty, ototoxicity, nephrotoxicity and bone marrow suppression. The nephrotoxic effect of CP is con- sidered to be one of its major limitations, where it arises in 20-30% of the treated patients, one third of which end up with irreversible kidney damage 2 . Different mechanisms have been reported de- scribing the pathogenesis of CP nephrotoxicity, including the production of nephrotoxic metabo- lites, vascular injury, inflammation, generation of free radicals and apoptotic pathways 1-4 . In gener- al, CP damages the S3 segment of the proximal tubules, where the expression of copper trans- porter receptor1 (Ctr1) and organic cation recep- tor2 (Oct2) is high. These two receptors actively transport CP into the kidney tubules contributing to the fact that the kidney has the highest concen- tration of CP compared to any other organ in the body 4,5 . The accumulated CP enters the cell and causes disturbance to the redox status either by reducing the endogenous antioxidant, such as GSH and NADPH, or by damaging the mito- chondrial inner membrane which releases free radicals such as reactive oxygen species (ROS) and reactive nitrogen species (RNS). The re- leased ROS and RNS induce intrinsic cell death leading to apoptosis 6,7 . Ellagic acid (EA) is a natural polyphenolic compound found in nuts and a wide range of veg- etables and fruits 8 . EA has an antioxidant 9 , anti- cancer 10 , antimutagenic 11 , and anti-inflammatory activity 12,13 . The antioxidant effect of EA on CP- induced cytotoxicity was evaluated by different studies. For example, it was reported that EA (2 mg/kg) can ameliorate CP-induced testicular dam- 2013; 17: 299-310