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Cisplatin-based chemotherapy is responsible for a large number of renal failures, and it is still associated with high rates of mortality today. Oleuropein (OLE) presents a plethora of pharmacological beneficial properties. In this study we investigated whether OLE could provide sufficient protection against cisplatin-induced nephrotoxicity. With this aim, Sprague-Dawley rats were divided into eight groups: control; 7 mg/kg/d cisplatin, 50 mg/kg, 100 mg/kg, and 200 mg/kg OLE; and treatment with OLE for 3 days starting at 24 hours following cisplatin injection. After exposure to the chemotherapy agent and OLE, oxidative DNA damage was quantitated in the renal tissue of experimental animals by measuring the amount of 8-hydroxy-2'-deoxyguanosine (8-OHdG) adducts. Malondialdehyde (MDA) level, total oxidative stress (TOS), and total antioxidant status (TAS) were assessed to determine the oxidative injury in kidney cells. The histology of the kidney was examined using four different staining methods: hematoxylin-eosin (H&E), periodic acid Schiff (PAS), Masson trichrome, and amyloid. In addition, the blood urea nitrogen (BUN), uric acid (UA), and creatinine (CRE) levels were established. Our experimental data showed that tissue 8-OHdG levels were significantly higher in the cisplatin group when compared to the control group. The glomerular cells were sensitive to cisplatin as tubular cells. In addition, treatment with cisplatin elevated the levels of BUN, UA, CRE, and TOS, but lowered the level of TAS compared to the control group. The OLE therapy modulated oxidative stress in order to restore normal kidney function and reduced the formation of 8-OHdG induced by cisplatin. Furthermore, the OLE treatment significantly reduced pathological findings in renal tissue. We demonstrate for the first time that OLE presents significant cytoprotective properties against cisplatin-induced genotoxicity by restoring the antioxidant system of the renal tissue. According to our findings, OLE is a promising novel natural source for the prevention of serious kidney damage in current chemotherapies.

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The current systemic treatments of the various solid tumors involve Cisplatin (CIS)-based chemotherapy. Due to its cytotoxicity, this approach is limited. Moreover, the safety of CIS is only discussed especially in breast and stomach cancers. Therefore, we, for the first time, explored the restorative efficacy of oleuropein (OLE), in stomach and lung injuries induced by CIS. Sprague-Dawley rats were divided into eight groups: control CIS, OLE and CIS + OLE. Single dose of (7 mg/kg) CIS was administered intraperitoneally to CIS and CIS + OLE groups. After 24 h, 50, 100 and 200 mg/kg OLE was given for three consecutive days to OLE and CIS + OLE groups. The 8-OH-dG, total oxidative/antioxidant status (TOS/TAS) and malondialdehyde (MDA) levels were evaluated and histopathological analyses were performed on the studied tissues. The results indicated that CIS significantly increased 8-OH-dG, MDA and TOS levels and caused severe tissue damages. However, high dose of OLE induced a significant decrease in the 8-OH-dG, MDA levels, an increase in TAS levels and it restores CIS-induced tissue damages. We hope that the results of this study will provide an impetus for future studies on novel therapeutic strategies including the protective use of oleuropein in gastric and lung cancers due to chemotherapy.

Indomethacin is generally used in clinical therapeutics as a non-steroidal anti-inflammatory drug.However, its use has been limited due to the gastrointestinal and renal toxic effects of this drug.These toxic effects were associated with not only the inhibition of prostaglandin synthesis but also drug-elevated oxidative stress. To ameliorate these toxicities, natural antioxidants can be used as an alternative and/or combination therapies. Therefore, the current study was conducted to assess the renoprotective effects of oleuropein against indomethacin-induced renal damages. Male Sprague-Dawley rats were pretreated with oleuropein (75, 150, and 300 mg/kg), and then treated with indomethacin (25 mg/kg). To evaluate kidney function, serum blood urea nitrogen, uric acid, and creatinine were measured. In addition, prostaglandin E 2 , tumor necrosis factor-alpha, endothelial nitric oxide synthase, caspase-3, oxidant/antioxidant status, and 8-Oxo-2 0 -deoxyguanosine levels were determined for the antioxidative and anti-inflammatory effects of oleuropein. Tissue sections were also histopathologically assessed. The biochemical and histopathological analysis proved the toxic effects of indomethacin on kidney. However, the pretreatment with oleuropein (300 mg/kg) protects kidney from indomethacin-induced damages. Our study proved that prior administration of oleuropein has renoprotective activity against indomethacin-associated toxicities. K E Y W O R D S8-OHdG, eNOS, histopathologic assessment, oleuropein, prostaglandin E2

The prevalence of cancer, in the world is increasing steadily. Despite intense research efforts, no approved therapy is yet available. Cisplatin is a chemotherapeutic drug but induces acute tissue injury. Oleuropein (OLE) is a major phenolic compound and used as a possible natural antioxidant, antimicrobial, and anticancer agent. We hypothesized that antioxidant activity of OLE may decrease cisplatin-induced oxidative stress and prevent to the development of chemotherapeutic complications including abnormality in hematological condition. Male Sprague Dawley rats were used in the experiments. Rats were randomly assigned to one of eight groups: control group; group treated with i.p. injection in a single dose of 7 mg/kg/day cisplatin; groups treated with 50, 100 and 200 mg/kg/day OLE (i.p.); and groups treated with OLE for 3 days starting at 24 h following cisplatin injection. First, hematological assessment was appreciated between control and experimental groups. Second, total oxidative stress (TOS) and total antioxidant capacity (TAC) levels of blood were measured by biochemical studies. In addition to this, oxidative DNA damage was determined by measuring as increases in 8-hydroxy-deoxyguanosine (8-OH-dG) adducts. The treatment with cisplatin elevated the TOS and 8-OH-dG levels that were then reversed by OLE. Reductions in antioxidant capacity with respect to corresponding controls were also restored by OLE treatment. These findings suggest that the OLE treatment against cisplatin-induced toxicity improves the function of blood cells and helps them to survive in the belligerent environment created by free radicals.

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