Abstract
Side effects of cisplatin, especially dose-dependent nephrotoxicity, are major factors limiting its use in cancer. Boldine ((S)-2, 9-dihydroxy-1, 10-dimethoxy-aporphine) is a natural alkaloid known for its strong antioxidant activity present in leaves/bark of boldo tree (Peumus boldus Molina), a native tree in Chile. Here, we aimed to investigate the nephroprotective effect of boldine and its underlying mechanisms on cisplatin-induced rat renal injury. Thirty Wistar albino rats divided into 5 groups (Control, Cis, Bold.40, Cis + Bold.20, Cis + Bold.40 groups) were used. Rats received boldine (20 or 40 mg/kg/day), or vehicle (saline) intraperitoneal for 14 days and a single dose cisplatin (7 mg/kg, ip) was applied on the 10th day to induce nephrotoxicity. Rats and kidney tissue were weighed to determine kidney index. Blood urea nitrojen (BUN) and creatinine levels, the amount of thiobarbituric acid reactive substances (TBARS, an index of lipid peroxidation), superoxide dismutase (SOD), glutathione peroxidase (GPx) enzyme activities and tumor necrosis factor alpha (TNF-α) levels were measured and histopathologic examination was performed. Inducible nitric oxide synthase (iNOS) and caspase-3 expressions were detected immunohistochemically. Nephrotoxicity induced by cisplatin was apparent by elevated levels of BUN, creatinine, kidney index, TBARS and TNF-α, and decreased body weight, SOD and GPx enzyme levels. Pretreatment with boldine protected the renal function at both boldine doses by fixing the renal damage markers, oxidative stress, caspase-3 and iNOS expression. Histopathological findings supported biochemical findings. Taken together these findings indicate that boldine has promising protective effect against cisplatin nephrotoxicity by improving oxidative stress, inflammation, histopathological alterations and by alleviating caspase 3 expression.
Highlights
Cisplatin, is a chemotherapeutic agent used against variety of cancers such as solid tumors, osteosarcoma, hematological malignancies, lymphoma, pulmonary, gastric, obstetric, urogenital, breast and neck cancers (Ghosh, 2019)
Cisplatin induced nephrotoxicity is closely associated with enhanced production of reactive oxygen species (ROS) and reactive nitrogen species (RNS), increasing lipid peroxidation and decreased antioxidant enzyme activities
nicotinamide adenine dinucleotide phosphate (NADPH) Oxidase 4 (Nox4), an NADPH oxidase, present in kidney tissues has been investigated for its role in kidney diseases (Meng et al, 2018)
Summary
Cisplatin (cis-diamminedichloroplatinum-II), is a chemotherapeutic agent used against variety of cancers such as solid tumors, osteosarcoma, hematological malignancies, lymphoma, pulmonary, gastric, obstetric, urogenital, breast and neck cancers (Ghosh, 2019). Cisplatin induced nephrotoxicity is closely associated with enhanced production of reactive oxygen species (ROS) and reactive nitrogen species (RNS), increasing lipid peroxidation and decreased antioxidant enzyme activities. Inflammation has been reported to play an important role in cisplatin nephrotoxicity (Qin et al, 2019). Produced ROS and RNS stimulate Nuclear Factor kappa B (NF-κB) pathway generating cytokines, enzymes and other mediators of inflammation including, tumor necrosis factor (TNF-α), interleukin-6 (IL-6), interleukin-1 beta (IL1β), cyclooxygenase-2 (COX-2), transforming growth factor-β (TGF-β), and inducible nitric oxide synthase (iNOS) (Kim et al, 2018a; Ueki et al, 2013). In vivo nephrotoxic dose of cisplatin leads to increase of necrosis and apoptosis in the kidney. Cisplatin treated renal epithelial cells activates caspase which has an important role in the apoptosis execution stage (Lee et al, 2001)
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