Boldine provides protective effect against nephrotoxicity induced by cisplatin in Wistar rats: Role of oxidative stress, inflammation and caspase-3 NERGIZ HACER TURGUT 1, *;HUSEYIN GUNGOR 2 ;MEHMET EKICI 3 ;MUMIN ALPER ERDOGAN 4 ;MEHMET ONDER KARAYIGIT 5 ; HAKI KARA 2 1 Department of Pharmacology, Faculty of Pharmacy, Izmir Katip Celebi University, Izmir, 35620, Turkey 2 Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Cumhuriyet University, Sivas, 58140, Turkey 3 Department of Physiology, Faculty of Veterinary Medicine, Cumhuriyet University, Sivas, 58140, Turkey 4 Department of Physiology, Faculty of Medicine, Izmir Katip Celebi University, Izmir, 35620, Turkey 5 Department of Pathology, Faculty of Veterinary Medicine, Cumhuriyet University, Sivas, 58140, Turkey Key words: Boldine, Caspase-3, Cisplatin nephrotoxicity, Inflammation, Oxidative stress 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. Introduction 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). Besides important anticancer activity, it also has severe adverse effects such as nephrotoxicity, ototoxicity, neurotoxicity and hepatotoxicity, and these side effects limit the use of cisplatin (Dos Santos et al ., 2012). Nephrotoxicity is the most prevalent, severe and dose limiting side effect of cisplatin treatment, and despite preventive measures, one third of patients experience renal damage. Due to its strong renal af finity, cisplatin usually accumulates in renal proximal tubule cells by damaging these cells with cellular necrosis, microvillus decrease and replacement of lysosomes. The concentration of cisplatin in these cells is almost five times the serum concentration which attributes to its dose limiting nephrotoxicity (Manohar and Leung, 2018). Although the molecular mechanism of cisplatin nephrotoxicity is not fully known, recent studies reveal that it is a multi-factor process involving apoptosis, necrosis, ischemia inflammation, oxidative stress and mitochondrial dysfunction (Karasawa and Steyger, 2015; Yilmaz et al ., 2004). *Address correspondence to: Nergiz Hacer Turgut, nergiz.turgut@ikcu.edu.tr Received: 20 November 2021; Accepted: 27 January 2022 BIOCELL ech T Press Science 2022 Doi: 10.32604/biocell.2022.020383 www.techscience.com/journal/biocell This work is licensed under a Creative Commons Attribution 4.0 International License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Published Online: 01 March 2022