Naringin attenuates oxaliplatin‐induced nephrotoxicity and hepatotoxicity: A molecular, biochemical, and histopathological approach in a rat model

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Abstract
Oxaliplatin (OXL) is a significant therapy agent for the worldwide increase in cancer cases. Naringin (4′,5,7‐trihydroxy flavonon 7‐rhamnoglucoside, NRG) has a wide range of biological and pharmacological activities, including antioxidant and anti‐inflammatory potentials. This research aimed to investigate NRG activity in OXL‐induced hepatorenal toxicity. Accordingly, OXL (4 mg/kg b.w.) in 5% glucose was injected intraperitoneally on the first, second, fifth, and sixth days, and NRG (50 and 100 mg/kg b.w.) was given orally 30 min before to treatment. Biochemical, genetic, and histological methods were utilized to investigate the function tests, oxidant/antioxidant status, inflammation, apoptosis, and endoplasmic reticulum (ER) stress pathways in kidney and liver tissues. Administration of NRG demonstrated an antioxidant effect by increasing the activities of OXL‐induced reduced antioxidant enzymes (superoxide dismutase, catalase, and glutathione peroxidase) and decreasing the elevated lipid peroxidation parameter malondialdehyde levels. Nuclear factor‐κB, tumor necrosis factor‐α, interleukin‐1β, and inducible nitric oxide synthase levels increased in OXL administered groups but reduced in NRG‐treated groups. In the OXL‐administered groups, NRG reduced the apoptosis‐inducing factors Caspase‐3 and B‐cell lymphoma 2 (Bcl‐2)‐associated X protein levels, while elevating the antiapoptotic factor Bcl‐2 levels. OXL triggered prolonged ER stress by increasing the levels of ER stress parameters activating transcription factor 6, protein kinase R‐like ER kinase, inositol‐requiring enzyme 1α, and glucose‐regulated protein 78. Therefore, with the NRG administration, this activity was reduced and the ER stress level decreased. Taken together, it was found that OXL induced toxicity by increasing the levels of urea and creatinine, alanine transaminase, aspartate aminotransferase, and alkaline phosphatase activities, inflammation, apoptosis, ER stress, and oxidants in the liver and kidney tissue, and NRG had a protective effect by reversing the deterioration in these pathways.

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