Vindoline mitigates cisplatin-mediated kidney damage by alleviating redox imbalance, apoptosis and inflammation through extracellular signal-regulated kinase pathway modulation.

Abstract

Although cisplatin (CP) is a frequently prescribed medication for the treatment of malignant tumours, its clinical application is restricted by a variety of adverse effects, particularly acute kidney injury. Currently, there are only a limited number of effective pharmacological strategies that can be employed to prevent kidney injury caused by CP. Vindoline is a monoterpene indole alkaloid that functions as both the biosynthetic and synthetic precursor of the therapeutically significant anticancer medications. This study evaluates the effects of vindoline in a rodent model of CP-induced nephrotoxicity and elucidates the underlying mechanisms. Male Wistar rats were categorized into four groups: control, control + vindoline, CP (5 mg/kg), and CP + vindoline (20 mg/kg). The CP group was administered a onetime intraperitoneal injection of CP, while the CP + vindoline group was administered vindoline for 10 days. Renal injury was evaluated through analyses of nephrotic markers like creatinine, urea, and blood urea nitrogen (BUN) by using kit method. Oxidative stress markers like malondialdehyde (MDA), reduced glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT) activities was measured using specific assay kits. Apoptosis-related protein expression (B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (Bax), caspase-3 and 9) in renal tissues was determined via Western blotting method. Our findings indicated that vindoline had the potential to significantly (P<0.05) reduce the levels of BUN and serum creatinine and attenuate CP-induced nephrotoxicity. Additionally, vindoline inhibited CP-induced oxidative stress by decreasing the level of MDA and significantly increasing the activities of GSH, SOD, and CAT (P<0.05). Vindoline attenuated CP-induced mononuclear cell infiltration, decreased (P<0.05) tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), and IL-1β levels, and inhibited nuclear factor kappaB (NF-κB) activation in renal tissues. Further, vindoline mitigated CP-induced apoptosis in renal tissues. Vindoline also considerably reduced p38, ERK1/2, and c-Jun-N-terminal kinase (JNK) expression. The findings indicate that vindoline mitigates CP-mediated nephrotoxicity by regulating oxidative imbalance, inflammation, and apoptosis through the ERK pathway.