Abstract:

AIM: It was aimed to evaluate in-vivo whether darbepoetin-alpha (DPO) application has a preventive role in the cisplatin-induced ototoxic effect. MATERIALS and METHODS: In the study, four groups were formed using 28 Wistar albino rats. Group 1 (intraperitoneal) IP saline given control group, Group 2 cisplatin (16mg/kg IP single dose), Group 3 DPO (25 μg/kg IP), and Group 4 is the group in which a single dose of 25 μg/kg IP DPO was administered 24 hours before and half an hour after cisplatin administration. Distortion product otoacoustic emission (DPOAE) and brainstem auditory evoked potentials (BAEP) were performed on rats before agent administration and on the 7th day of the experiment. After hearing measurements, the rats were sacrificed. Apoptotic cell death in ear tissue, caspase-3, -8, -9 expression, Inducible Nitric Oxide Synthase (iNOS), Neuronal Nitric Oxide Synthase (nNOS) expression levels, antioxidant Nrf2 (Nuclear factor (erythroid-derived 2)) - like 2) and related Heme oxygenase-1 (HO-1), NAD(P)H quinone oxidoreductase 1 (NQQ1) were studied by immunohistochemical method. Serum glutathione (GSH) and anti-inflammatory TNF-α and IL-1β protein levels were determined using ELISA kits. RESULTS: The hearing loss was detected at all frequencies showing ototoxic effects compared to control in hearing measurements with cisplatin application. In the examinations performed at the immunohistochemical tissue level, structural changes in the inner ear, necrosis, and necroptosis in the brain and nerve tissues were detected in the cisplatin-administered group. The preventive effects of darbepoetin on the inner ear and brain damage induced by cisplatin are detected by apoptotic protein expressions and oxidative stress-related markers, iNOS and nNOS, Nrf-2 and related HO-1, NQO1, serum GSH, and TNF-α and IL-1β proteins. CONCLUSION: In this study, the protective effects of DPO in ototoxicity caused by cisplatin were demonstrated by reducing apoptosis, increasing antioxidant Nrf-2 and target proteins and glutathione levels, and through anti-inflammatory proteins.