Protective effects of 1,2,3-triazole derivative KPR-A020 against cisplatin-induced ototoxicity in murine cochlear cultures

Cisplatin (cis-diaminedichloridoplatinum(II), cis-[PtCl2(NH3)(2)]) is an effective chemotherapeutic agent in the treatment of several types of malignant solid tumors but its clinical use is associated with ototoxicity. Several studies have investigated the effect of antioxidants on cisplatin-induced ototoxicity in mice. The triazole KPR-A020 has been shown to play a protective role against mitochondrial dysfunction by reducing the production of mitochondrial reactive oxygen species (ROS). The effect of KPR-A020 on cisplatin-induced ototoxicity was examined using cultures of cochlear explants. Healthy mice were randomly divided into 4 groups: control, treated with cisplatin alone (CP), treated with cisplatin and KPR-A020 (CP + KPR-A020), and treated with KPR-A020 alone (KPR-A020). The cochlear explants were harvested for histological and immunohistochemical examinations. Biochemical analyses of the explants revealed that pre-treatment with KPR-A020 prevented an increase in mitochondrial ROS levels. Moreover, the CP + KPR-A020 group showed better hair cell survival than the CP group. Immunohistochemical examinations of cochlear explants stained with anti-caspase-3 revealed greater immunopositivity in the CP group. The CP + KPR-A020 group showed significantly less immunopositivity than the CP group (P < 0.05). Thus, it appears that KPR-A020 protects hair cells in the organ of Corti from cisplatin-induced toxicity by decreasing the production of mitochondrial ROS. The results of this study suggest that KPRA020 can be used as an antioxidant and antiapoptotic agent to prevent hearing loss caused by cisplatin induced-oxidative stress. (C) 2017 Elsevier B.V. All rights reserved.