PJ34 protects hair cells from cisplatin‐induced ototoxicity in vitro: possible relation to inhibition of PARP-1-AIF-mediated parthanatos

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PARP inhibitor PJ34 exerts anti-inflammatory and neuroprotective effects by regulating parthanatos. The objective of this study was to investigate the protective effects of PJ34 on auditory cells against cisplatin-induced injury as well as to explore the potential mechanisms involved in its action. Flow cytometry, immunofluorescence staining, Western blot, Mitochondrial membrane potential (MMP) assay and MitoSox red staining were employed to detect apoptosis, determine the expression levels of cleaved caspase-3, PARP-1, and AIF, measure MMP levels, and evaluate the levels of reactive oxygen species (ROS) in the corresponding HEI-OC1 auditory cells, ovarian cancer cell lines, and mouse cochlear hair cells. Our results demonstrated that exposure to 30 μM cisplatin activated cleaved caspase-3, PARP-1, and induced AIF nuclear translocation, leading to a decrease in MMP and an increase in ROS levels, which induced auditory cell death. Treatment with 2.5 μM PJ34 attenuated the hyperactivation of PARP-1 and nuclear translocation of AIF after cisplatin exposure, rescued the reduction of MMP and ROS accumulation, and thus protected auditory cells from cisplatin-induced cellular damage. Furthermore, PJ34 enhanced the sensitivity of ovarian cancer cell lines to cisplatin treatment. In conclusion, our findings suggest that PJ34 may attenuate cisplatin-induced hair cell death by regulating PARP-1-mediated parthanatos. Interestingly, PJ34 shows promise as a potential novel therapeutic agent for the prevention and/or treatment of cisplatin-induced ototoxicity.

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