Otoprotective effect of MnTBAP in cisplatin-induced hearing loss

Objective Cisplatin, a life-saving chemotherapeutic drug, causes ototoxicity. Although sodium thiosulfate is used to prevent ototoxicity in pediatric patients, no other intervention has been approved for clinical use against cisplatin-induced hearing loss. Hence, there is an urgent need to identify drugs that prevent cisplatin ototoxicity. Methods CBA/J mice were treated with cisplatin (3 mg/kg, i.p., daily for 5 days), and MnTBAP (10 mg/kg, i.p., daily for 8 days) was used to inhibit cisplatin-induced ototoxicity. Auditory brainstem responses (ABRs) and distortion product otoacoustic emissions (DPOAEs) were recorded before and after treatment to assess hearing loss, while immunohistochemistry with anti-Myosin-VIIa was conducted to examine hair cell loss, with phalloidin to examine spiral ganglion neuron (SGN) loss, and with anti-nitrotyrosine to assess nitrotyrosine levels. Results Cisplatin treatment elevated the nitrotyrosine levels in hair cells and SGNs and increased the loss of these cells in the middle and basal cochlear regions. A negative correlation was observed between cisplatin-induced changes in the hair cell count or SGN density and nitrotyrosine levels. Cisplatin treatment elevated the hearing thresholds, as indicated by the ABRs, and lowered the DPOAE amplitudes, suggesting cisplatin-induced hearing loss. However, MnTBAP cotreatment prevented the cisplatin-induced changes in hearing sensitivity and reversed the morphological changes. Conclusion The otoprotection observed with MnTBAP cotreatment along with the attenuation of cisplatin-induced increase in nitrotyrosine levels in the cochlea indicates its potential as an inhibitor of cochlear nitrative stress and its utility in mitigating cisplatin-induced ototoxicity.