Unveiling neural impairment and the underlying molecular mechanisms of cisplatin-induced cochlear damage

BACKGROUND: Cisplatin is a common chemotherapy drug for solid tumors in both adults and children. A significant side effect is sensorineural hearing loss. While previous research has focused on damage to cochlear hair cells caused by cisplatin, its impact on neural damage is still less understood. This study aimed to examine how cisplatin affects cochlear neural structures and the associated molecular mechanisms.METHODS: To this aim, we used male adult Wistar rats treated with cisplatin (12 mg/kg, IP). To assess the detrimental effect of cisplatin treatment we performed functional analysis before and after 3 days from the treatment. Morphological and molecular analyses were performed to examine neuronal damage, primary afferent fiber morphology, and the molecular processes underpinning cisplatin detrimental effects on cochlear tissues.RESULTS: Our functional results showed an increase of the auditory threshold of about 20 dB after cisplatin treatment. Morphological evaluations supported these findings by demonstrating reduced viability of spiral ganglion neurons and decreased density of afferent fibers following cisplatin treatment. At the molecular level, we observed reduced activation of the TrkB receptor, leading to decreased phosphorylation levels of AKT, alongside a significant increase of p75 expression.CONCLUSIONS: Our results reveal that cisplatin treatment induces substantial damage to the cochlea, resulting in hearing impairment. This result is evidenced by decreased neuronal survival and alterations of primary afferent fiber integrity caused by activation of pro-apoptotic pathways. These findings provide insights into the neural damage caused by cisplatin responsible for hearing loss and tinnitus experienced by patients underwent to chemotherapy and highlight potential molecular targets to mitigate cisplatin-induced cochlear toxicity.