NADH against noise-induced hearing loss: Evidence from models of "temporary" and "permanent" deafness

Exposure to different types of noise for varying durations can lead to damage in different parts of the auditory pathway, such as synapse and hair cell loss, resulting in temporary or permanent threshold shifts. Noise-induced hearing loss (NIHL) involves intricate mechanisms in its pathogenesis, with oxidative stress and glutamate excitotoxicity considered important factors. Currently, there is a lack of effective drugs for NIHL. This study exhibited noise-induced hidden hearing loss (NIHHL) and noise-induced permanent hearing loss in CBA/CaJ mouse models and found that pre-administration of NADH via intraperitoneal injection effectively mitigated noise-induced damage in both models. NIHHL mice exhibited threshold recovery at 14 days post-exposure but mild sustained synapse loss. NIHL mice developed persistent threshold elevation with irreversible ribbon synapse and outer hair cells (OHC) damage. NADH pretreatment mitigated temporary threshold shifts in the NIHHL model, while in the NIHL model, it reduced threshold elevation, attenuated synapse and OHC loss, and preserved stereocilia bundle integrity. Furthermore, pretreatment with NADH significantly reduced cochlear Ca²⁺ levels and delayed the time to peak Ca²⁺ concentration in NIHL mice. Concurrently, upregulated mGluR expression and dynamic changes in P-PKC levels were observed, with P-PKC exhibiting a trend consistent with Ca²⁺ fluctuations. Additionally, cochlear ROS levels decreased, while NRF2 was rapidly upregulated and underwent nuclear translocation in OHCs, accompanied by enhanced mRNA expression of its downstream antioxidant factors. These results indicated that the mitigation of hearing loss by NADH pretreatment in NIHL mice may involve both the mGluR-PKCCa²⁺ and NRF2 pathways.