Alpha-lipoic acid pretreatment attenuates TNF-α-triggered auditory hair cell damage via Nrf2 signaling-mediated antioxidant activity

Excessive generation of reactive oxygen species (ROS) and proinflammatory cytokines is a pivotal mechanism causing sensorineural hearing loss (SNHL) through damage to auditory hair cells. In particular, high expression levels of tumor necrosis factoralpha (TNF-α) were observed in SNHL. Alpha-lipoic acid (ALA) has demonstrated protective effects against cochlear hair cell damage and hearing deterioration. This study investigated the protective effect of ALA against TNF-α-triggered ototoxicity in auditory hair cells and in a noise-induced hearing loss mouse model. Cells were pretreated with ALA prior to TNF-α treatment, after which cell viability, ROS generation, and nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated antioxidant activity were assessed. In addition, we observed the hearing levels, the number of outer hair cells (OHCs), and Nrf2-related protein expression in ALA-pretreated mice before noise exposure. ALA pretreatment significantly enhanced cell viability, suppressed ROS production, and activated Nrf2-mediated antioxidant activity compared with TNF-α treatment alone. In the animal model, noise-exposed mice exhibited elevated TNF-α expression in cochlear tissues. ALA pretreatment decreased the auditory brainstem response threshold and reduced OHCs damage. Furthermore, ALA administration upregulated Nrf2-related antioxidant protein expression in cochlear tissues. Taken together, these findings suggest that ALA pretreatment confers cytoprotective effects against TNF-α-triggered auditory hair cell damage through activation of the Nrf2 signaling- mediated antioxidant activity.