Curcumin protects against the age-related hearing loss by attenuating apoptosis and senescence via activating Nrf2 signaling in cochlear hair cells

Age-related hearing loss (ARHL) is a most widespread neurodegenerative disease affecting the elderly population, but effective pharmacological treatments remain limited. Curcumin is a bioactive compound of Curcuma longa with antioxidant properties. Herein, we looked into the effects of curcumin on the H2O2-induced oxidative stress in cochlear hair cells and hearing function in an ARHL animal model (C57BL/6J mice). We found that pretreatment of curcumin could attenuate H2O2-induced apoptosis and cell senescence in auditory hair cells and prevent mitochondrial function dysfunction. More specifically, Western blot and luciferase activity assay showed that curcumin activated the nuclear translocation of Nrf2, which in turn triggered the activation of its downstream target gene Heme Oxygenase1 (HO-1). The enhanced Nrf2 and HO-1 activity by curcumin was blocked by the AKT inhibitor LY294002, indicating the protective effect of curcumin was mainly achieved by activating Nrf2/HO-1 through the AKT pathway. Furthermore, the knockdown of Nrf2 with siRNA diminished the protective effects of Nrf2 against apoptosis and senescence, consolidating the pivotal role of Nrf2 in the protective effect of curcumin on auditory hair cells. More importantly, curcumin (10 mg/kg/d) could attenuate progressive hearing loss in C57BL/6J mice, as evident from the reduced threshold of auditory nerve brainstem response. Administration of curcumin also elevated the expression of Nrf2 and reduced the expression of cleaved-caspase-3, p21, and γ-H2AX in cochlear. This study is the first to demonstrate that curcumin can prevent oxidative stress-induced auditory hair cell degeneration through Nrf2 activation, highlighting its potential therapeutic value in preventing ARHL.