Involvement of Oxidative Stress, Inflammation, and Glutamate in Ototoxicity, and their Attenuation by Simultaneous Activation of Nrf2 and Elevation of Antioxidant Compounds

Diverse groups of ototoxic agents and gene mutation induce hearing disorders. Several studies showed that increased oxidative stress, inflammation, and glutamate are involved in the initiation and progression of hearing disorders. Therefore, reducing these biochemical defects before and after exposure to ototoxic agents may prevent and improve the management of hearing loss. Previous studies with a single agent have yielded variable benefits in hearing disorders. This review briefly presents evidence for the involvement of oxidative stress, inflammation, and glutamate in the initiation and progression of hearing disorders. It proposes a novel concept that simultaneous elevation of the levels of antioxidant enzymes, dietary and endogenous antioxidant compounds, and reduction in the levels of glutamate may be necessary for the optimal benefits in prevention and improved management of hearing disorders. Supplementation with micronutrients can elevate the levels of antioxidant compounds and reduce the levels of glutamate. However, increasing the levels of antioxidant enzymes is complex requiring an activation of the nuclear transcriptional factor-2 (Nrf2). This review briefly describes the regulation of activation of Nrf2, and proposes a micronutrient mixture that can simultaneously activate Nrf2, enhance the dietary and endogenous antioxidant compounds levels, and inhibit the release and toxicity of glutamate for prevention and improved management of hearing loss.