Multifunctional Redox Modulators Protect Auditory, Visual, and Cognitive Function

Significance: Oxidative stress contributes to vision, hearing and neurodegenerative disorders. Currently, no treatments prevent these disorders; therefore, there is an urgent need for redox modulators that can prevent these disorders. Recent Advances: Oxidative stress is associated with the generation of reactive oxygen species (ROS) and reactive nitrogen species, metal dyshomeostasis, and mitochondrial dysfunction. Here, we discuss the role that oxidative stress and metal dyshomeostasis play in hearing loss, visual impairments, and neurodegeneration and discuss the benefits of a new class of multifunctional redox modulators (MFRMs) that suppress sensory and neural degeneration. MFRMs not only reduce free radicals but also independently bind transition metals associated with the generation of hydroxyl radicals. The MFRMs redistribute zinc from neurotoxic amyloid beta zinc (A beta:Zn) complexes to the cytoplasm, facilitating the degradation of A beta plaques by matrix metalloprotease-2 (MMP-2). Although MFRMs bind copper (Cu1+, Cu2+), iron (Fe2+, Fe3+), zinc (Zn2+), and manganese (Mn2+), they do not deplete free cytoplasmic Zn+2 and they protect mitochondria from Mn+2-induced dysfunction. Oral administration of MFRMs reduce ROS-induced cataracts, protect the retina from light-induced degeneration, reduce neurotoxic A beta:Zn plaque formation, and protect auditory hair cells from noise-induced hearing loss. Critical Issues: Regulation of redox balance is essential for clinical efficacy in maintaining sensory functions. Future Directions: Future use of these MFRMs requires additional pharmacokinetic, pharmacodynamics, and toxicological data to bring them into widespread clinical use. Additional animal studies are also needed to determine whether MFRMs can prevent neurodegeneration, dementia, and other forms of vision and hearing loss.