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Exposure to loud noises can damage the synapses connecting nerves and hair cells in the cochlea of the ear, causing noise-induced hearing loss that can be permanent. Effective strategies to prevent or reverse this damage and the associated hearing loss are lacking. The coenzyme nicotinamide adenine dinucleotide (NAD+) can protect neurons from damage in vitro, but its activity in vivo has proven difficult to test because the compound degrades quickly in serum and is not readily taken up by cells. A group of researchers found a way around that limitation by testing the effects of the NAD+ precursor nicotinamide riboside (NR), which enters cells much more easily than does NAD+. Administration of NR to C57BL/6 mice, which are highly susceptible to noise-induced hearing loss, boosted levels of NAD+ in the cochlea and prevented damage to cochlear synapses after noise exposure (Cell Metab. 20, 1059–1068; 2014). As a result, the NR-treated mice did not develop short- or long-term noise-induced hearing loss. Notably, they were protected whether NR was administered before or after noise exposure. Administration of NR prior to noise exposure similarly protected mice of two other strains from synaptic damage and resulting hearing loss, indicating that the effects persisted across genetic backgrounds.

The researchers investigated the biochemical mechanism underlying the protective effects of NR and found that they were mediated by the NAD+-dependent mitochondrial protein sirtuin 3 (SIRT3). Transgenic mice overexpressing SIRT3 were resistant to noise-induced hearing loss even in the absence of NR administration, and knockout mice lacking SIRT3 derived no protective benefit from NR administration.

Kevin Brown (University of North Carolina School of Medicine, Chapel Hill) led the study while he was at Weill Medical College (Cornell University, New York, NY). He explained the importance of the findings in a press release: “One of the major limitations in managing disorders of the inner ear, including hearing loss, is there are a very limited number of treatment options. This discovery identifies a unique pathway and a potential drug therapy to treat noise-induced hearing loss.” NR administration may have other clinical applications as well. In a commentary published alongside the article in Cell Metabolism, Charles Brenner (Carver College of Medicine, University of Iowa, Iowa City), who was not associated with the study, wrote, “future experiments are expected to clarify...whether NR can be used to prevent or treat additional neurodegenerative diseases and conditions.”