Molecular basis of hair cell loss.

Mechanisms that lead to the death of hair cells are reviewed. Exposure to noise, the use of ototoxic drugs that damage the cochlea and old age are accompanied by hair cell death. Outer hair cells are often more susceptible than inner hair cells, partly because of an intrinsically greater susceptibility; high frequency cells are also more vulnerable. A common factor in hair cell loss following age-related changes and exposure to ototoxic drugs or high noise levels is the generation of reactive oxygen species, which can trigger intrinsic apoptosis (the mitochondrial pathway). However, hair cell death is sometimes produced via an extracellular signal pathway triggering extrinsic apoptosis. Necrosis and necroptosis also play a role and, in various situations in which cochlear damage occurs, a balance exists between these possible routes of cell death, with no one mechanism being exclusively activated. Finally, the numerous studies on these mechanisms of hair cell death have led to the identification of many potential therapeutic agents, some of which have been used to attempt to treat people exposed to damaging events, although clinical trials are not yet conclusive. Continued work in this area is likely to lead to clinical treatments that could be used to prevent or ameliorate hearing loss.