Mechanisms of hair cell death and protection.
OBJECTIVE
Sensory hair cells are mechanotransducers of the inner ear that are essential for hearing and balance. Hair cell death commonly occurs following acoustic trauma or exposure to ototoxins, such as the aminoglycoside antibiotics and the antineoplastic agent cisplatin. Loss of these inner ear sensory cells can lead to permanent sensorineural hearing loss, balance disturbance, or both. Currently, the only effective clinical intervention is prevention from exposure to known ototoxic insults. To help improve therapeutic strategies, a better understanding of the molecular mechanisms underlying hair cell degeneration is required. Current knowledge of these cell death mechanisms and potential therapeutic targets are discussed in this review.


RESULTS
Studies have shown that caspase-9 and caspase-3 are key mediators of hair cell death induced by noise, aminoglycosides, and cisplatin. The Bcl-2 family consists of a group of proapoptotic and antiapoptotic molecules that act upstream of and regulate caspase activation. Recent studies have shed light on the roles of molecules acting more upstream, including mitogen-activated protein kinases and p53.


CONCLUSIONS
The mechanisms of sensory hair cell degeneration in response to different ototoxic stimuli share a final common pathway: caspase activation. Inhibition of caspases prevents or delays hair cell death and may preserve hearing/balance function. Inhibition of mitogen-activated protein kinases protects against noise-induced and aminoglycoside-induced but not cisplatin-induced hair cell death, which suggests divergent upstream regulatory mechanisms.
Cheng
Alan G
AG
Virginia Merrill Bloedel Hearing Research Center, Department of Otolaryngology-Head and Neck Surgery, University of Washington Medical Center, 1959 NE Pacific Street, Seattle, WA 98195, USA. aglcheng@u.washington.edu
Cunningham
Lisa L
LL
Rubel
Edwin W
EW
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D020169:Caspases / Q000502:physiology; D016923:Cell Death / Q000502:physiology; D002478:Cells, Cultured; D003051:Cochlea / Q000166:cytology*; D019610:Cytoprotection / Q000502:physiology; D016158:Genes, p53 / Q000502:physiology; D006199:Hair Cells, Auditory, Inner / Q000502:physiology*; D018069:Hair Cells, Vestibular / Q000502:physiology*; D006317:Hearing Loss, Noise-Induced / Q000517:prevention & control; D048031:JNK Mitogen-Activated Protein Kinases / Q000502:physiology; D008928:Mitochondria / Q000378:metabolism; D009410:Nerve Degeneration; D051025:bcl-Associated Death Protein / Q000502:physiology
D051025:bcl-Associated Death Protein; D048031:JNK Mitogen-Activated Protein Kinases; D020169:Caspases