Neurotoxicity Research

, Volume 24, Issue 3, pp 307–319

Salicylate Selectively Kills Cochlear Spiral Ganglion Neurons by Paradoxically Up-regulating Superoxide

Original Article

DOI: 10.1007/s12640-013-9384-5

Cite this article as:
Deng, L., Ding, D., Su, J. et al. Neurotox Res (2013) 24: 307. doi:10.1007/s12640-013-9384-5

Abstract

Aspirin and its active ingredient salicylate are potent antioxidants that have been reported to be neuro- and otoprotective. However, when consumed in large quantities, these drugs can cause temporary hearing loss and tinnitus. Moreover, recent studies indicate that after several days of treatment, salicylate selectively destroys the spiral ganglion neurons and auditory nerve fibers that relay sounds from the sensory hair cells to the brain. Why salicylate selectively damages spiral ganglion neurons while sparing the hair cells and supports cells is unclear. Here we show that high dose of salicylate trigger an apoptotic response in spiral ganglion neurons characterized morphologically by soma shrinkage and nuclear condensation and fragmentation plus activation of extrinsic initiator caspase-8 and intrinsic initiator caspase-9 several days after the onset of drug treatment. Salicylate treatment triggered an upsurge in the toxic superoxide radical only in spiral ganglion neurons, but not in neighboring hair cells and support cells. Mn TMPyP pentachloride, a cell permeable scavenger of superoxide blocked the expression of superoxide staining in spiral ganglion neurons and almost completely blocked the damage to the nerve fibers and spiral ganglion neurons. NMDA receptor activation is known to increase neuronal superoxide levels. Since NMDA receptors are mainly found on spiral ganglion neurons and since salicylate enhances NMDA receptor currents, the selective killing of spiral ganglion neurons is likely a consequence of enhanced and sustained activation of NMDA receptors by salicylate.

Keywords

Salicylate Spiral ganglion Superoxide Hair cells Apoptosis Caspase 

Abbreviations

DHE

Dihydroethidium (DHE)

HBSS

Hank’s balanced salt solution

IHC

Inner hair cell

PyP

Mn TMPyP pentachloride

OHC

Outer hair cell

PBS

Phosphate-buffered saline

SGN

Spiral ganglion neuron

SS

Sodium salicylate

TUNEL

Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Center for Hearing and DeafnessUniversity at BuffaloBuffaloUSA
  2. 2.Department of Otolaryngology Head and Neck Surgery, First Affiliated HospitalGuangxi Medical UniversityGuangxiChina

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