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

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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.

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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

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Acknowledgments

Research supported in part by grant from the State Scholarship Fund of China (2011845025 to L.D.), the National Natural Science Foundation of China (30860098, 81060082 to J.S.) and NIH grants (R01DC009091-05; R01DC009219-05 to R.S.).

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Authors and Affiliations

  1. Center for Hearing and Deafness, University at Buffalo, 137 Cary Hall, Buffalo, NY, 14214, USA

    Lili Deng, Dalian Ding, Senthilvelan Manohar & Richard Salvi

  2. Department of Otolaryngology Head and Neck Surgery, First Affiliated Hospital, Guangxi Medical University, Nanning, 530021, Guangxi, China

    Lili Deng & Jiping Su

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  1. Lili Deng
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  2. Dalian Ding
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Correspondence to Jiping Su or Richard Salvi.

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Deng, L., Ding, D., Su, J. et al. Salicylate Selectively Kills Cochlear Spiral Ganglion Neurons by Paradoxically Up-regulating Superoxide. Neurotox Res 24, 307–319 (2013). https://doi.org/10.1007/s12640-013-9384-5

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