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Salicylate Initiates Apoptosis in the Spiral Ganglion Neuron of Guinea Pig Cochlea by Activating Caspase-3

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Abstract

Salicylate-induced ototoxicity leading to sensorineural hearing loss (SNHL) and tinnitus is well documented. However, the exact mechanisms are poorly defined. Caspase-3 is a member of the class of effector caspases and has been activated in nearly every model of apoptosis. To examine its role in salicylate-induced injury, we subjected guinea pigs to treatment with a specific inhibitor zDEVD-FMK via the round window niche (RWN) followed by a systemic injection of salicylate at a dose of 200 mg·kg−1·d−1 i.p. for 10 consecutive days. For those animals administered with salicylate, immunohistochemical studies revealed that caspase-3 was activated in the spiral ganglion neurons (SGNs) and method of terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling (TUNEL) to identify neuronal apoptosis showed that fragmented nuclei were distributed in Rosenthal’s canal. Topical administration of the zDEVD-FMK at a concentration of 500 mM blocked caspase-3 activation and had an effect in reducing the number of TUNEL-positive auditory neurons. In contrast, the inhibitor at a concentration of 125 or 250 mM caused no variation in the expression of activated caspase-3, or in the ratio of TUNEL-positive neurons. These results indicate that caspase-3 is a crucial mediator of apoptosis induced by salicylate in the primary auditory neuron in vivo, and suggest that the specific inhibitor at a relatively high concentration may be therapeutically beneficial in salicylate-induced apoptosis.

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Abbreviations

AI:

Apoptosis index

AOD:

Average optical density

APL:

Artificial perilymph

DPOAEs:

Distortion product otoacoustic emission

IHCs:

Inner hair cells

IOD:

Integrated optical density

OC:

The organ of Corti

OHCs:

Outer hair cells

RWN:

Round window niche

SGNs:

Spiral ganglion neurons

SNHL:

Sensorineural hearing loss

TUNEL:

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

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Acknowledgments

This study was supported by National Natural Science Foundation of China (No. 30860312) and China Postdoctoral Science Foundation (No. 20080440819). We thank Mr. Daniel J. Clark for his careful proofreading.

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Authors and Affiliations

  1. Department of Otorhinolaryngology-Head and Neck Surgery, First Affiliated Hospital of Guangxi Medical University, 22# Shuangyong Road, 530021, Nanning, Guangxi, People’s Republic of China

    Hao Feng, Shi-Hua Yin, An-Zhou Tang & Song-Hua Tan

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  1. Hao Feng
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  2. Shi-Hua Yin
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Correspondence to Shi-Hua Yin or An-Zhou Tang.

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Feng, H., Yin, SH., Tang, AZ. et al. Salicylate Initiates Apoptosis in the Spiral Ganglion Neuron of Guinea Pig Cochlea by Activating Caspase-3. Neurochem Res 36, 1108–1115 (2011). https://doi.org/10.1007/s11064-011-0455-9

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