Abstract
Aminoglycoside antibiotics-induced hearing loss is a common sensorineural impairment. Spiral ganglion neurons (SGNs) are first-order neurons of the auditory pathway and are critical for the maintenance of normal hearing. In the present study, we investigated the time-course of morphological changes and the degeneration process of spiral ganglion cells (SGCs) following chronic kanamycin-induced deafness and determined whether the endoplasmic reticulum (ER) stress was involved in the degeneration of SGNs. We detected density changes in SGCs and the expressions of Bip, inositol requirement 1 (IRE1)α, activating transcription factor-6α, p-PERK, p-eIF2α, CHOP, and caspase-12 at each time point after kanamycin treatment. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining was also performed. The number of SGC deletions reached ∼50% at the 70th day after kanamycin administration and the ER of most SGCs were dilated. The expression of p-PERK, p-eIF2α, p-IRE1α, Bip, caspase-12, and Chop was significantly unregulated after kanamycin treatment. The number of SGCs that were positive for both TUNEL and caspase-12 increased from day 7 to 28. Taken together, these data demonstrate that ER stress was involved in kanamycin-induced apoptosis of SGNs. Kanamycin-induced SGN apoptosis is mediated, at least in part, by ER stress-induced upregulation of CHOP and caspase-12.
- Apoptosis
- degeneration process
- endoplasmic reticulum stress
- spiral ganglion neurons
Abbreviations
- ABRs,
- evoked auditory brain stem responses;
- ASK1,
- apoptosis signal regulating kinase 1;
- ATF6,
- activating transcription factor 6;
- CDK1,
- cyclin dependent kinase 1;
- CHOP,
- C/EBP Homologous Protein;
- dUTP,
- 2′-deoxyuridine 5′-triphosphate;
- ER,
- endoplasmic reticulum;
- ERAD,
- Endoplasmic Reticulum Associated Degradation;
- IRE1,
- inositol requirement 1;
- JNK,
- c-Jun N-terminal kinase;
- LSD,
- Least significant difference;
- PERK,
- interferon-induced double stranded RNA-activated protein kinase (PRKR) -like endoplasmic reticulum kinase;
- ROS,
- reactive oxygen species;
- SGCs,
- spiral ganglion cells;
- SGN,
- spiral ganglion neuron;
- SNHL,
- severe sensorineural hearing loss;
- SPL,
- sound pressure level;
- TEM,
- transmission electron microscopy;
- TUNEL,
- terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling;
- UPR,
- unfolded protein response.
- © 2019 The Author(s).
This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY).