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Rapamycin Protects Spiral Ganglion Neurons from Gentamicin-Induced Degeneration In Vitro

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Abstract

Gentamicin, one of the most widely used aminoglycoside antibiotics, is known to have toxic effects on the inner ear. Taken up by cochlear hair cells and spiral ganglion neurons (SGNs), gentamicin induces the accumulation of reactive oxygen species (ROS) and initiates apoptosis or programmed cell death, resulting in a permanent and irreversible hearing loss. Since the survival of SGNs is specially required for cochlear implant, new procedures that prevent SGN cell loss are crucial to the success of cochlear implantation. ROS modulates the activity of the mammalian target of rapamycin (mTOR) signaling pathway, which mediates apoptosis or autophagy in cells of different organs. However, whether mTOR signaling plays an essential role in the inner ear and whether it is involved in the ototoxic side effects of gentamicin remain unclear. In the present study, we found that gentamicin induced apoptosis and cell loss of SGNs in vivo and significantly decreased the density of SGN and outgrowth of neurites in cultured SGN explants. The phosphorylation levels of ribosomal S6 kinase and elongation factor 4E binding protein 1, two critical kinases in the mTOR complex 1 (mTORC1) signaling pathway, were modulated by gentamicin application in the cochlea. Meanwhile, rapamycin, a specific inhibitor of mTORC1, was co-applied with gentamicin to verify the role of mTOR signaling. We observed that the density of SGN and outgrowth of neurites were significantly increased by rapamycin treatment. Our finding suggests that mTORC1 is hyperactivated in the gentamicin-induced degeneration of SGNs, and rapamycin promoted SGN survival and outgrowth of neurites.

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Acknowledgments

This work was supported by the 973 Program of China (grant number 2014CB943002), the National Natural Science Foundation of China (grant number 31500841), the Guangdong Natural Science Foundation (grant number 2017A030313178), the Program for Changjiang Scholars and Innovative Research Team in University (IRT16R37), and Medical Scientific Research Foundation of Guangdong Province (grant number A2015445).

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Authors and Affiliations

  1. Department of Physiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China

    Shasha Guo, Nana Xu, Peng Chen, Xiaofei Qi, Cuixian Li & Jie Tang

  2. State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China

    Ying Liu & Sheng Liu

  3. Key Laboratory of Mental Health of the Ministry of Education, Southern Medical University, Guangzhou, China

    Cuixian Li & Jie Tang

  4. Institute of Mental Health, Southern Medical University, Guangzhou, China

    Cuixian Li & Jie Tang

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  1. Shasha Guo
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  2. Nana Xu
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  3. Peng Chen
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  4. Ying Liu
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  7. Cuixian Li
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Correspondence to Cuixian Li or Jie Tang.

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Guo, S., Xu, N., Chen, P. et al. Rapamycin Protects Spiral Ganglion Neurons from Gentamicin-Induced Degeneration In Vitro. JARO 20, 475–487 (2019). https://doi.org/10.1007/s10162-019-00717-3

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