Regeneration of Cochlear Synapses by Systemic Administration of a Bisphosphonate

Richard Seist; Mingjie Tong; Lukas D Landegger; Sasa Vasilijic; Hiroshi Hyakusoku; Sachiyo Katsumi; Charles E McKenna; Albert S B Edge; Konstantina M Stankovic

doi:10.3389/fnmol.2020.00087

Regeneration of Cochlear Synapses by Systemic Administration of a Bisphosphonate

Front Mol Neurosci. 2020 Jul 14:13:87. doi: 10.3389/fnmol.2020.00087. eCollection 2020.

Authors

Richard Seist^{1

2

3}, Mingjie Tong^{1

2}, Lukas D Landegger^{1

2

4}, Sasa Vasilijic^{1

2}, Hiroshi Hyakusoku^{1

2

5}, Sachiyo Katsumi^{1

2}, Charles E McKenna⁶, Albert S B Edge^{1

2

7

8}, Konstantina M Stankovic^{1

2

7

8

9}

Affiliations

¹ Eaton-Peabody Laboratories, Department of Otolaryngology - Head and Neck Surgery, Massachusetts Eye and Ear, Boston, MA, United States.
² Department of Otolaryngology - Head and Neck Surgery, Harvard Medical School, Boston, MA, United States.
³ Department of Otorhinolaryngology-Head and Neck Surgery, Paracelsus Medical University, Salzburg, Austria.
⁴ Department of Otorhinolaryngology-Head and Neck Surgery, Medical University of Vienna, Vienna, Austria.
⁵ Department of Otorhinolaryngology, Yokosuka Kyosai Hospital, Kanagawa, Japan.
⁶ Department of Chemistry, University of Southern California, Los Angeles, CA, United States.
⁷ Speech and Hearing Bioscience and Technology Program, Harvard Medical School, Boston, MA, United States.
⁸ Harvard Stem Cell Institute, Cambridge, MA, United States.
⁹ Program in Therapeutic Science, Harvard Medical School, Boston, MA, United States.

Abstract

Sensorineural hearing loss (SNHL) caused by noise exposure and attendant loss of glutamatergic synapses between cochlear spiral ganglion neurons (SGNs) and hair cells is the most common sensory deficit worldwide. We show here that systemic administration of a bisphosphonate to mice 24 h after synaptopathic noise exposure regenerated synapses between inner hair cells and SGNs and restored cochlear function. We further demonstrate that this effect is mediated by inhibition of the mevalonate pathway. These results are highly significant because they suggest that bisphosphonates could reverse cochlear synaptopathy for the treatment of SNHL.

Keywords: auditory nerve; bisphosphonate; cochlear synaptopathy; drug repurposing; hidden hearing loss; mevalonate pathway; noise-induced hearing loss; synapse regeneration.

Abstract

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