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Some Ototoxic Drugs Destroy Cochlear Support Cells Before Damaging Sensory Hair Cells

Abstract

A wide variety of ototoxic drugs are capable of damaging the sensory hair cells in the mammalian cochlea resulting in permanent hearing loss. However, the toxic properties of these drugs suggest that some could potentially damage cochlear support cells as well. To test the hypothesis, we treated postnatal day three rat cochlear cultures with toxic doses of gentamicin, cisplatin, mefloquine, and cadmium. Gentamicin primarily destroyed the hair cells and disrupted the intercellular connection with the surrounding support cells. Gentamicin-induced hair cell death was initiated through the caspase-9 intrinsic apoptotic pathway followed by activation of downstream executioner caspase-3. In contrast, cisplatin, mefloquine, and cadmium initially damaged the support cells and only later damaged the hair cells. Support cell death was initiated through the caspase-8 extrinsic apoptotic pathway followed later by downstream activation of caspase-3. Cisplatin, mefloquine, and cadmium significantly reduced the expression of actin and laminin, in the extracellular matrix, leading to significant disarray of the sensory epithelium.

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Abbreviations

Cd:

Cadmium

CIS:

Cisplatin

DC:

Deiters cell

ECM:

Extracellular matrix

GM:

Gentamycin

HC:

Hensen cells

IHC:

Inner hair cells

IS:

Inner sulcus

ISC:

Inner sulcus cells

MEF:

Mefloquine

OHC:

Outer hair cells

OS:

Outer sulcus

PC:

Pillar cell

PBS:

Phosphate buffered saline

SC:

Support cells

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Funding

The research is supported in part by a grant from NIOSH (R01OH010235) and in part by the Foundation of Science and Technology Commission of Shanghai Municipality (#15140900900).

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Correspondence to Richard Salvi.

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Ding, D., Zhang, J., Jiang, H. et al. Some Ototoxic Drugs Destroy Cochlear Support Cells Before Damaging Sensory Hair Cells. Neurotox Res 37, 743–752 (2020). https://doi.org/10.1007/s12640-020-00170-8

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  • DOI: https://doi.org/10.1007/s12640-020-00170-8

Keywords

  • Hair cells
  • Support cells
  • Cochlea
  • Apoptosis
  • Necrosis
  • Ototoxicity
  • Caspase