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Natural Compounds as Occult Ototoxins? Ginkgo biloba Flavonoids Moderately Damage Lateral Line Hair Cells

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Abstract

Several drugs, including aminoglycosides and platinum-based chemotherapy agents, are well known for their ototoxic properties. However, FDA-approved drugs are not routinely tested for ototoxicity, so their potential to affect hearing often goes unrecognized. This issue is further compounded for natural products, where there is a lack of FDA oversight and the manufacturer is solely responsible for ensuring the safety of their products. Natural products such as herbal supplements are easily accessible and commonly used in the practice of traditional eastern and alternative medicine. Using the zebrafish lateral line, we screened a natural products library to identify potential ototoxins. We found that the flavonoids quercetin and kaempferol, both from the Gingko biloba plant, demonstrated significant ototoxicity, killing up to 30 % of lateral line hair cells. We then examined a third Ginkgo flavonoid, isorhamnetin, and found similar levels of ototoxicity. After flavonoid treatment, surviving hair cells demonstrated reduced uptake of the vital dye FM 1-43FX, suggesting that the health of the remaining hair cells was compromised. We then asked if these flavonoids enter hair cells through the mechanotransduction channel, which is the site of entry for many known ototoxins. High extracellular calcium or the quinoline derivative E6 berbamine significantly protected hair cells from flavonoid damage, implicating the transduction channel as a site of flavonoid uptake. Since known ototoxins activate cellular stress responses, we asked if reactive oxygen species were necessary for flavonoid ototoxicity. Co-treatment with the antioxidant D-methionine significantly protected hair cells from each flavonoid, suggesting that antioxidant therapy could prevent hair cell loss. How these products affect mammalian hair cells is still an open question and will be the target of future experiments. However, this research demonstrates the potential for ototoxic damage caused by unregulated herbal supplements and suggests that further supplement characterization is warranted.

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Acknowledgements

This research was supported by the National Institutes of Health award R15DC013900 and Washington State University Vancouver funds to A.B.C. We thank Matthew Kruger, Travis Long, and Heather Wiedenhoft for experimental assistance and Chris Riso and Alex Young for fish husbandry expertise. We also thank two anonymous reviewers for the comments that significantly improved the manuscript.

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Authors and Affiliations

  1. College of Arts and Sciences, Washington State University, Vancouver, WA, 98686, USA

    Sarah Neveux, Nicole K. Smith, Anna Roche & Allison B. Coffin

  2. Camas High School, Camas, WA, 98607, USA

    Anna Roche

  3. RTI International, Research Triangle Park, NC, 27709, USA

    Bruce E. Blough & Wimal Pathmasiri

  4. Department of Integrative Physiology and Neuroscience, Washington State University, Vancouver, WA, 98686, USA

    Allison B. Coffin

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  1. Sarah Neveux
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Correspondence to Nicole K. Smith or Allison B. Coffin.

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Sarah Neveux and Nicole K. Smith contributed equally to this work.

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Neveux, S., Smith, N.K., Roche, A. et al. Natural Compounds as Occult Ototoxins? Ginkgo biloba Flavonoids Moderately Damage Lateral Line Hair Cells. JARO 18, 275–289 (2017). https://doi.org/10.1007/s10162-016-0604-6

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