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Hearing Loss and Otopathology Following Systemic and Intracerebroventricular Delivery of 2-Hydroxypropyl-Beta-Cyclodextrin

  • Scott Cronin
  • Austin Lin
  • Kelsey Thompson
  • Mark Hoenerhoff
  • R. Keith DuncanEmail author
Research Article

Abstract

Cyclodextrins are simple yet powerful molecules widely used in medicinal formulations and industry for their ability to stabilize and solubilize guest compounds. However, recent evidence shows that 2-hydroxypropyl-β-cyclodextrin (HPβCD) causes severe hearing loss in mice, selectively killing outer hair cells (OHC) within 1 week of subcutaneous drug treatment. In the current study, the impact of HPβCD on auditory physiology and pathology was explored further as a function of time and route of administration. When administered subcutaneously or directly into cerebrospinal fluid, single injections of HPβCD caused up to 60 dB threshold shifts and widespread OHC loss in a dose-dependent manner. Combined dosing caused no greater deficit, suggesting a common mode of action. After drug treatment, OHC loss progressed over time, beginning in the base and extending toward the apex, creating a sharp transition between normal and damaged regions of the cochlea. Administration into cerebrospinal fluid caused rapid ototoxicity when compared to subcutaneous delivery. Despite the devastating effect on the cochlea, HPβCD was relatively safe to other peripheral and central organ systems; specifically, it had no notable nephrotoxicity in contrast to other ototoxic compounds like aminoglycosides and platinum-based drugs. As cyclodextrins find expanding medicinal applications, caution should be exercised as these drugs possess a unique, poorly understood, ototoxic mechanism.

Keywords

cochlea hearing loss ototoxicity cyclodextrin drug delivery 

Notes

Acknowledgments

The authors thank Ms. Diane Prieskorn for technical assistance in establishing mouse stereotactic injections and Mr. Jong-Seung Kim for assistance with plastic sections of the inner ear. This work was supported by grant awards from the Hearing Health Foundation (S.C.) and NIH-NIDCD P30 DC005188.

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Copyright information

© Association for Research in Otolaryngology 2015

Authors and Affiliations

  • Scott Cronin
    • 1
    • 2
  • Austin Lin
    • 2
  • Kelsey Thompson
    • 2
  • Mark Hoenerhoff
    • 3
  • R. Keith Duncan
    • 1
    • 2
    Email author
  1. 1.Department of Otolaryngology-Head and Neck SurgeryUniversity of MichiganAnn ArborUSA
  2. 2.Department of Otolaryngology-Head and Neck Surgery, Kresge Hearing Research InstituteUniversity of MichiganAnn ArborUSA
  3. 3.Unit for Laboratory Animal MedicineUniversity of MichiganAnn ArborUSA

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