title: Hearing loss and hair cell death in mice given the cholesterol-chelating agent hydroxypropyl-β-cyclodextrin.
abstract: Cyclodextrins are sugar compounds that are increasingly finding medicinal uses due to their ability to complex with hydrophobic molecules. One cyclodextrin in particular, 2-hydroxypropyl-β-cyclodextrin (HPβCD), is used as a carrier to solubilize lipophilic drugs and is itself being considered as a therapeutic agent for treatment of Niemann-Pick Type C disease, due to its ability to mobilize cholesterol. Results from toxicological studies suggest that HPβCD is generally safe, but a recent study has found that it causes hearing loss in cats. Whether the hearing loss occurred via death of cochlear hair cells, rendering it permanent, was unexplored. In the present study, we examined peripheral auditory function and cochlear histology in mice after subcutaneous injection of HPβCD to test for hearing loss and correlate any observed auditory deficits with histological findings. On average, auditory brainstem response thresholds were elevated at 4, 16, and 32 kHz in mice one week after treatment with 8,000 mg/kg. In severely affected mice all outer hair cells were missing in the basal half of the cochlea. In many cases, surviving hair cells in the cochlear apex exhibited abnormal punctate distribution of the motor protein prestin, suggesting long term changes to membrane composition and integrity. Mice given a lower dose of 4,000 mg/kg exhibited hearing loss only after repeated doses, but these threshold shifts were temporary. Therefore, cyclodextrin-induced hearing loss was complex, involving cell death and other more subtle influences on cochlear physiology.
authors.affiliation: Kresge Hearing Research Institute, Department of Otolaryngology - Head and Neck Surgery, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Crumling
authors.forename: Liqian
authors.initials: L
authors.lastname: Liu
authors.forename: Paul V
authors.initials: PV
authors.lastname: Thomas
authors.forename: Jennifer
authors.initials: J
authors.lastname: Benson
authors.forename: Ariane
authors.initials: A
authors.lastname: Kanicki
authors.forename: Lisa
authors.initials: L
authors.lastname: Kabara
authors.forename: Karin
authors.initials: K
authors.lastname: Hälsey
authors.forename: David
authors.initials: D
authors.lastname: Dolan
authors.forename: R Keith
authors.initials: RK
authors.lastname: Duncan
mesh_terms: D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000818:Animals; D000924:Anticholesteremic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004353:Drug Evaluation, Preclinical; D006198:Hair Cells, Auditory / Q000187:drug effects* / Q000502:physiology; D034381:Hearing Loss / Q000139:chemically induced* / Q000473:pathology; D007263:Infusions, Parenteral; D051379:Mice; D047392:beta-Cyclodextrins / Q000008:administration & dosage / Q000009:adverse effects* / Q000494:pharmacology
chemical_list: D000924:Anticholesteremic Agents; D047392:beta-Cyclodextrins; D000073738:2-Hydroxypropyl-beta-cyclodextrin