title: Hearing Loss and Otopathology Following Systemic and Intracerebroventricular Delivery of 2-Hydroxypropyl-Beta-Cyclodextrin.
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.
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, University of Michigan, 1500 East Medical Center Drive, Taubman Clinic 1A, Ann Arbor, MI, 48109, USA.|Department of Otolaryngology-Head and Neck Surgery, Kresge Hearing Research Institute, University of Michigan, 1150 West Medical Center Drive, 5323 Medical Science Building I, Ann Arbor, MI, 48109-5616, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Cronin
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Kresge Hearing Research Institute, University of Michigan, 1150 West Medical Center Drive, 5323 Medical Science Building I, Ann Arbor, MI, 48109-5616, USA.
authors.forename: Austin
authors.initials: A
authors.lastname: Lin
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Kresge Hearing Research Institute, University of Michigan, 1150 West Medical Center Drive, 5323 Medical Science Building I, Ann Arbor, MI, 48109-5616, USA.
authors.forename: Kelsey
authors.initials: K
authors.lastname: Thompson
authors.affiliation: Unit for Laboratory Animal Medicine, University of Michigan, North Campus Research Complex, Building 36, Room 178, 2800 Plymouth Road, Ann Arbor, MI, 48103, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Hoenerhoff
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, University of Michigan, 1500 East Medical Center Drive, Taubman Clinic 1A, Ann Arbor, MI, 48109, USA. rkduncan@umich.edu.|Department of Otolaryngology-Head and Neck Surgery, Kresge Hearing Research Institute, University of Michigan, 1150 West Medical Center Drive, 5323 Medical Science Building I, Ann Arbor, MI, 48109-5616, USA. rkduncan@umich.edu.
authors.forename: R Keith
authors.initials: RK
authors.lastname: Duncan
mesh_terms: D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000818:Animals; D001309:Auditory Threshold / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D018072:Hair Cells, Auditory, Outer / Q000187:drug effects* / Q000473:pathology; D034381:Hearing Loss / Q000139:chemically induced*; D007276:Injections, Intraventricular; D051379:Mice; D047392:beta-Cyclodextrins / Q000633:toxicity*
chemical_list: D047392:beta-Cyclodextrins; D000073738:2-Hydroxypropyl-beta-cyclodextrin
keywords: cochlea; cyclodextrin; drug delivery; hearing loss; ototoxicity