2-Hydroxypropyl-β-cyclodextrin Ototoxicity in Adult Rats: Rapid Onset and Massive Destruction of Both Inner and Outer Hair Cells Above a Critical Dose

Abstract

2-hydroxypropyl-β-cyclodextrin (HPβCD), a cholesterol chelator, is being used to treat diseases associated with abnormal cholesterol metabolism such as Niemann-Pick C1 (NPC1) However, the high doses of HPβCD needed to slow disease progression may cause hearing loss. Previous studies in mice have suggested that HPβCD ototoxicity results from selective outer hair cells (OHC) damage. However, it is unclear if HPβCD causes the same type of damage or is more or less toxic to other species such as rats, which are widely used in toxicity research.To address these issues, rats were given a subcutaneous injection of HPβCD between 500 and 4000 mg/kg. Distortion product otoacoustic emissions (DPOAE), the cochlear summating potential (SP) and compound action potential (CAP) were used to assess cochlear function followed by quantitative analysis of OHC and inner hair cell (IHC) loss. The 3000 and 4000 mg/kg doses abolished DPOAE and greatly reduced SP and CAP amplitudes. These functional deficits were associated with nearly complete loss of OHC as well as ~80% IHC loss over the basal two-thirds of the cochlea. The 2000 mg/kg dose abolished DPOAE and significantly reduced SP and CAP amplitudes at the high frequencies. These deficits were linked to OHC and IHC losses in the high-frequency region of the cochlea. Little or no damage occurred with 500 or 1000 mg/kg of HPβCD. The HPβCD-induced functional and structural deficits in rats occurred suddenly, involved damage to both IHC and OHC and was more severe than that reported in mice.Terms of use and reuse: academic research for non-commercial purposes, see here for full terms. http://www.springer.com/gb/openaccess/authors-rights/aam-terms-v1

Spatiotemporal Developmental Upregulation of Prestin Correlates With the Severity and Location of Cyclodextrin-Induced Outer Hair Cell Loss and Hearing Loss

“…Our procedures for measuring DPOAEs and CAPs have been described in a recent publication ( Liu et al, 2020 ). The rats in Experiment #2 that were treated with a single 4,000 mg/kg dose of HPβCD at P5, P10, or P15 and the saline Control group were evaluated 8-weeks post-treatment.…”

“…Our procedures for recording the CAP are described in a recent publication ( Liu et al, 2020 ). Tone bursts were generated (5 ms duration, 1 ms rise/fall time, cosine2-gated, 2–60 kHz, TDT RX6 Multifunction Processor, 200 kHz sampling rate) and sent to a half-inch condenser microphone/sound source (ACO ½” microphone driven in reverse).…”

“…Much of the previous literature on HPβCD ototoxicity in mice has focused on its early, selective destruction of OHCs with little evidence of damage to IHCs, ANFs, or SGNs (Crumling et al, 2012(Crumling et al, , 2017Takahashi et al, 2016;Zhou et al, 2018). However, recent studies from our lab have revealed that HPβCD unexpectedly causes massive, delayed degeneration of rat IHCs, PCs, ANFs, SGNs, and much of the organ of Corti (Ding et al, 2020;Liu et al, 2020). The abrupt onset of this massive secondary loss of IHCs, ANFs, and SGNs differs from the progressive loss of SGNs seen after most other ototoxic drug insults or traumatic noise exposures (Koitchev et al, 1982;Bichler et al, 1983;Yagi et al, 2000;Lin et al, 2011).…”

“…However, when npc1 –/– mice are treated with high systemic doses of HPβCD, the compound overcomes the cholesterol transport deficits allowing the release of excess sterols thereby alleviating symptoms ( Liu et al, 2010 ; Ramirez et al, 2010 ; Taylor A. M. et al, 2012 ). Although HPβCD slows NPC1 neurodegeneration, the high therapeutic doses employed can cause hearing loss ( Ward et al, 2010 ; Crumling et al, 2012 ; King et al, 2014 ; Cronin et al, 2015 ; Maarup et al, 2015 ; Liu et al, 2020 ). Cyclodextrin-induced hearing loss has an abrupt onset due to the rapid degeneration of outer hair cells (OHC; Crumling et al, 2012 , 2017 ; Cronin et al, 2015 ; Takahashi et al, 2016 ).…”

“…Cyclodextrin-induced hearing loss has an abrupt onset due to the rapid degeneration of outer hair cells (OHC; Crumling et al, 2012 , 2017 ; Cronin et al, 2015 ; Takahashi et al, 2016 ). Over time, the inner hair cells (IHCs), spiral ganglion neurons (SGNs), and auditory nerve fibers (ANFs) eventually degenerate following high-dose cyclodextrin treatment, but the time course over which this occurs is unclear ( Liu et al, 2020 ; Ding et al, 2021 ). Because HPβCD initially destroys only OHCs and because cholesterol modulates OHC electromotility mediated by prestin ( Rajagopalan et al, 2007 ), it was assumed that this selective damage was related to the expression of the electromotile protein prestin located in the plasma membrane along the OHC lateral wall ( Takahashi et al, 2016 ; Crumling et al, 2017 ).…”