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.

Intrathecal 2-hydroxypropyl-beta-cyclodextrin in a single patient with Niemann–Pick C1

“…No significant improvement was seen on measurements of pure tone audiometry to suggest that postponing a dose had a significant effect on hearing threshold. The mechanism underlying HP-β-CD mediated ototoxicity is multifactorial, and based on mouse studies includes outer hair cell loss and more subtle changes to the architecture of the cochlear membrane [22]. This mechanism shares some qualities of aminoglycoside-induced ototoxicity.…”

“…A more recent study found that HP-β-CD injected directly into the cisterna magna of cats prevented the onset of pre-symptomatic cerebellar dysfunction but was found to produce an increase in hearing threshold [11, 12]. Intrathecal HP-β-CD was similarly found to produce dose-dependent ototoxicity in mice as well [13]. The only published human studies of HP-β-CD involved the administration of intravenous and then intracerebroventricular HP-β-CD to Japanese patients with advanced disease.…”

Treatment of Niemann–Pick Type C Disease by Histone Deacetylase Inhibitors

“…A clinical trial for HPBCD therapy is currently underway [65]. Significant side effects that have been observed in cat and mouse models of NPC include hearing impairment and lung complications [66].…”

Localization and proteomic characterization of cholesterol-rich membrane microdomains in the inner ear

“…In cats and mice, systemic application of 2-hydroxypropyl-beta-cyclodextrin causes substantial outer hair cell death and hearing loss with no obvious pathology in other systems [27, 89]. The unique sensitivity of the ear to cyclodextrins is perplexing given the ubiquitous distribution of cholesterol in cells throughout the body.…”

“…While only caveolin and BK-type potassium channels have been biochemically identified in DRMs of cochlea [18], there is growing evidence that cholesterol-enriched microdomains may be involved in a wide range of processes in the inner ear, including sensory transduction[20] and cochlear mechanics [21–24]. Moreover, disruption of these microdomains with cholesterol-chelating cyclodextrins causes aberrant electrophysiological behavior [18, 22, 23, 25, 26], while systemic delivery of cyclodextrins causes profound hearing loss and outer hair cell death with no apparent effect on other systems [27]. …”