Hydroxypropyl-β-cyclodextrin causes massive damage to the developing auditory and vestibular system

2-hydroxypropyl-β-cyclodextrin (HPβCD), a cholesterol chelator used to treat Niemann-Pick C1 (NPC1) lysosomal storage disease, causes hearing loss in mammals by preferentially destroying outer hair cells. Because cholesterol plays an important role in early neural development, it was hypothesized that HPβCD would cause more extensive damage to postnatal cochlear and vestibular structures in than adult rats [1]. This hypothesis was tested by administering HPβCD to adult rats and postnatal day 3 (P3) cochlear and vestibular organ cultures. Adult rats treated with HPβCD developed hearing impairment and outer hair cell loss 3-day post-treatment; damage increased with dose from the high frequency base toward the low-frequency apex. The HPβCD-induced histopathologies were more severe and widespread in cochlear and vestibular cultures at P3 than in adults. HPβCD destroyed both outer and inner hair cells, auditory nerve fibers and spiral ganglion neurons as well as type I and type II vestibular hair cells and vestibular ganglion neurons. The early stage of HPβCD damage involved disruption of hair cell mechanotransduction and destruction of stereocilia. HPβCD-mediated apoptosis in P3 cultures was most-strongly initiated by activation of the extrinsic caspase-8 cell death pathway in cochlear and vestibular hair cells and neurons followed by activation of executioner caspase-3. Thus, HPβCD is toxic to all types of postnatal cochlear and vestibular hair cells and neurons in vitro whereas in vivo it only appears to destroy outer hair cells in adult cochleae. The more severe HPβCD-induced damage in postnatal cultures could be due to greater drug bioavailability in vitro and/or greater vulnerability of the developing inner ear.

 In another study [2] rats were given a subcutaneous injection of HPβCD between 500 and 4000 mg/kg and 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 were more severe than those reported in mice.

Earlier studies have already linked the use of HPβCD to significant hearing loss in several species, including humans [3]. Evidence in mice supports a rapid onset of hearing loss that is dose-dependent. Ototoxicity can occur following central or peripheral drug delivery, with either route resulting in the preferential loss of cochlear outer hair cells (OHCs) within hours of dosing. The long-term impact of HPβCD use as a maintenance drug, and the mechanism(s) of ototoxicity, are still unknown. β-cyclodextrins preferentially target membrane cholesterol, but other lipid species and proteins may be directly or indirectly involved. Moreover, as cholesterol is ubiquitous in cell membranes, it remains unclear why OHCs are preferentially susceptible to HPβCD. It is possible that HPβCD acts upon several targets—for example, ion channels, tight junctions, membrane integrity, and bioenergetics—that collectively increase the sensitivity of OHCs over other cell types.

On the possible mechanism see an earlier post on Cyclodextrin News.

[1] Ding D, Manohar S, Jiang H, Salvi R. Hydroxypropyl-β-cyclodextrin causes massive damage to the developing auditory and vestibular system. Hear Res. 2020; 39, :08073.
doi: 10.1016/j.heares.2020.108073.

[2] Liu, X., Ding, D., Chen, G.-D., Li, L., Jiang, H., & Salvi, R. 2-Hydroxypropyl-β-cyclodextrin Ototoxicity in Adult Rats: Rapid Onset and Massive Destruction of Both Inner and Outer Hair Cells Above a Critical Dose. Neurotoxicity Research 2020; 38, 808-823. doi:10.1007/s12640-020-00252-7

[3] Crumling, M.A., King, K.A., Duncan R.A. Cyclodextrins and Iatrogenic Hearing Loss: New Drugs with Significant Risk. Front. Cell. Neurosci., 2017; 11, 355. https://doi.org/10.3389/fncel.2017.00355