Abstract
2-Hyroxypropyl-beta-cyclodextrin (HPβCD) is being used to treat Niemann-Pick C1, a fatal neurodegenerative disease caused by abnormal cholesterol metabolism. HPβCD slows disease progression, but unfortunately causes severe, rapid onset hearing loss by destroying the outer hair cells (OHC). HPβCD-induced damage is believed to be related to the expression of prestin in OHCs. Because prestin is postnatally upregulated from the cochlear base toward the apex, we hypothesized that HPβCD ototoxicity would spread from the high-frequency base toward the low-frequency apex of the cochlea. Consistent with this hypothesis, cochlear hearing impairments and OHC loss rapidly spread from the high-frequency base toward the low-frequency apex of the cochlea when HPβCD administration shifted from postnatal day 3 (P3) to P28. HPβCD-induced histopathologies were initially confined to the OHCs, but between 4- and 6-weeks post-treatment, there was an unexpected, rapid and massive expansion of the lesion to include most inner hair cells (IHC), pillar cells (PC), peripheral auditory nerve fibers, and spiral ganglion neurons at location where OHCs were missing. The magnitude and spatial extent of HPβCD-induced OHC death was tightly correlated with the postnatal day when HPβCD was administered which coincided with the spatiotemporal upregulation of prestin in OHCs. A second, massive wave of degeneration involving IHCs, PC, auditory nerve fibers and spiral ganglion neurons abruptly emerged 4–6 weeks post-HPβCD treatment. This secondary wave of degeneration combined with the initial OHC loss results in a profound, irreversible hearing loss.
Highlights
Cyclodextrins are widely used in many industries because they can encapsulate hydrophobic compounds within a hydrophobic shell (Okamura et al, 2002; Laza-Knoerr et al, 2010; Loftsson and Brewster, 2010)
Several mechanisms have been suggested (Crumling et al, 2017), selective cyclodextrin ototoxicity is believed to be correlated with prestin expression in outer hair cells (OHC) because knockout mice missing this protein are more resistant to cyclodextrin damage than wild type mice (Takahashi et al, 2016) or mutant mice with a non-electromotile form of prestin (Zhou et al, 2018)
The functional deficits observed in our postnatal rats treated with HPβCD were closely correlated with the temporal and spatial upregulation of prestin in OHCs indicating that prestin, or some other unknown factor associated with its expression, is critically important for initiating cyclodextrin-induced OHC loss
Summary
Cyclodextrins are widely used in many industries because they can encapsulate hydrophobic compounds within a hydrophobic shell (Okamura et al, 2002; Laza-Knoerr et al, 2010; Loftsson and Brewster, 2010). 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 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). There was still considerable OHC loss in the apical turn of prestin knockout mice. While these results indicate that prestin is important, other factors may contribute to cyclodextrin ototoxicity
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