Direct administration of 2-Hydroxypropyl-Beta-Cyclodextrin into guinea pig cochleae: Effects on physiological and histological measurements

Abstract

2-Hydroxypropyl-Beta-Cyclodextrin (HPβCD) can be used to treat Niemann-Pick type C disease, Alzheimer’s disease, and atherosclerosis. But, a consequence is that HPβCD can cause hearing loss. HPβCD was recently found to be toxic to outer hair cells (OHCs) in the organ of Corti. Previous studies on the chronic effects of in vivo HPβCD toxicity did not know the intra-cochlear concentration of HPβCD and attributed variable effects on OHCs to indirect drug delivery to the cochlea. We studied the acute effects of known HPβCD concentrations administered directly into intact guinea pig cochleae. Our novel approach injected solutions through pipette sealed into scala tympani in the cochlear apex. Solutions were driven along the length of the cochlear spiral toward the cochlear aqueduct in the base. This method ensured that therapeutic levels were achieved throughout the cochlea, including those regions tuned to mid to low frequencies and code speech vowels and background noise. A wide variety of measurements were made. Results were compared to measurements from ears treated with the HPβCD analog methyl-β-cyclodextrin (MβCD), salicylate that is well known to attenuate the gain of the cochlear amplifier, and injection of artificial perilymph alone (controls). Histological data showed that OHCs appeared normal after treatment with a low dose of HPβCD, and physiological data was consistent with attenuation of cochlear amplifier gain and disruption of non-linearity associated with transferring acoustic sound into neural excitation, an origin of distortion products that are commonly used to objectively assess hearing and hearing loss. A high dose of HPβCD caused sporadic OHC losses and markedly affected all physiologic measurements. MβCD caused virulent destruction of OHCs and physiologic responses. Toxicity of HPβCD to OHC along the cochlear length is variable even when a known intra-cochlear concentration is administered, at least for the duration of our acute studies.

Cyclodextrins and Iatrogenic Hearing Loss: New Drugs with Significant Risk

“…The onset of the hearing loss in humans appears to be rapid, which aligns with preclinical reports (Cronin et al, 2015 ; Lichtenhan et al, 2017 ). Some patients reported auditory symptoms (e.g., tinnitus, aural fullness) within hours of the infusion, and loss of OAE and changes in pure-tone thresholds were documented hours after administration.…”

“…One possibility is altered ion homeostasis within the cochlear duct. Direct application of HPβCD into the guinea pig cochlea does not seem to impact endocochlear potential (Lichtenhan et al, 2017 ) and histopathological effects on the mouse lateral wall appear absent (Crumling et al, 2012 ; Cronin et al, 2015 ). However, in many epithelial systems, cyclodextrins effectively disrupt tight-junction barriers (Francis et al, 1999 ; Lynch et al, 2007 ), leading to one of their major uses in drug delivery (epidermal patches).…”

Communication pathways to and from the inner ear and their contributions to drug delivery

“…A patient with Nieman-Pick C1 disorder treated with intrathecal 2-Hydroxypropyl-Beta-Cyclodextrin subsequently developed bilateral high-frequency hearing loss (Maarup et al, 2015) comparable to that seen in in similarly-treated animals (Crumling et al, 2012; Cronin et al, 2015). 2-Hydroxypropyl-Beta-Cyclodextrin is toxic to outer hair cells (Lichtenhan et al, 2017) due to its ability to bind cholesterol. These studies suggest that drug movements between CSF and perilymph across the cochlear aqueduct may not always be insignificant in humans.…”

Complex polymorphisms in endocytosis genes suggest alpha-cyclodextrin as a treatment for breast cancer

“…[ 141 ] Both intracochlear HPβCD and, in particular, MβCD were seen to be ototoxic in Guinea pigs. [ 142 ] This ototoxicity is believed to be due to depriving prestin (SLC26A5 ) in outer hair cells of cholesterol. [ 143 – 145 ]…”