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

View Article: PubMed Central - PubMed

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.

No MeSH data available.


Organ of Corti histology from each of the four cochlear turns of one exemplar guinea pig ears after apical injection of 27 mM HPβCD.Damage was greater in the cochlear base that is tuned to high frequencies.
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pone.0175236.g007: Organ of Corti histology from each of the four cochlear turns of one exemplar guinea pig ears after apical injection of 27 mM HPβCD.Damage was greater in the cochlear base that is tuned to high frequencies.

Mentions: Sensory cells within the organ of Corti were evaluated using light microscopy and serial sections of plastic embedded cochleae (Fig 6). All sensory and non-sensory cells were well preserved in the control and 13 mM HPβCD groups. Effects from treatment with 27 mM HPβCD were variable, ranging from well-preserved to severely damaged outer and inner hair cells. Ears with severe IHC and OHC damage had greater effects at the base than apex (Fig 7). While some of this variability in OHC loss may be attributable to the relatively short time-frame of our acute study, interanimal variability is nevertheless consistent with that reported from Crumling et al. [5] and Cronin et al. [6] who studied the chronic effects of HPβCD treatment. Treatment with MβCD consistently caused severe damage directly to the OHCs and IHCs or the regions around these sensory cells. During the time course of these experiments with HPβCD, MβCD, or artificial perilymph (controls), lateral wall structures, including the spiral ligament fibrocytes, stria vascularis, spiral ganglion neurons did not appear to be altered. Specific morphometry was not performed in these structures, but there was no evidence of stria swelling or fluid leakage, the spiral ligament fibrocytes populated the ligament as in control ears, and there were no signs of myelin unwrapping from the spiral ganglion cell soma or evidence of cell swelling. Histological analysis was not performed for treatment with salicylate as the effects are well known or well-characterized [13, 21].


Direct administration of 2-Hydroxypropyl-Beta-Cyclodextrin into guinea pig cochleae: Effects on physiological and histological measurements
Organ of Corti histology from each of the four cochlear turns of one exemplar guinea pig ears after apical injection of 27 mM HPβCD.Damage was greater in the cochlear base that is tuned to high frequencies.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5383289&req=5

pone.0175236.g007: Organ of Corti histology from each of the four cochlear turns of one exemplar guinea pig ears after apical injection of 27 mM HPβCD.Damage was greater in the cochlear base that is tuned to high frequencies.
Mentions: Sensory cells within the organ of Corti were evaluated using light microscopy and serial sections of plastic embedded cochleae (Fig 6). All sensory and non-sensory cells were well preserved in the control and 13 mM HPβCD groups. Effects from treatment with 27 mM HPβCD were variable, ranging from well-preserved to severely damaged outer and inner hair cells. Ears with severe IHC and OHC damage had greater effects at the base than apex (Fig 7). While some of this variability in OHC loss may be attributable to the relatively short time-frame of our acute study, interanimal variability is nevertheless consistent with that reported from Crumling et al. [5] and Cronin et al. [6] who studied the chronic effects of HPβCD treatment. Treatment with MβCD consistently caused severe damage directly to the OHCs and IHCs or the regions around these sensory cells. During the time course of these experiments with HPβCD, MβCD, or artificial perilymph (controls), lateral wall structures, including the spiral ligament fibrocytes, stria vascularis, spiral ganglion neurons did not appear to be altered. Specific morphometry was not performed in these structures, but there was no evidence of stria swelling or fluid leakage, the spiral ligament fibrocytes populated the ligament as in control ears, and there were no signs of myelin unwrapping from the spiral ganglion cell soma or evidence of cell swelling. Histological analysis was not performed for treatment with salicylate as the effects are well known or well-characterized [13, 21].

View Article: PubMed Central - PubMed

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.

No MeSH data available.