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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.


Related in: MedlinePlus

Endocochlear potential (EP) measured from inside the endolymphatic space of the third cochlear turn.The blue rectangle identifies the 15-minute injection. Voltages to the left of the rectangle are the average EP from ~10 minutes before the injection start. Measurement ranks along the y-axis indicate which solution caused the largest effect, smallest effects are at the top of the figure and largest effects at the bottom. Injection of artificial perilymph alone (control) did not affect EP. Injection of 13 mM HPβCD and salicylate caused slight and temporary effects. Treatment with 27 mM HPβCD did not abolish the EP but MβCD caused total abolition. N = 3 for each treatment group.
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pone.0175236.g003: Endocochlear potential (EP) measured from inside the endolymphatic space of the third cochlear turn.The blue rectangle identifies the 15-minute injection. Voltages to the left of the rectangle are the average EP from ~10 minutes before the injection start. Measurement ranks along the y-axis indicate which solution caused the largest effect, smallest effects are at the top of the figure and largest effects at the bottom. Injection of artificial perilymph alone (control) did not affect EP. Injection of 13 mM HPβCD and salicylate caused slight and temporary effects. Treatment with 27 mM HPβCD did not abolish the EP but MβCD caused total abolition. N = 3 for each treatment group.

Mentions: Endocochlear potential (EP) measurements were made in the third cochlear turn (Fig 3). Artificial perilymph injection (control) did not markedly affect the EP. Treatment with 13 mM HPβCD and salicylate caused transient and temporary effects: 13 mM HPβCD caused EP to increase during injection and then returned to pre-injection values during the time immediately after injection while, in contrast, salicylate caused EP to decrease before gradually returning toward pre-injection values. Treatment with 27 mM HPβCD moderately affected the EP, causing transient increases during injection that returned to pre-injection values during the time immediately after injection before markedly declining further. MβCD caused a brief increase in EP then total abolition before the injection was complete. EP changes are mirrored by changes in the magnitude of the silent current, e.g., an EP decrease is consistent with a decrease in the standing current through outer hair cells in silence [27]. The time courses of effects on EP during treatment are not identical to the time courses of effects on CM (cf. Figs 3 and 4), which is consistent with the origin of these measurements being different even though they were made with the same electrode in the endolymphatic space of the third cochlear turn.


Direct administration of 2-Hydroxypropyl-Beta-Cyclodextrin into guinea pig cochleae: Effects on physiological and histological measurements
Endocochlear potential (EP) measured from inside the endolymphatic space of the third cochlear turn.The blue rectangle identifies the 15-minute injection. Voltages to the left of the rectangle are the average EP from ~10 minutes before the injection start. Measurement ranks along the y-axis indicate which solution caused the largest effect, smallest effects are at the top of the figure and largest effects at the bottom. Injection of artificial perilymph alone (control) did not affect EP. Injection of 13 mM HPβCD and salicylate caused slight and temporary effects. Treatment with 27 mM HPβCD did not abolish the EP but MβCD caused total abolition. N = 3 for each treatment group.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0175236.g003: Endocochlear potential (EP) measured from inside the endolymphatic space of the third cochlear turn.The blue rectangle identifies the 15-minute injection. Voltages to the left of the rectangle are the average EP from ~10 minutes before the injection start. Measurement ranks along the y-axis indicate which solution caused the largest effect, smallest effects are at the top of the figure and largest effects at the bottom. Injection of artificial perilymph alone (control) did not affect EP. Injection of 13 mM HPβCD and salicylate caused slight and temporary effects. Treatment with 27 mM HPβCD did not abolish the EP but MβCD caused total abolition. N = 3 for each treatment group.
Mentions: Endocochlear potential (EP) measurements were made in the third cochlear turn (Fig 3). Artificial perilymph injection (control) did not markedly affect the EP. Treatment with 13 mM HPβCD and salicylate caused transient and temporary effects: 13 mM HPβCD caused EP to increase during injection and then returned to pre-injection values during the time immediately after injection while, in contrast, salicylate caused EP to decrease before gradually returning toward pre-injection values. Treatment with 27 mM HPβCD moderately affected the EP, causing transient increases during injection that returned to pre-injection values during the time immediately after injection before markedly declining further. MβCD caused a brief increase in EP then total abolition before the injection was complete. EP changes are mirrored by changes in the magnitude of the silent current, e.g., an EP decrease is consistent with a decrease in the standing current through outer hair cells in silence [27]. The time courses of effects on EP during treatment are not identical to the time courses of effects on CM (cf. Figs 3 and 4), which is consistent with the origin of these measurements being different even though they were made with the same electrode in the endolymphatic space of the third cochlear turn.

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.


Related in: MedlinePlus