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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

Panel A: Cochlear response harmonics recorded with a round window electrode to 90 dB SPL 500 Hz tone bursts. The semi-transparent blue rectangle identifies the 15 minute duration of solution injections into the cochlear apex. The ranking of measurements on the y-axis was determined by the effect of the solution on the amplitude of 3f1 of the cochlear response, with the measurements associated with the smallest effect at the top of the figure progressing to the largest effect at the bottom of the figure. N = 3 for each treatment. Panels B-D: Even and odd order harmonic amplitude measurements expressed as a function of operating point estimates nonlinearities involved with transferring acoustic sound into neural excitation (fTR). Even and odd order distortions from exemplar ears in the control and salicylate groups follow trajectories of the second and third derivative of a function that can describe fTR and are consistent with previous experiments that injected gel into the cochlear apex to cause sustained displacement of the organ of Corti (Panels B&C). Effects from 13 mM HPβCD are unprecedented and cannot be explained by sustained displacement of the organ of Corti or apparent OHC loss (Fig 6C and Fig 6B), but the marked change operating point estimates inform the interpretation of affects fTR are the likely origin of dramatic changes to DPOAE amplitude measurements (Fig 5).
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pone.0175236.g008: Panel A: Cochlear response harmonics recorded with a round window electrode to 90 dB SPL 500 Hz tone bursts. The semi-transparent blue rectangle identifies the 15 minute duration of solution injections into the cochlear apex. The ranking of measurements on the y-axis was determined by the effect of the solution on the amplitude of 3f1 of the cochlear response, with the measurements associated with the smallest effect at the top of the figure progressing to the largest effect at the bottom of the figure. N = 3 for each treatment. Panels B-D: Even and odd order harmonic amplitude measurements expressed as a function of operating point estimates nonlinearities involved with transferring acoustic sound into neural excitation (fTR). Even and odd order distortions from exemplar ears in the control and salicylate groups follow trajectories of the second and third derivative of a function that can describe fTR and are consistent with previous experiments that injected gel into the cochlear apex to cause sustained displacement of the organ of Corti (Panels B&C). Effects from 13 mM HPβCD are unprecedented and cannot be explained by sustained displacement of the organ of Corti or apparent OHC loss (Fig 6C and Fig 6B), but the marked change operating point estimates inform the interpretation of affects fTR are the likely origin of dramatic changes to DPOAE amplitude measurements (Fig 5).

Mentions: Cochlear response harmonics to 90 dB SPL 500 Hz tone bursts were measured from animals in the control, salicylate, and 13 mM HPβCD groups (Fig 8). These are the experimental groups where cochlear response was still present after solution administration. Artificial perilymph injections (control) did not affect even order harmonic distortion (fTR asymmetry, Fig 8A, gray), but caused a small and transient decrease in odd order harmonic amplitude (fTR saturation) at ~18 min. after the injection start (Fig 8A, black). Salicylate caused a slight and brief increase in even order harmonic distortion amplitude immediately after injection (Fig 8A, olive), and a decrease in odd order harmonic amplitude that recovered to levels greater than pre-injection levels. (i.e., and “overshoot”; Fig 8A, green). HPβCD caused opposing effects in even and odd order harmonic distortion. The amplitude of even order harmonics maximally decreased at ~21 min after the injection start. In contrast, the amplitude of odd order harmonics increased to a maximum at ~22 min. Both even and odd order harmonics recovered to near pre-injection levels. We suspect that recovery of even and odd order harmonics, as well as slight recovery of DPOAE amplitudes, may have originated from minimal damage that precedes cell death and causes temporary functional deficit. These effects and recoveries suggest that a function which can describe the sigmoidal, saturating, nonlinearities involved with transferring acoustic sound into neural excitation was morphing during our acute experiments.


Direct administration of 2-Hydroxypropyl-Beta-Cyclodextrin into guinea pig cochleae: Effects on physiological and histological measurements
Panel A: Cochlear response harmonics recorded with a round window electrode to 90 dB SPL 500 Hz tone bursts. The semi-transparent blue rectangle identifies the 15 minute duration of solution injections into the cochlear apex. The ranking of measurements on the y-axis was determined by the effect of the solution on the amplitude of 3f1 of the cochlear response, with the measurements associated with the smallest effect at the top of the figure progressing to the largest effect at the bottom of the figure. N = 3 for each treatment. Panels B-D: Even and odd order harmonic amplitude measurements expressed as a function of operating point estimates nonlinearities involved with transferring acoustic sound into neural excitation (fTR). Even and odd order distortions from exemplar ears in the control and salicylate groups follow trajectories of the second and third derivative of a function that can describe fTR and are consistent with previous experiments that injected gel into the cochlear apex to cause sustained displacement of the organ of Corti (Panels B&C). Effects from 13 mM HPβCD are unprecedented and cannot be explained by sustained displacement of the organ of Corti or apparent OHC loss (Fig 6C and Fig 6B), but the marked change operating point estimates inform the interpretation of affects fTR are the likely origin of dramatic changes to DPOAE amplitude measurements (Fig 5).
© Copyright Policy
Related In: Results  -  Collection

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

pone.0175236.g008: Panel A: Cochlear response harmonics recorded with a round window electrode to 90 dB SPL 500 Hz tone bursts. The semi-transparent blue rectangle identifies the 15 minute duration of solution injections into the cochlear apex. The ranking of measurements on the y-axis was determined by the effect of the solution on the amplitude of 3f1 of the cochlear response, with the measurements associated with the smallest effect at the top of the figure progressing to the largest effect at the bottom of the figure. N = 3 for each treatment. Panels B-D: Even and odd order harmonic amplitude measurements expressed as a function of operating point estimates nonlinearities involved with transferring acoustic sound into neural excitation (fTR). Even and odd order distortions from exemplar ears in the control and salicylate groups follow trajectories of the second and third derivative of a function that can describe fTR and are consistent with previous experiments that injected gel into the cochlear apex to cause sustained displacement of the organ of Corti (Panels B&C). Effects from 13 mM HPβCD are unprecedented and cannot be explained by sustained displacement of the organ of Corti or apparent OHC loss (Fig 6C and Fig 6B), but the marked change operating point estimates inform the interpretation of affects fTR are the likely origin of dramatic changes to DPOAE amplitude measurements (Fig 5).
Mentions: Cochlear response harmonics to 90 dB SPL 500 Hz tone bursts were measured from animals in the control, salicylate, and 13 mM HPβCD groups (Fig 8). These are the experimental groups where cochlear response was still present after solution administration. Artificial perilymph injections (control) did not affect even order harmonic distortion (fTR asymmetry, Fig 8A, gray), but caused a small and transient decrease in odd order harmonic amplitude (fTR saturation) at ~18 min. after the injection start (Fig 8A, black). Salicylate caused a slight and brief increase in even order harmonic distortion amplitude immediately after injection (Fig 8A, olive), and a decrease in odd order harmonic amplitude that recovered to levels greater than pre-injection levels. (i.e., and “overshoot”; Fig 8A, green). HPβCD caused opposing effects in even and odd order harmonic distortion. The amplitude of even order harmonics maximally decreased at ~21 min after the injection start. In contrast, the amplitude of odd order harmonics increased to a maximum at ~22 min. Both even and odd order harmonics recovered to near pre-injection levels. We suspect that recovery of even and odd order harmonics, as well as slight recovery of DPOAE amplitudes, may have originated from minimal damage that precedes cell death and causes temporary functional deficit. These effects and recoveries suggest that a function which can describe the sigmoidal, saturating, nonlinearities involved with transferring acoustic sound into neural excitation was morphing during our acute experiments.

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