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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

Auditory Nerve Overlapped Waveform (ANOW) amplitude measurements.The blue, semi-transparent rectangle identifies the 15 minute duration of apical injections. The values presented on the far left of the figure are average amplitude measurements from the ~10 minutes of data before the injection start. The ranking of measurements on the y-axis corresponds to the effect of the solution, 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. Salicylate, HPβCD, and MβCD treatments caused total abolition of ANOW, but artificial perilymph alone (control) did not. N = 3 for each treatment group.
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pone.0175236.g002: Auditory Nerve Overlapped Waveform (ANOW) amplitude measurements.The blue, semi-transparent rectangle identifies the 15 minute duration of apical injections. The values presented on the far left of the figure are average amplitude measurements from the ~10 minutes of data before the injection start. The ranking of measurements on the y-axis corresponds to the effect of the solution, 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. Salicylate, HPβCD, and MβCD treatments caused total abolition of ANOW, but artificial perilymph alone (control) did not. N = 3 for each treatment group.

Mentions: Auditory Nerve Overlapped Waveform (ANOW) measurements (Fig 2) show that the apical injection technique can treat the apical half of the cochlear spiral, a region that classic round window administration cannot [11]. The ANOW originates from afferent auditory nerve fibers in the apical cochlear half and can quantify low-frequency auditory thresholds [10, 25]. ANOW amplitudes from supra-threshold, 50 dB SPL sound levels were ablated by salicylate, HPβCD, and MβCD treatments, but not by artificial perilymph alone (control; Fig 2). Subtle changes to ANOW from control ears during the time of injection suggest that perhaps some ANOW changes in ears treated with toxic solutions resulted from mechanical disturbances from the fast apical injection approach used for these experiments. Nevertheless, unlike CAPs, ANOW amplitude measurements were fully abolished with all four treatments, consistent with the ANOW being more sensitive than CAPs to cochlear manipulations and diseased states [26].


Direct administration of 2-Hydroxypropyl-Beta-Cyclodextrin into guinea pig cochleae: Effects on physiological and histological measurements
Auditory Nerve Overlapped Waveform (ANOW) amplitude measurements.The blue, semi-transparent rectangle identifies the 15 minute duration of apical injections. The values presented on the far left of the figure are average amplitude measurements from the ~10 minutes of data before the injection start. The ranking of measurements on the y-axis corresponds to the effect of the solution, 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. Salicylate, HPβCD, and MβCD treatments caused total abolition of ANOW, but artificial perilymph alone (control) did not. N = 3 for each treatment group.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0175236.g002: Auditory Nerve Overlapped Waveform (ANOW) amplitude measurements.The blue, semi-transparent rectangle identifies the 15 minute duration of apical injections. The values presented on the far left of the figure are average amplitude measurements from the ~10 minutes of data before the injection start. The ranking of measurements on the y-axis corresponds to the effect of the solution, 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. Salicylate, HPβCD, and MβCD treatments caused total abolition of ANOW, but artificial perilymph alone (control) did not. N = 3 for each treatment group.
Mentions: Auditory Nerve Overlapped Waveform (ANOW) measurements (Fig 2) show that the apical injection technique can treat the apical half of the cochlear spiral, a region that classic round window administration cannot [11]. The ANOW originates from afferent auditory nerve fibers in the apical cochlear half and can quantify low-frequency auditory thresholds [10, 25]. ANOW amplitudes from supra-threshold, 50 dB SPL sound levels were ablated by salicylate, HPβCD, and MβCD treatments, but not by artificial perilymph alone (control; Fig 2). Subtle changes to ANOW from control ears during the time of injection suggest that perhaps some ANOW changes in ears treated with toxic solutions resulted from mechanical disturbances from the fast apical injection approach used for these experiments. Nevertheless, unlike CAPs, ANOW amplitude measurements were fully abolished with all four treatments, consistent with the ANOW being more sensitive than CAPs to cochlear manipulations and diseased states [26].

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