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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

An analysis of cochlear microphonic (CM, red) measured from inside the endolymphatic space of the third cochlear turn in an exemplar ear before and after 13 mM HPβCD treatment.Pre-treatment (top panels): the best fit to the empirical CM was achieved with a typical Boltzmann analysis (Panel A, blue). Post-treatment (bottom panels): the best fit to empirical CM data was to a simple sine wave (Panel B, light green). These analyses suggest that mechanoelectric transduction was effectively linearized for the relatively high 90 dB SPLs used to evoke the CM. It is likely that saturation, or nonlinearity, of mechanoelectric transduction after 13 mM HPβCD treatment occurs at higher sound pressure levels that what we used here.
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pone.0175236.g010: An analysis of cochlear microphonic (CM, red) measured from inside the endolymphatic space of the third cochlear turn in an exemplar ear before and after 13 mM HPβCD treatment.Pre-treatment (top panels): the best fit to the empirical CM was achieved with a typical Boltzmann analysis (Panel A, blue). Post-treatment (bottom panels): the best fit to empirical CM data was to a simple sine wave (Panel B, light green). These analyses suggest that mechanoelectric transduction was effectively linearized for the relatively high 90 dB SPLs used to evoke the CM. It is likely that saturation, or nonlinearity, of mechanoelectric transduction after 13 mM HPβCD treatment occurs at higher sound pressure levels that what we used here.

Mentions: Here we discuss how the effects to the asymmetry, saturation, and sensitivity of fTR related to the changes found to DPOAE amplitude measurements. Administering 13 mM HPβCD did not cause apparent changes to CM amplitude recorded inside the endolymphatic space but caused a large reduction of DPOAE amplitudes (cf. Figs 4 and 5 purple, ~15 minutes after the start of injection). These results suggest intact mechanoelectric transduction but marked attenuation of cochlear amplifier gain. We investigated this further by analyzing CM measurements made before, and 30 minutes after, the start of injection (Fig 10). Before treatment, the CM (Fig 10A, red) fit well to a typical Boltzmann function (Fig 10A, blue) but not to a Boltzmann function without saturation (Vsat from the Boltzmann analysis, Fig 10A, green). These fits to pre-treatment empirical CM can be seen both in the Boltzmann analysis (Fig 10A.1) and the time domain (Fig 10A.2 and 10A.3). During treatment, the CM (red) fit well to a simple sine wave (Fig 10B, light green). But, to achieve a fit to a Boltzmann function, Vsat had to be set to infinity (Fig 10B, light blue). These fits to empirical CM measurements made during treatment can be appreciated in both the Boltzmann analysis (Fig 10B.1) and the time domain (Fig 10B.2 and 10B.3). We suspect that saturation of CM amplitude would have occurred at sound pressure levels much higher than what was used for these experiments because there was no apparent loss of OHC stereocilia and bodies after 13 mM HPβCD treatment. The unexpected result of normal CM amplitude measured inside scala media in the face of maximal decreases in DPOAE amplitude during treatment of 13 mM HPβCD treatment likely originate from lack of saturation to the in vivo fTR. The near normal CM amplitude measured inside the endolymphatic space (Fig 4) and transient enhancement of EP measurements (Fig 3) made during 13 mM HPβCD treatment could be explained if decreased current flow through OHCs increases the overall resistance between endolymph and perilymph. That is to say, decreased current flow would reduce the OHC-generated potential, but with less shunting to perilymph the amplitude recorded from endolymph may not be reduced to the same degree.


Direct administration of 2-Hydroxypropyl-Beta-Cyclodextrin into guinea pig cochleae: Effects on physiological and histological measurements
An analysis of cochlear microphonic (CM, red) measured from inside the endolymphatic space of the third cochlear turn in an exemplar ear before and after 13 mM HPβCD treatment.Pre-treatment (top panels): the best fit to the empirical CM was achieved with a typical Boltzmann analysis (Panel A, blue). Post-treatment (bottom panels): the best fit to empirical CM data was to a simple sine wave (Panel B, light green). These analyses suggest that mechanoelectric transduction was effectively linearized for the relatively high 90 dB SPLs used to evoke the CM. It is likely that saturation, or nonlinearity, of mechanoelectric transduction after 13 mM HPβCD treatment occurs at higher sound pressure levels that what we used here.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0175236.g010: An analysis of cochlear microphonic (CM, red) measured from inside the endolymphatic space of the third cochlear turn in an exemplar ear before and after 13 mM HPβCD treatment.Pre-treatment (top panels): the best fit to the empirical CM was achieved with a typical Boltzmann analysis (Panel A, blue). Post-treatment (bottom panels): the best fit to empirical CM data was to a simple sine wave (Panel B, light green). These analyses suggest that mechanoelectric transduction was effectively linearized for the relatively high 90 dB SPLs used to evoke the CM. It is likely that saturation, or nonlinearity, of mechanoelectric transduction after 13 mM HPβCD treatment occurs at higher sound pressure levels that what we used here.
Mentions: Here we discuss how the effects to the asymmetry, saturation, and sensitivity of fTR related to the changes found to DPOAE amplitude measurements. Administering 13 mM HPβCD did not cause apparent changes to CM amplitude recorded inside the endolymphatic space but caused a large reduction of DPOAE amplitudes (cf. Figs 4 and 5 purple, ~15 minutes after the start of injection). These results suggest intact mechanoelectric transduction but marked attenuation of cochlear amplifier gain. We investigated this further by analyzing CM measurements made before, and 30 minutes after, the start of injection (Fig 10). Before treatment, the CM (Fig 10A, red) fit well to a typical Boltzmann function (Fig 10A, blue) but not to a Boltzmann function without saturation (Vsat from the Boltzmann analysis, Fig 10A, green). These fits to pre-treatment empirical CM can be seen both in the Boltzmann analysis (Fig 10A.1) and the time domain (Fig 10A.2 and 10A.3). During treatment, the CM (red) fit well to a simple sine wave (Fig 10B, light green). But, to achieve a fit to a Boltzmann function, Vsat had to be set to infinity (Fig 10B, light blue). These fits to empirical CM measurements made during treatment can be appreciated in both the Boltzmann analysis (Fig 10B.1) and the time domain (Fig 10B.2 and 10B.3). We suspect that saturation of CM amplitude would have occurred at sound pressure levels much higher than what was used for these experiments because there was no apparent loss of OHC stereocilia and bodies after 13 mM HPβCD treatment. The unexpected result of normal CM amplitude measured inside scala media in the face of maximal decreases in DPOAE amplitude during treatment of 13 mM HPβCD treatment likely originate from lack of saturation to the in vivo fTR. The near normal CM amplitude measured inside the endolymphatic space (Fig 4) and transient enhancement of EP measurements (Fig 3) made during 13 mM HPβCD treatment could be explained if decreased current flow through OHCs increases the overall resistance between endolymph and perilymph. That is to say, decreased current flow would reduce the OHC-generated potential, but with less shunting to perilymph the amplitude recorded from endolymph may not be reduced to the same degree.

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