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

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.

[1]  L. Fenart,et al.  Cyclodextrins as Emerging Therapeutic Tools in the Treatment of Cholesterol-Associated Vascular and Neurodegenerative Diseases , 2016, Molecules.

[2]  A. Salt,et al.  Drug delivery into the cochlear apex: Improved control to sequentially affect finely spaced regions along the entire length of the cochlear spiral , 2016, Journal of Neuroscience Methods.

[3]  A. Salt,et al.  Drug Diffusion to the Apex of the Human Cochlea? A Comment on "Kang WS, Nguyen K, McKenna CE, Sewell WF, McKenna MJ, Jung DH. Intracochlear Drug Delivery Through the Oval Window in Fresh Cadaveric Human Temporal Bones". , 2016, Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology.

[4]  M. McKenna,et al.  Measurement of Ototoxicity Following Intracochlear Bisphosphonate Delivery , 2016, Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology.

[5]  John J. Guinan,et al.  The auditory nerve overlapped waveform (ANOW): A new objective measure of low-frequency hearing , 2015 .

[6]  J. Lichtenhan,et al.  An analysis of cochlear response harmonics: Contribution of neural excitation. , 2015, The Journal of the Acoustical Society of America.

[7]  E. Eskin,et al.  The Genetic Architecture of Hearing Impairment in Mice: Evidence for Frequency-Specific Genetic Determinants , 2015, G3: Genes, Genomes, Genetics.

[8]  Stefan Jacob,et al.  Outer Hair Cell Lateral Wall Structure Constrains the Mobility of Plasma Membrane Proteins , 2015, PLoS genetics.

[9]  M. Hoenerhoff,et al.  Hearing Loss and Otopathology Following Systemic and Intracerebroventricular Delivery of 2-Hydroxypropyl-Beta-Cyclodextrin , 2015, Journal of the Association for Research in Otolaryngology.

[10]  A. Salt,et al.  Perilymph Kinetics of FITC-Dextran Reveals Homeostasis Dominated by the Cochlear Aqueduct and Cerebrospinal Fluid , 2015, Journal of the Association for Research in Otolaryngology.

[11]  L. Hughes,et al.  Dynorphin release by the lateral olivocochlear efferents may inhibit auditory nerve activity: A cochlear drug delivery study , 2014, Neuroscience Letters.

[12]  J. Guinan,et al.  The Auditory Nerve Overlapped Waveform (ANOW) Originates in the Cochlear Apex , 2014, Journal of the Association for Research in Otolaryngology.

[13]  C. Guatimosim,et al.  Membrane cholesterol regulates different modes of synaptic vesicle release and retrieval at the frog neuromuscular junction , 2013, The European journal of neuroscience.

[14]  A. Salt,et al.  Large endolymphatic potentials from low-frequency and infrasonic tones in the guinea pig. , 2013, The Journal of the Acoustical Society of America.

[15]  Jeffery T Lichtenhan,et al.  A New Auditory Threshold Estimation Technique for Low Frequencies: Proof of Concept , 2013, Ear and hearing.

[16]  Jennifer Benson,et al.  Hearing Loss and Hair Cell Death in Mice Given the Cholesterol-Chelating Agent Hydroxypropyl-β-Cyclodextrin , 2012, PloS one.

[17]  M. Beal,et al.  Neuroprotection by cyclodextrin in cell and mouse models of Alzheimer disease , 2012, The Journal of experimental medicine.

[18]  J. Lichtenhan.  Effects of Low-Frequency Biasing on Otoacoustic and Neural Measures Suggest that Stimulus-Frequency Otoacoustic Emissions Originate Near the Peak Region of the Traveling Wave , 2012, Journal of the Association for Research in Otolaryngology.

[19]  Y. Negulyaev,et al.  Cholesterol depletion-induced inhibition of stretch-activated channels is mediated via actin rearrangement. , 2011, Biochemical and biophysical research communications.

[20]  W. Brownell,et al.  Membrane cholesterol modulates cochlear electromechanics , 2011, Pflügers Archiv - European Journal of Physiology.

[21]  Andrew J. Oxenham,et al.  Otoacoustic Estimation of Cochlear Tuning: Validation in the Chinchilla , 2010, Journal of the Association for Research in Otolaryngology.

[22]  D. Ory,et al.  Chronic Cyclodextrin Treatment of Murine Niemann-Pick C Disease Ameliorates Neuronal Cholesterol and Glycosphingolipid Storage and Disease Progression , 2009, PloS one.

[23]  A. Salt,et al.  Estimating the operating point of the cochlear transducer using low-frequency biased distortion products. , 2009, The Journal of the Acoustical Society of America.

[24]  A. Salt,et al.  Displacements of the organ of Corti by gel injections into the cochlear apex , 2009, Hearing Research.

[25]  J. Lichtenhan,et al.  The influence of noise exposure on the parameters of a convolution model of the compound action potential. , 2008, The Journal of the Acoustical Society of America.

[26]  J. Lichtenhan,et al.  Temporary hearing loss influences post-stimulus time histogram and single neuron action potential estimates from human compound action potentials. , 2008, The Journal of the Acoustical Society of America.

[27]  C. O'Neill,et al.  Methyl-β-Cyclodextrin Increases Permeability of Caco-2 Cell Monolayers by Displacing Specific Claudins from Cholesterol Rich Domains Associated with Tight Junctions , 2007, Cellular Physiology and Biochemistry.

[28]  M. McKenna,et al.  A method for intracochlear drug delivery in the mouse , 2006, Journal of Neuroscience Methods.

[29]  Jeffrey T Borenstein,et al.  Inner ear drug delivery via a reciprocating perfusion system in the guinea pig. , 2005, Journal of controlled release : official journal of the Controlled Release Society.

[30]  M. Cheatham,et al.  Cochlear function in Prestin knockout mice , 2004, The Journal of physiology.

[31]  A. Salt,et al.  The influence of transducer operating point on distortion generation in the cochlea. , 2004, The Journal of the Acoustical Society of America.

[32]  J. Lichtenhan,et al.  Influence of hearing sensitivity on mechano-electric transduction. , 2003, The Journal of the Acoustical Society of America.

[33]  M. Charles Liberman,et al.  Prestin is required for electromotility of the outer hair cell and for the cochlear amplifier , 2002, Nature.

[34]  M. Chertoff,et al.  Deriving a cochlear transducer function from low-frequency modulation of distortion product otoacoustic emissions. , 2002, The Journal of the Acoustical Society of America.

[35]  A. Salt,et al.  Quantification of solute entry into cochlear perilymph through the round window membrane , 2001, Hearing Research.

[36]  M. Chertoff,et al.  Properties and Quantification of Linear and Nonlinear Systems , 2001 .

[37]  M. Chertoff,et al.  Differentiation of cochlear pathophysiology in ears damaged by salicylate or a pure tone using a nonlinear systems identification technique. , 1998, The Journal of the Acoustical Society of America.

[38]  Manfred Kössl,et al.  Acoustical and electrical biasing of the cochlea partition. Effects on the acoustic two tone distortions f2−f1 and 2f1−f2 , 1997, Hearing Research.

[39]  Manfred Kössl,et al.  The acoustic two-tone distortions 2f1-f2 and f2-f1 and their possible relation to changes in the operating point of the cochlear amplifier , 1996, Hearing Research.

[40]  J. Santos-Sacchi,et al.  Effects of Salicylate and Lanthanides on Outer Hair Cell Motility and Associated Gating Charge , 1996, The Journal of Neuroscience.

[41]  S J Norton,et al.  Vulnerability and adaptation of distortion product otoacoustic emissions to endocochlear potential variation. , 1993, The Journal of the Acoustical Society of America.

[42]  S. Kujawa,et al.  Intracochlear salicylate reduces low-intensity acoustic and cochlear microphonic distortion products , 1992, Hearing Research.

[43]  W. E. Brownell,et al.  Concomitant salicylate-induced alterations of outer hair cell subsurface cisternae and electromotility , 1991, Journal of neurocytology.

[44]  W. Brownell,et al.  Effects of salicylate on shape, electromotility and membrane characteristics of isolated outer hair cells from guinea pig cochlea. , 1991, Acta oto-laryngologica.

[45]  W. Brownell,et al.  Fine structure of the intracochlear potential field. I. The silent current. , 1990, Biophysical journal.

[46]  A. Nuttall,et al.  Characterization of an EPSP-like potential recorded remotely from the round window. , 1989, The Journal of the Acoustical Society of America.

[47]  J J Eggermont,et al.  Narrow-band AP latencies in normal and recruiting human ears. , 1979, The Journal of the Acoustical Society of America.