Preferential Cochleotoxicity of Cisplatin

Cisplatin-induced ototoxicity in humans is more predominant in the cochlea than in the vestibule. Neither definite nor substantial vestibular dysfunction after cisplatin treatment has been consistently reported in the current literature. Inner ear hair cells seem to have intrinsic characteristics that make them susceptible to direct exposure to cisplatin. The existing literature suggests, however, that cisplatin might have different patterns of drug trafficking across the blood-labyrinth-barrier, or different degrees of cisplatin uptake to the hair cells in the cochlear and vestibular compartments. This review proposes an explanation for the preferential cochleotoxicity of cisplatin based on current evidence as well as the anatomy and physiology of the inner ear. The endocochlear potential, generated by the stria vascularis, acting as the driving force for hair cell mechanoelectrical transduction might also augment cisplatin entry into cochlear hair cells. Better understanding of the stria vascularis might shed new light on cochleotoxic mechanisms and inform the development of otoprotective interventions to moderate cisplatin associated ototoxicity.

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Development of mammalian endocochlear potential: normal ontogeny and effects of anoxia

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1986.250.3.r493 ◽

1986 ◽

Vol 250 (3) ◽

pp. R493-R498 ◽

Cited By ~ 1

Author(s):

N. K. Woolf ◽

A. F. Ryan ◽

J. P. Harris

Keyword(s):

Glucose Metabolism ◽

Mongolian Gerbil ◽

Hair Cells ◽

Stria Vascularis ◽

Organ Of Corti ◽

Endocochlear Potential ◽

Cochlear Microphonic ◽

Cochlear Hair Cells ◽

Apical Membranes ◽

Cochlear Microphonic Potential

The development of the positive endocochlear potential (EP), the negative anoxic EP, and the organ of Corti potential were measured at various postnatal ages in the Mongolian gerbil, beginning at 8 days after birth (DAB). The organ of Corti potential (OCP) was present at 8 DAB but averaged 21% less than the adult value. OCP increased regularly with age, reaching adult values of -90 mV by 14 DAB. The positive EP was first observed at 10 DAB, at which age it averaged only 2-3 mV. This potential increased monotonically between 10 and 20 DAB, by which time it had reached the adult value of 75 mV. Anoxia did not result in a negative EP until 12 DAB, at which age this potential averaged -7 mV. The negative anoxic EP matured more rapidly than the positive EP, achieving the adult value of 40 mV by 18 DAB. During development the positive EP appeared to closely parallel the maturation of glucose metabolism in the stria vascularis. The negative anoxic EP was more closely related temporally to the development of cochlear microphonic potential (CM) thresholds. It is hypothesized that changes which occur between 10 and 16 DAB in the apical membranes of the cochlear hair cells contribute to the maturation of both CM and the negative anoxic EP.

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The endocochlear potential depends on two K+ diffusion potentials and an electrical barrier in the stria vascularis of the inner ear

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.0711463105 ◽

2008 ◽

Vol 105 (5) ◽

pp. 1751-1756 ◽

Cited By ~ 109

Author(s):

F. Nin ◽

H. Hibino ◽

K. Doi ◽

T. Suzuki ◽

Y. Hisa ◽

...

Keyword(s):

Inner Ear ◽

Stria Vascularis ◽

Endocochlear Potential ◽

Diffusion Potentials

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Generating inner ear organoids containing putative cochlear hair cells from human pluripotent stem cells

Cell Death and Disease ◽

10.1038/s41419-018-0967-1 ◽

2018 ◽

Vol 9 (9) ◽

Cited By ~ 10

Author(s):

Minjin Jeong ◽

Molly O’Reilly ◽

Nerissa K. Kirkwood ◽

Jumana Al-Aama ◽

Majlinda Lako ◽

...

Keyword(s):

Stem Cells ◽

Inner Ear ◽

Hair Cells ◽

Pluripotent Stem Cells ◽

Human Pluripotent Stem Cells ◽

Cochlear Hair Cells

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Generation of Cochlear Hair Cells from Sox2 Positive Supporting Cells via DNA Demethylation

International Journal of Molecular Sciences ◽

10.3390/ijms21228649 ◽

2020 ◽

Vol 21 (22) ◽

pp. 8649

Author(s):

Xin Deng ◽

Zhengqing Hu

Keyword(s):

Transgenic Mice ◽

Inner Ear ◽

Hair Cells ◽

Dna Methyltransferase ◽

Dna Demethylation ◽

Egfp Expression ◽

Supporting Cells ◽

Cochlear Hair Cells ◽

Auditory Hair Cells ◽

Adult Mice

Regeneration of auditory hair cells in adult mammals is challenging. It is also difficult to track the sources of regenerated hair cells, especially in vivo. Previous paper found newly generated hair cells in deafened mouse by injecting a DNA methyltransferase inhibitor 5-azacytidine into the inner ear. This paper aims to investigate the cell sources of new hair cells. Transgenic mice with enhanced green fluorescent protein (EGFP) expression controlled by the Sox2 gene were used in the study. A combination of kanamycin and furosemide was applied to deafen adult mice, which received 4 mM 5-azacytidine injection into the inner ear three days later. Mice were followed for 3, 5, 7 and 14 days after surgery to track hair cell regeneration. Immunostaining of Myosin VIIa and EGFP signals were used to track the fate of Sox2-expressing supporting cells. The results show that (i) expression of EGFP in the transgenic mice colocalized the supporting cells in the organ of Corti, and (ii) the cell source of regenerated hair cells following 5-azacytidine treatment may be supporting cells during 5–7 days post 5-azacytidine injection. In conclusion, 5-azacytidine may promote the conversion of supporting cells to hair cells in chemically deafened adult mice.

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A Tmc1 mutation reduces calcium permeability and expression of mechanoelectrical transduction channels in cochlear hair cells

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1908058116 ◽

2019 ◽

Vol 116 (41) ◽

pp. 20743-20749 ◽

Cited By ~ 3

Author(s):

Maryline Beurg ◽

Amanda Barlow ◽

David N. Furness ◽

Robert Fettiplace

Keyword(s):

Hair Cells ◽

Single Channel ◽

Maximum Amplitude ◽

Outer Hair Cells ◽

Single Amino Acid ◽

Wild Type ◽

Cochlear Hair Cells ◽

Proximate Cause ◽

Mechanoelectrical Transduction ◽

Calcium Permeability

Mechanoelectrical transducer (MET) currents were recorded from cochlear hair cells in mice with mutations of transmembrane channel-like protein TMC1 to study the effects on MET channel properties. We characterized a Tmc1 mouse with a single-amino-acid mutation (D569N), homologous to a dominant human deafness mutation. Measurements were made in both Tmc2 wild-type and Tmc2 knockout mice. By 30 d, Tmc1 pD569N heterozygote mice were profoundly deaf, and there was substantial loss of outer hair cells (OHCs). MET current in OHCs of Tmc1 pD569N mutants developed over the first neonatal week to attain a maximum amplitude one-third the size of that in Tmc1 wild-type mice, similar at apex and base, and lacking the tonotopic size gradient seen in wild type. The MET-channel Ca2+ permeability was reduced 3-fold in Tmc1 pD569N homozygotes, intermediate deficits being seen in heterozygotes. Reduced Ca2+ permeability resembled that of the Tmc1 pM412K Beethoven mutant, a previously studied semidominant mouse mutation. The MET channel unitary conductance, assayed by single-channel recordings and by measurements of current noise, was unaffected in mutant apical OHCs. We show that, in contrast to the Tmc1 M412K mutant, there was reduced expression of the TMC1 D569N channel at the transduction site assessed by immunolabeling, despite the persistence of tip links. The reduction in MET channel Ca2+ permeability seen in both mutants may be the proximate cause of hair-cell apoptosis, but changes in bundle shape and protein expression in Tmc1 D569N suggest another role for TMC1 apart from forming the channel.

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KCNJ10 (Kir4.1) potassium channel knockout abolishes endocochlear potential

AJP Cell Physiology ◽

10.1152/ajpcell.00312.2001 ◽

2002 ◽

Vol 282 (2) ◽

pp. C403-C407 ◽

Cited By ~ 210

Author(s):

Daniel C. Marcus ◽

Tao Wu ◽

Philine Wangemann ◽

Paulo Kofuji

Keyword(s):

Driving Force ◽

Stria Vascularis ◽

Endocochlear Potential ◽

Sensory Transduction ◽

Basal Cells ◽

Transport Pathways ◽

Main Charge ◽

Marginal Cells ◽

Intermediate Cells ◽

Two Barriers

Stria vascularis of the cochlea generates the endocochlear potential and secretes K+. K+ is the main charge carrier and the endocochlear potential the main driving force for the sensory transduction that leads to hearing. Stria vascularis consists of two barriers, marginal cells that secrete potassium and basal cells that are coupled via gap junctions to intermediate cells. Mice lacking the KCNJ10 (Kir4.1) K+ channel in strial intermediate cells did not generate an endocochlear potential. Endolymph volume and K+ concentration ([K+]) were reduced. These studies establish that the KCNJ10 K+ channel provides the molecular mechanism for generation of the endocochlear potential in concert with other transport pathways that establish the [K+] difference across the channel. KCNJ10 is also a limiting pathway for K+ secretion.

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A Precisely Defined Role for the Tip Link-Associated Protein TMIE in the Mechanoelectrical Transduction Channel Complex of Inner Ear Hair Cells

Neuron ◽

10.1016/j.neuron.2014.11.015 ◽

2014 ◽

Vol 84 (5) ◽

pp. 889-891 ◽

Cited By ~ 2

Author(s):

Wolfgang Liedtke

Keyword(s):

Inner Ear ◽

Hair Cells ◽

Mechanoelectrical Transduction ◽

Tip Link

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Hearing and hair cells

Sensory Transduction ◽

10.1093/oso/9780198835028.003.0006 ◽

2019 ◽

pp. 99-131

Author(s):

Gordon L. Fain

Keyword(s):

Hair Cells ◽

Endocochlear Potential ◽

Outer Hair Cells ◽

Sensory Transduction ◽

Basilar Papilla ◽

Sensory Receptors ◽

Anatomy And Physiology ◽

Electrical Resonance ◽

Present Understanding

“Hearing and hair cells” is the sixth chapter of the book Sensory Transduction and begins with hearing in insects, describing the anatomy and physiology of tympanal organs and Johnston’s organ. It reviews the literature on vertebrate hair cells, which are the sensory receptors of the inner ear. It begins with the anatomy of hair cells and then describes tip links, hair cell transduction proteins, and our present understanding of the nature and identity of the mechanoreceptive channels, including the role of channel gating in bundle stiffness and adaptation of hair cells. A review is given of the anatomy and physiology of the organs of the lateral line, the vestibular system, and the cochlea, together with a description of endolymph and the endocochlear potential, outer hair cells and tuning in mammals, and the role of electrical resonance in tuning in the turtle basilar papilla.

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