Immunological Damage to the Inner Ear: Current and Future Therapeutic Strategies

AbstractTip-link as force-sensor in the hearing conveys the mechanical force originating from sound to ion-channels while maintaining the integrity of the entire sensory assembly in inner-ear. This delicate balance between structure and function of tip-links is regulated by Ca2+-ions present in endolymph. Mutations at the Ca2+-binding sites of tip-links often lead to congenital deafness, sometimes syndromic defects impairing vision along with hearing. Although such mutations are already identified, it is still not clear how the mutants alter the structure-function properties of the force-sensors associated with diseases. With an aim to decipher the differences in force-conveying properties of the force-sensors in molecular details, we identified the conformational variability of mutant and wild-type tip-links at the single-molecule level using FRET at the endolymphatic Ca2+ concentrations and subsequently measured the force-responsive behavior using single-molecule force spectroscopy with an AFM. AFM allowed us to mimic the high and wide range of force ramps (103 - 106 pN.s−1) as experienced in the inner ear. We performed in silico network analyses to learn that alterations in the conformations of the mutants interrupt the natural force-propagation paths through the sensors and make the mutant tip-links vulnerable to input forces from sound stimuli. We also demonstrated that a Ca2+ rich environment can restore the force-response of the mutant tip-links which may eventually facilitate the designing of better therapeutic strategies to the hearing loss.Significance StatementForce-sensors in inner ear are the key components in the hearing. Mutations in force-sensors often lead to congenital hearing loss. Loss of hearing has become a threat to humanity, with over 5% of world population suffering from deafness and 40% of which is congenital, primarily due to mutations in the sensory machinery in inner-ear. A better understanding of the molecular mechanism of the underlined hearing loss due to mutations is, therefore, necessary for better therapeutics to deaf. Here with a zoomed region of the force-sensors, we pointed out the differences in the force-propagation properties of the mutant and wild-type force-sensors. Our observation on restoring of functions of mutants in Ca2+-rich buffer indicates methods of developing low-cost therapeutic strategies against deafness.

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Analysis of Pharmacokinetics in the Cochlea of the Inner Ear

Frontiers in Pharmacology ◽

10.3389/fphar.2021.633505 ◽

2021 ◽

Vol 12 ◽

Author(s):

Seishiro Sawamura ◽

Genki Ogata ◽

Kai Asai ◽

Olga Razvina ◽

Takeru Ota ◽

...

Keyword(s):

Hearing Loss ◽

Sensorineural Hearing Loss ◽

Inner Ear ◽

Analytical Techniques ◽

Acoustic Trauma ◽

Therapeutic Agents ◽

Therapeutic Strategies ◽

Clinical Impact ◽

Sensorineural Hearing ◽

Global Population

Hearing loss affects >5% of the global population and therefore, has a great social and clinical impact. Sensorineural hearing loss, which can be caused by different factors, such as acoustic trauma, aging, and administration of certain classes of drugs, stems primarily from a dysfunction of the cochlea in the inner ear. Few therapeutic strategies against sensorineural hearing loss are available. To develop effective treatments for this disease, it is crucial to precisely determine the behavior of ototoxic and therapeutic agents in the microenvironment of the cochlea in live animals. Since the 1980s, a number of studies have addressed this issue by different methodologies. However, there is much less information on pharmacokinetics in the cochlea than that in other organs; the delay in ontological pharmacology is likely due to technical difficulties with accessing the cochlea, a tiny organ that is encased with a bony wall and has a fine and complicated internal structure. In this review, we not only summarize the observations and insights obtained in classic and recent studies on pharmacokinetics in the cochlea but also describe relevant analytical techniques, with their strengths, limitations, and prospects.

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Otoconia formation in the chick embryo

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100076494 ◽

1983 ◽

Vol 41 ◽

pp. 572-573

Author(s):

C.D. Fermin ◽

M. Igarashi

Keyword(s):

Chick Embryo ◽

Inner Ear ◽

Gallus Domesticus ◽

The Body ◽

Abnormal Behavior ◽

Intensive Study ◽

Basic Fuchsin ◽

Gestational Period ◽

Sensory Epithelia ◽

Transmission Electron

Otoconia are microscopic geometric structures that cover the sensory epithelia of the utricle and saccule (gravitational receptors) of mammals, and the lagena macula of birds. The importance of otoconia for maintanance of the body balance is evidenced by the abnormal behavior of species with genetic defects of otolith. Although a few reports have dealt with otoconia formation, some basic questions remain unanswered. The chick embryo is desirable for studying otoconial formation because its inner ear structures are easily accessible, and its gestational period is short (21 days of incubation).The results described here are part of an intensive study intended to examine the morphogenesis of the otoconia in the chick embryo (Gallus- domesticus) inner ear. We used chick embryos from the 4th day of incubation until hatching, and examined the specimens with light (LM) and transmission electron microscopy (TEM). The embryos were decapitated, and fixed by immersion with 3% cold glutaraldehyde. The ears and their parts were dissected out under the microscope; no decalcification was used. For LM, the ears were embedded in JB-4 plastic, cut serially at 5 micra and stained with 0.2% toluidine blue and 0.1% basic fuchsin in 25% alcohol.

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