Sphingosine 1-phosphate signaling pathway in inner ear biology. New therapeutic strategies for hearing loss?

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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Drug Delivery to the Inner Ear: Strategies and Their Therapeutic Implications for Sensorineural Hearing Loss

Current Drug Delivery ◽

10.2174/156720112800389098 ◽

2012 ◽

Vol 9 (3) ◽

pp. 231-242 ◽

Cited By ~ 28

Author(s):

Teresa Rivera ◽

Lorena Sanz ◽

Guadalupe Camarero ◽

Isabel Varela-Nieto

Keyword(s):

Drug Delivery ◽

Hearing Loss ◽

Sensorineural Hearing Loss ◽

Inner Ear ◽

Sensorineural Hearing ◽

Therapeutic Implications

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Hearing loss in inner ear and systemic autoimmune disease: A systematic review of post‐cochlear implantation outcomes

Laryngoscope Investigative Otolaryngology ◽

10.1002/lio2.563 ◽

2021 ◽

Author(s):

Jonathan Lee ◽

Kirsty Biggs ◽

Jameel Muzaffar ◽

Manohar Bance ◽

Peter Monksfield

Keyword(s):

Systematic Review ◽

Hearing Loss ◽

Autoimmune Disease ◽

Inner Ear ◽

Cochlear Implantation ◽

Systemic Autoimmune Disease

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Cochlear Nerve Canal Stenosis: Association With MYH14 and MYH9 Genes

Ear Nose & Throat Journal ◽

10.1177/0145561321996839 ◽

2021 ◽

pp. 014556132199683

Author(s):

Wenqi Liang ◽

Line Wang ◽

Xinyu Song ◽

Fenqi Gao ◽

Pan Liu ◽

...

Keyword(s):

Hearing Loss ◽

Next Generation Sequencing ◽

Inner Ear ◽

Internal Auditory Canal ◽

Cochlear Nerve ◽

Transverse Diameter ◽

Congenital Hearing Loss ◽

Canal Stenosis ◽

Ear Anomalies ◽

Generation Sequencing

The bony cochlear nerve canal transmits the cochlear nerve as it passes from the fundus of the internal auditory canal to the cochlea. Stenosis of the cochlear nerve canal, defined as a diameter less than 1.0 mm in transverse diameter, is associated with inner ear anomalies and severe to profound congenital hearing loss. We describe an 11-month-old infant with nonsyndromic congenital sensorineural hearing loss with cochlear nerve canal stenosis. Next-generation sequencing revealed heterozygous mutations in MYH9 and MYH14, encoding for the inner ear proteins myosin heavy chain IIA and IIC. The patient’s hearing was rehabilitated with bilateral cochlear implantation.

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Inner Ear and Muscle Developmental Defects in Smpx-Deficient Zebrafish Embryos

International Journal of Molecular Sciences ◽

10.3390/ijms22126497 ◽

2021 ◽

Vol 22 (12) ◽

pp. 6497

Author(s):

Anna Ghilardi ◽

Alberto Diana ◽

Renato Bacchetta ◽

Nadia Santo ◽

Miriam Ascagni ◽

...

Keyword(s):

Hearing Loss ◽

Inner Ear ◽

Hair Cells ◽

Muscle Fibers ◽

Underlying Mechanism ◽

Loss Of Function ◽

Zebrafish Model ◽

Developmental Defects ◽

Inner Ear Development ◽

Syndromic Hearing Loss

The last decade has witnessed the identification of several families affected by hereditary non-syndromic hearing loss (NSHL) caused by mutations in the SMPX gene and the loss of function has been suggested as the underlying mechanism. In the attempt to confirm this hypothesis we generated an Smpx-deficient zebrafish model, pointing out its crucial role in proper inner ear development. Indeed, a marked decrease in the number of kinocilia together with structural alterations of the stereocilia and the kinocilium itself in the hair cells of the inner ear were observed. We also report the impairment of the mechanotransduction by the hair cells, making SMPX a potential key player in the construction of the machinery necessary for sound detection. This wealth of evidence provides the first possible explanation for hearing loss in SMPX-mutated patients. Additionally, we observed a clear muscular phenotype consisting of the defective organization and functioning of muscle fibers, strongly suggesting a potential role for the protein in the development of muscle fibers. This piece of evidence highlights the need for more in-depth analyses in search for possible correlations between SMPX mutations and muscular disorders in humans, thus potentially turning this non-syndromic hearing loss-associated gene into the genetic cause of dysfunctions characterized by more than one symptom, making SMPX a novel syndromic gene.

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Ultrasound Microbubbles Enhance the Efficacy of Insulin-Like Growth Factor-1 Therapy for the Treatment of Noise-Induced Hearing Loss

Molecules ◽

10.3390/molecules26123626 ◽

2021 ◽

Vol 26 (12) ◽

pp. 3626

Author(s):

Yi-Chun Lin ◽

Yuan-Yung Lin ◽

Hsin-Chien Chen ◽

Chao-Yin Kuo ◽

Ai-Ho Liao ◽

...

Keyword(s):

Hearing Loss ◽

Growth Factor ◽

Inner Ear ◽

Outer Hair Cells ◽

Round Window Membrane ◽

Insulin Like Growth Factor ◽

Noise Induced Hearing Loss ◽

Ear Diseases ◽

Brainstem Response ◽

Ultrasound Microbubbles

The application of insulin-like growth factor 1 (IGF-1) to the round window membrane (RWM) is an emerging treatment for inner ear diseases. RWM permeability is the key factor for efficient IGF-1 delivery. Ultrasound microbubbles (USMBs) can increase drug permeation through the RWM. In the present study, the enhancing effect of USMBs on the efficacy of IGF-1 application and the treatment effect of USMB-mediated IGF-1 delivery for noise-induced hearing loss (NIHL) were investigated. Forty-seven guinea pigs were assigned to three groups: the USM group, which received local application of recombinant human IGF-1 (rhIGF-1, 10 µg/µL) following application of USMBs to the RWM; the RWS group, which received IGF-1 application alone; and the saline-treated group. The perilymphatic concentration of rhIGF-1 in the USM group was 1.95- and 1.67- fold of that in the RWS group, 2 and 24 h after treatment, respectively. After 5 h of 118 dB SPL noise exposure, the USM group had the lowest threshold shift in auditory brainstem response, least loss of cochlear outer hair cells, and least reduction in the number of synaptic ribbons on postexposure day 28 among the three groups. The combination of USMB and IGF-1 led to a better therapeutic response to NIHL. Two hours after treatment, the USM group had significantly higher levels of Akt1 and Mapk3 gene expression than the other two groups. The most intense immunostaining for phosphor-AKT and phospho-ERK1/2 was detected in the cochlea in the USM group. These results suggested that USMB can be applied to enhance the efficacy of IGF-1 therapy in the treatment of inner ear diseases.

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