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Molecular Mechanisms of Sensorineural Hearing Loss and Development of Inner Ear Therapeutics

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: closed (31 October 2020) | Viewed by 36763

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editor

Dr. Srdjan Vlajkovic

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Guest Editor
Department of Physiology and The Eisdell Moore Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand
Interests: sensory systems; auditory neuroscience; inner ear diseases; inner ear therapeutics; hearing loss; inflammation; oxidative stress
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

According to the World Health Organisation, around 466 million people worldwide have disabling hearing loss and it is estimated that by 2050 this number will increase to 900 million. The vast majority of the hearing loss is sensorineural due to disease, degeneration or trauma to the cochlea of the inner ear. The etiology of sensorineural hearing loss (SNHL) is complex and multifactorial arising from congenital and acquired causes. Congenital hearing loss commonly manifests as hearing deficits at birth or during early development, while acquired hearing loss is usually sustained in later life as a result of infection, exposure to excessive noise, ototoxic drugs or progression with age (presbyacusis).

Substantial progress has been made in recent years towards understanding the underlying mechanisms of SNHL and the discovery of novel therapeutic targets to prevent and mitigate the hearing loss. In addition, the link between hearing loss and dementia has been established, with the view that hearing loss prevention may also protect cognitive function.

The aim of this special issue is to advance our understanding of the causes and mechanisms of hearing loss and propose novel strategies to protect and restore hearing. We invite investigators to contribute original research articles and review articles that will address the mechanisms of SNHL caused by cochlear injury or gene mutations, biomarkers of hearing loss, biological restoration of hearing and prevention of cognitive deficits associated with presbyacusis.

Potential topics include, but are not limited to:
• Molecular and cellular mechanisms of SNHL
• Age-related inflammaging in the inner ear
• Cochlear neuropathy and hidden hearing loss
• Genetic hearing loss
• Meniere’s disease and tinnitus
• Biomarkers of hearing loss
• The link between hearing loss and dementia
• Preservation of residual hearing after cochlear implantation
• Hair cell regeneration
• Cell-, drug-, and gene-based therapies to restore hearing
• Drug delivery to the inner ear

Dr. Srdjan M Vlajkovic
Guest Editor

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

  • Mechanisms of hearing loss
  • Biomarkers of hearing loss
  • Therapeutic interventions for hearing loss
  • Hearing loss and dementia

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Published Papers (10 papers)

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Editorial

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4 pages, 174 KiB  
Editorial
Molecular Mechanisms of Sensorineural Hearing Loss and Development of Inner Ear Therapeutics
by Srdjan M. Vlajkovic and Peter R. Thorne
Int. J. Mol. Sci. 2021, 22(11), 5647; https://doi.org/10.3390/ijms22115647 - 26 May 2021
Cited by 15 | Viewed by 3198
Abstract
The sense of hearing enables us to enjoy sounds and music and engage with other people [...] Full article
(This article belongs to the Special Issue Molecular Mechanisms of Sensorineural Hearing Loss and Development of Inner Ear Therapeutics)

Research

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17 pages, 2833 KiB  
Article
Chronic Oral Selegiline Treatment Mitigates Age-Related Hearing Loss in BALB/c Mice
by Judit Szepesy, Viktória Humli, János Farkas, Ildikó Miklya, Júlia Tímár, Tamás Tábi, Anita Gáborján, Gábor Polony, Ágnes Szirmai, László Tamás, László Köles, Elek Sylvester Vizi and Tibor Zelles
Int. J. Mol. Sci. 2021, 22(6), 2853; https://doi.org/10.3390/ijms22062853 - 11 Mar 2021
Cited by 5 | Viewed by 3581
Abstract
Age-related hearing loss (ARHL), a sensorineural hearing loss of multifactorial origin, increases its prevalence in aging societies. Besides hearing aids and cochlear implants, there is no FDA approved efficient pharmacotherapy to either cure or prevent ARHL. We hypothesized that selegiline, an antiparkinsonian drug, [...] Read more.
Age-related hearing loss (ARHL), a sensorineural hearing loss of multifactorial origin, increases its prevalence in aging societies. Besides hearing aids and cochlear implants, there is no FDA approved efficient pharmacotherapy to either cure or prevent ARHL. We hypothesized that selegiline, an antiparkinsonian drug, could be a promising candidate for the treatment due to its complex neuroprotective, antioxidant, antiapoptotic, and dopaminergic neurotransmission enhancing effects. We monitored by repeated Auditory Brainstem Response (ABR) measurements the effect of chronic per os selegiline administration on the hearing function in BALB/c and DBA/2J mice, which strains exhibit moderate and rapid progressive high frequency hearing loss, respectively. The treatments were started at 1 month of age and lasted until almost a year and 5 months of age, respectively. In BALB/c mice, 4 mg/kg selegiline significantly mitigated the progression of ARHL at higher frequencies. Used in a wide dose range (0.15–45 mg/kg), selegiline had no effect in DBA/2J mice. Our results suggest that selegiline can partially preserve the hearing in certain forms of ARHL by alleviating its development. It might also be otoprotective in other mammals or humans. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Sensorineural Hearing Loss and Development of Inner Ear Therapeutics)
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19 pages, 3759 KiB  
Article
Regulator of G Protein Signalling 4 (RGS4) as a Novel Target for the Treatment of Sensorineural Hearing Loss
by Christine Fok, Milan Bogosanovic, Madhavi Pandya, Ravindra Telang, Peter R. Thorne and Srdjan M. Vlajkovic
Int. J. Mol. Sci. 2021, 22(1), 3; https://doi.org/10.3390/ijms22010003 - 22 Dec 2020
Cited by 11 | Viewed by 3743
Abstract
We and others have previously identified signalling pathways associated with the adenosine A1 receptor (A1R) as important regulators of cellular responses to injury in the cochlea. We have shown that the “post-exposure” treatment with adenosine A1R agonists confers [...] Read more.
We and others have previously identified signalling pathways associated with the adenosine A1 receptor (A1R) as important regulators of cellular responses to injury in the cochlea. We have shown that the “post-exposure” treatment with adenosine A1R agonists confers partial protection against acoustic trauma and other forms of sensorineural hearing loss (SNHL). The aim of this study was to determine if increasing A1R responsiveness to endogenous adenosine would have the same otoprotective effect. This was achieved by pharmacological targeting of the Regulator of G protein Signalling 4 (RGS4). RGS proteins inhibit signal transduction pathways initiated by G protein-coupled receptors (GPCR) by enhancing GPCR deactivation and receptor desensitisation. A molecular complex between RGS4 and neurabin, an intracellular scaffolding protein expressed in neural and cochlear tissues, is the key negative regulator of A1R activity in the brain. In this study, Wistar rats (6–8 weeks) were exposed to traumatic noise (110 dBSPL, 8–16 kHz) for 2 h and a small molecule RGS4 inhibitor CCG-4986 was delivered intratympanically in a Poloxamer-407 gel formulation for sustained drug release 24 or 48 h after noise exposure. Intratympanic administration of CCG-4986 48 h after noise exposure attenuated noise-induced permanent auditory threshold shifts by up to 19 dB, whilst the earlier drug administration (24 h) led to even better preservation of auditory thresholds (up to 32 dB). Significant improvement of auditory thresholds and suprathreshold responses was linked to improved survival of sensorineural tissues and afferent synapses in the cochlea. Our studies thus demonstrate that intratympanic administration of CCG-4986 can rescue cochlear injury and hearing loss induced by acoustic overexposure. This research represents a novel paradigm for the treatment of various forms of SNHL based on regulation of GPCR. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Sensorineural Hearing Loss and Development of Inner Ear Therapeutics)
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19 pages, 3227 KiB  
Article
Changes in microRNA Expression in the Cochlear Nucleus and Inferior Colliculus after Acute Noise-Induced Hearing Loss
by Sohyeon Park, Seung Hee Han, Byeong-Gon Kim, Myung-Whan Suh, Jun Ho Lee, Seung Ha Oh and Moo Kyun Park
Int. J. Mol. Sci. 2020, 21(22), 8792; https://doi.org/10.3390/ijms21228792 - 20 Nov 2020
Cited by 9 | Viewed by 2670
Abstract
Noise-induced hearing loss (NIHL) can lead to secondary changes that induce neural plasticity in the central auditory pathway. These changes include decreases in the number of synapses, the degeneration of auditory nerve fibers, and reorganization of the cochlear nucleus (CN) and inferior colliculus [...] Read more.
Noise-induced hearing loss (NIHL) can lead to secondary changes that induce neural plasticity in the central auditory pathway. These changes include decreases in the number of synapses, the degeneration of auditory nerve fibers, and reorganization of the cochlear nucleus (CN) and inferior colliculus (IC) in the brain. This study investigated the role of microRNAs (miRNAs) in the neural plasticity of the central auditory pathway after acute NIHL. Male Sprague–Dawley rats were exposed to white band noise at 115 dB for 2 h, and the auditory brainstem response (ABR) and morphology of the organ of Corti were evaluated on days 1 and 3. Following noise exposure, the ABR threshold shift was significantly smaller in the day 3 group, while wave II amplitudes were significantly larger in the day 3 group compared to the day 1 group. The organ of Corti on the basal turn showed evidence of damage and the number of surviving outer hair cells was significantly lower in the basal and middle turn areas of the hearing loss groups relative to controls. Five and three candidate miRNAs for each CN and IC were selected based on microarray analysis and quantitative reverse transcription PCR (RT-qPCR). The data confirmed that even short-term acoustic stimulation can lead to changes in neuroplasticity. Further studies are needed to validate the role of these candidate miRNAs. Such miRNAs may be used in the early diagnosis and treatment of neural plasticity of the central auditory pathway after acute NIHL. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Sensorineural Hearing Loss and Development of Inner Ear Therapeutics)
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16 pages, 2517 KiB  
Article
Constant Light Dysregulates Cochlear Circadian Clock and Exacerbates Noise-Induced Hearing Loss
by Chao-Hui Yang, Chung-Feng Hwang, Jiin-Haur Chuang, Wei-Shiung Lian, Feng-Sheng Wang, Ethan I. Huang and Ming-Yu Yang
Int. J. Mol. Sci. 2020, 21(20), 7535; https://doi.org/10.3390/ijms21207535 - 13 Oct 2020
Cited by 15 | Viewed by 2759
Abstract
Noise-induced hearing loss is one of the major causes of acquired sensorineural hearing loss in modern society. While people with excessive exposure to noise are frequently the population with a lifestyle of irregular circadian rhythms, the effects of circadian dysregulation on the auditory [...] Read more.
Noise-induced hearing loss is one of the major causes of acquired sensorineural hearing loss in modern society. While people with excessive exposure to noise are frequently the population with a lifestyle of irregular circadian rhythms, the effects of circadian dysregulation on the auditory system are still little known. Here, we disturbed the circadian clock in the cochlea of male CBA/CaJ mice by constant light (LL) or constant dark. LL significantly repressed circadian rhythmicity of circadian clock genes Per1, Per2, Rev-erbα, Bmal1, and Clock in the cochlea, whereas the auditory brainstem response thresholds were unaffected. After exposure to low-intensity (92 dB) noise, mice under LL condition initially showed similar temporary threshold shifts to mice under normal light–dark cycle, and mice under both conditions returned to normal thresholds after 3 weeks. However, LL augmented high-intensity (106 dB) noise-induced permanent threshold shifts, particularly at 32 kHz. The loss of outer hair cells (OHCs) and the reduction of synaptic ribbons were also higher in mice under LL after noise exposure. Additionally, LL enhanced high-intensity noise-induced 4-hydroxynonenal in the OHCs. Our findings convey new insight into the deleterious effect of an irregular biological clock on the auditory system. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Sensorineural Hearing Loss and Development of Inner Ear Therapeutics)
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18 pages, 3390 KiB  
Article
Altered Gap Junction Network Topography in Mouse Models for Human Hereditary Deafness
by Sara Eitelmann, Laura Petersilie, Christine R. Rose and Jonathan Stephan
Int. J. Mol. Sci. 2020, 21(19), 7376; https://doi.org/10.3390/ijms21197376 - 6 Oct 2020
Cited by 4 | Viewed by 2727
Abstract
Anisotropic gap junctional coupling is a distinct feature of astrocytes in many brain regions. In the lateral superior olive (LSO), astrocytic networks are anisotropic and oriented orthogonally to the tonotopic axis. In CaV1.3 knock-out (KO) and otoferlin KO mice, where auditory [...] Read more.
Anisotropic gap junctional coupling is a distinct feature of astrocytes in many brain regions. In the lateral superior olive (LSO), astrocytic networks are anisotropic and oriented orthogonally to the tonotopic axis. In CaV1.3 knock-out (KO) and otoferlin KO mice, where auditory brainstem nuclei are deprived from spontaneous cochlea-driven neuronal activity, neuronal circuitry is disturbed. So far it was unknown if this disturbance is also accompanied by an impaired topography of LSO astrocyte networks. To answer this question, we immunohistochemically analyzed the expression of astrocytic connexin (Cx) 43 and Cx30 in auditory brainstem nuclei. Furthermore, we loaded LSO astrocytes with the gap junction-permeable tracer neurobiotin and assessed the network shape and orientation. We found a strong elevation of Cx30 immunoreactivity in the LSO of CaV1.3 KO mice, while Cx43 levels were only slightly increased. In otoferlin KO mice, LSO showed a slight increase in Cx43 as well, whereas Cx30 levels were unchanged. The total number of tracer-coupled cells was unaltered and most networks were anisotropic in both KO strains. In contrast to the WTs, however, LSO networks were predominantly oriented parallel to the tonotopic axis and not orthogonal to it. Taken together, our data demonstrate that spontaneous cochlea-driven neuronal activity is not required per se for the formation of anisotropic LSO astrocyte networks. However, neuronal activity is required to establish the proper orientation of networks. Proper formation of LSO astrocyte networks thus necessitates neuronal input from the periphery, indicating a critical role of neuron-glia interaction during early postnatal development in the auditory brainstem. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Sensorineural Hearing Loss and Development of Inner Ear Therapeutics)
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17 pages, 4709 KiB  
Article
Induced Short-Term Hearing Loss due to Stimulation of Age-Related Factors by Intermittent Hypoxia, High-Fat Diet, and Galactose Injection
by Dong Jun Park, Sunmok Ha, Jin Sil Choi, Su Hoon Lee, Jeong-Eun Park and Young Joon Seo
Int. J. Mol. Sci. 2020, 21(19), 7068; https://doi.org/10.3390/ijms21197068 - 25 Sep 2020
Cited by 18 | Viewed by 3489
Abstract
Age-related hearing loss (ARHL) is the most common sensory disorder among the elderly, associated with aging and auditory hair cell death due to oxidative-stress-induced mitochondrial dysfunction. Although transgenic mice and long-term aging induction cultures have been used to study ARHL, there are currently [...] Read more.
Age-related hearing loss (ARHL) is the most common sensory disorder among the elderly, associated with aging and auditory hair cell death due to oxidative-stress-induced mitochondrial dysfunction. Although transgenic mice and long-term aging induction cultures have been used to study ARHL, there are currently no ARHL animal models that can be stimulated by intermittent environmental changes. In this study, an ARHL animal model was established by inducing continuous oxidative stress to promote short-term aging of cells, determined on the basis of expression of hearing-loss-induced phenotypes and aging-related factors. The incidence of hearing loss was significantly higher in dual- and triple-exposure conditions than in intermittent hypoxic conditions, high-fat diet (HFD), or d-galactose injection alone. Continuous oxidative stress and HFD accelerated cellular aging. An increase in Ucp2, usually expressed during mitochondrial dysfunction, was observed. Expression of Cdh23, Slc26a4, Kcnq4, Myo7a, and Myo6, which are ARHL-related factors, were modified by oxidative stress in the cells of the hearing organ. We found that intermittent hypoxia, HFD, and galactose injection accelerated cellular aging in the short term. Thus, we anticipate that the development of this hearing loss animal model, which reflects the effects of intermittent environmental changes, will benefit future research on ARHL. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Sensorineural Hearing Loss and Development of Inner Ear Therapeutics)
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Graphical abstract

13 pages, 13104 KiB  
Article
Expression and Localization of BDNF/TrkB System in the Zebrafish Inner Ear
by Antonino Germanà, Maria Cristina Guerrera, Rosaria Laurà, Maria Levanti, Marialuisa Aragona, Kamel Mhalhel, Germana Germanà, Giuseppe Montalbano and Francesco Abbate
Int. J. Mol. Sci. 2020, 21(16), 5787; https://doi.org/10.3390/ijms21165787 - 12 Aug 2020
Cited by 15 | Viewed by 3652
Abstract
Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, is involved in multiple and fundamental functions of the central and peripheral nervous systems including sensory organs. Despite recent advances in knowledge on the functional significance of BDNF and TrkB in the regulation [...] Read more.
Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, is involved in multiple and fundamental functions of the central and peripheral nervous systems including sensory organs. Despite recent advances in knowledge on the functional significance of BDNF and TrkB in the regulation of the acoustic system of mammals, the localization of BDNF/TrkB system in the inner ear of zebrafish during development, is not well known. Therefore, the goal of the present study is to analyze the age-dependent changes using RT-PCR, Western Blot and single and double immunofluorescence of the BDNF and its specific receptor in the zebrafish inner ear. The results showed the mRNA expression and the cell localization of BDNF and TrkB in the hair cells of the crista ampullaris and in the neuroepithelium of the utricle, saccule and macula lagena, analyzed at different ages. Our results demonstrate that the BDNF/TrkB system is present in the sensory cells of the inner ear, during whole life. Therefore, this system might play a key role in the development and maintenance of the hair cells in adults, suggesting that the zebrafish inner ear represents an interesting model to study the involvement of the neurotrophins in the biology of sensory cells Full article
(This article belongs to the Special Issue Molecular Mechanisms of Sensorineural Hearing Loss and Development of Inner Ear Therapeutics)
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Review

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13 pages, 951 KiB  
Review
Activation of KCNQ4 as a Therapeutic Strategy to Treat Hearing Loss
by John Hoon Rim, Jae Young Choi, Jinsei Jung and Heon Yung Gee
Int. J. Mol. Sci. 2021, 22(5), 2510; https://doi.org/10.3390/ijms22052510 - 2 Mar 2021
Cited by 17 | Viewed by 4771
Abstract
Potassium voltage-gated channel subfamily q member 4 (KCNQ4) is a voltage-gated potassium channel that plays essential roles in maintaining ion homeostasis and regulating hair cell membrane potential. Reduction of the activity of the KCNQ4 channel owing to genetic mutations is responsible for nonsyndromic [...] Read more.
Potassium voltage-gated channel subfamily q member 4 (KCNQ4) is a voltage-gated potassium channel that plays essential roles in maintaining ion homeostasis and regulating hair cell membrane potential. Reduction of the activity of the KCNQ4 channel owing to genetic mutations is responsible for nonsyndromic hearing loss, a typically late-onset, initially high-frequency loss progressing over time. In addition, variants of KCNQ4 have also been associated with noise-induced hearing loss and age-related hearing loss. Therefore, the discovery of small compounds activating or potentiating KCNQ4 is an important strategy for the curative treatment of hearing loss. In this review, we updated the current concept of the physiological role of KCNQ4 in the inner ear and the pathologic mechanism underlying the role of KCNQ4 variants with regard to hearing loss. Finally, we focused on currently developed KCNQ4 activators and their pros and cons, paving the way for the future development of specific KCNQ4 activators as a remedy for hearing loss. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Sensorineural Hearing Loss and Development of Inner Ear Therapeutics)
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14 pages, 264 KiB  
Review
Hyperbaric Oxygenation as Adjunctive Therapy in the Treatment of Sudden Sensorineural Hearing Loss
by Dorota Olex-Zarychta
Int. J. Mol. Sci. 2020, 21(22), 8588; https://doi.org/10.3390/ijms21228588 - 14 Nov 2020
Cited by 21 | Viewed by 4749
Abstract
Sudden sensorineural hearing loss seems to become a serious social health problem in modern societies. According to the World Health Organization (WHO) reports, adult-onset sensorineural hearing loss is found to be one of the leading diseases at the global level, especially in high-income [...] Read more.
Sudden sensorineural hearing loss seems to become a serious social health problem in modern societies. According to the World Health Organization (WHO) reports, adult-onset sensorineural hearing loss is found to be one of the leading diseases at the global level, especially in high-income countries, and is foreseen to move up from the 14th to 7th leading cause of the global burden of diseases by the year 2030. Although the direct mortality rate of this disease is very low, its influence on quality of life is huge; that is the reason why the implementation of the most effective and the safest therapies for the patient is crucial for minimizing the risk of complications and adverse reactions to treatment. The aim of this paper is to present hyperbaric oxygen therapy (HBOT) as a medical procedure useful in the treatment of sudden sensorineural hearing loss as adjunctive therapy of high efficacy. This paper focuses on the molecular mechanisms of action and clinical effectiveness of HBOT in the treatment of idiopathic sudden deafness, taking into consideration both the benefits and potential risks of its implementation. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Sensorineural Hearing Loss and Development of Inner Ear Therapeutics)
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