Hearing Loss Treatment Report

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Research

Making the Case for Research on Disease-Modifying Treatments to Tackle Post-lingual Progressive Sensorineural Hearing Loss

https://www.frontiersin.org/articles/10.3389/fneur.2020.00290/full

Front. Neurol., 21 April 2020 | https://doi.org/10.3389/fneur.2020.00290
Making the Case for Research on Disease-Modifying Treatments to Tackle Post-lingual Progressive Sensorineural Hearing Loss
Vincent Van Rompaey1,2*
1Department of Otorhinolaryngology and Head & Neck Surgery, Antwerp University Hospital, Edegem, Belgium
2Department of Translational Neurosciences, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium

Influence of Cochlear Dead Regions on Hearing Outcome in Sudden Sensorineural Hearing Loss

https://journals.lww.com/otology-neurotology/Citation/2020/08000/Influence_of_Cochlear_Dead_Regions_on_Hearing.6.aspx

https://www.ncbi.nlm.nih.gov/pubmed/32658395?dopt=Abstract

Influence of Cochlear Dead Regions on Hearing Outcome in Sudden Sensorineural Hearing Loss.

Otol Neurotol. 2020 Aug;41(7):889-894

Authors: Choi JE, Shim HJ, An YH, Yoo S, Mun SK, Chang MY, Park MH, Jun BC, Moon IJ

Abstract

OBJECTIVE: The aims of this multicenter study were to prospectively evaluate the prevalence of dead regions (DRs) in sudden sensorineural hearing loss (SSNHL) and compare the clinical characteristics and hearing outcomes of SSNHL according to the presence of DRs.

STUDY DESIGN: Prospective study.

SETTING: Multicenter study.

PATIENTS AND METHODS: The threshold-equalizing noise (TEN) test was prospectively performed on a total of 130 patients diagnosed with SSNHL. All patients received systemic steroid therapy and/or intratympanic steroid injection within 1 month after onset. Pure-tone audiograms and the TEN test were conducted before and after steroid treatment. Age, sex, side of affected ear, recurrence, onset of symptoms, presence of dizziness, and comorbid diseases were also collected. The prevalence of DRs in SSNHL and clinical factors related to the DRs were assessed. Hearing outcomes for SSNHL according to DRs were evaluated in 68 patients who followed a pure-tone audiogram.

RESULTS: The overall prevalence of one or more DRs in SSNHL evaluated using the TEN test was 20.8% (27/130 subjects) and the overall frequency-specific prevalence of DR was 6.7% (61/910 DRs). Although the DRs (+)and DR (-) groups had similar initial pure-tone thresholds, the DRs (+) group had significantly worse initial WRS compared to the DRs (-) group (p = 0.015). The presence of DRs was not associated with hearing recovery in a multivariate logistic regression model, but it was significantly associated with the degree of hearing gain in a multivariate linear regression model (p = 0.018).

CONCLUSIONS: The presence of DRs can be considered one of the poor prognostic factors for SSNHL and the TEN test may contribute to assess the prognosis of SSNHL in clinical settings.

PMID: 32658395 [PubMed – as supplied by publisher]

Diagnostic and Therapeutic Applications of Genomic Medicine in Sensorineural Hearing Loss

https://www.sciencedirect.com/science/article/abs/pii/S0378111920303462?via%3Dihub

https://www.ncbi.nlm.nih.gov/pubmed/32304785?dopt=Abstract

Related Articles

Diagnostic and Therapeutic Applications of Genomic Medicine in Progressive, Late-Onset, Nonsyndromic Sensorineural Hearing Loss.

Gene. 2020 Apr 15;:144677

Authors: Jimenez JE, Nourbakhsh A, Colbert B, Mittal R, Yan D, Green CL, Nisenbaum E, Liu G, Bencie N, Rudman J, Blanton SH, Zhong Liu X

Abstract

The progressive, late-onset, nonsyndromic, sensorineural hearing loss (PNSHL) is the most common cause of sensory impairment globally, with presbycusis affecting greater than a third of individuals over the age of 65. The etiology underlying PNSHL include presbycusis, noise-induced hearing loss, drug ototoxicity, and delayed-onset autosomal dominant hearing loss (AD PNSHL). The objective of this article is to discuss the potential diagnostic and therapeutic applications of genomic medicine in PNSHL. Genomic factors contribute greatly to PNSHL. The heritability of presbycusis ranges from 25 to 75%. Current therapies for PNSHL range from sound amplification to cochlear implantation (CI). PNSHL is an excellent candidate for genomic medicine approaches as it is common, has well-described pathophysiology, has a wide time window for treatment, and is amenable to local gene therapy by currently utilized procedural approaches. AD PNSHL is especially suited to genomic medicine approaches that can disrupt the expression of an aberrant protein product. Gene therapy is emerging as a potential therapeutic strategy for the treatment of PNSHL. Viral gene delivery approaches have demonstrated promising results in human clinical trials for two inherited causes of blindness and are being used for PNSHL in animal models and a human trial. Non-viral gene therapy approaches are useful in situations where a transient biologic effect is needed or for delivery of genome editing reagents (such as CRISPR/Cas9) into the inner ear. Many gene therapy modalities that have proven efficacious in animal trials have potential to delay or prevent PNSHL in humans. The development of new treatment modalities for PNSHL will lead to improved quality of life of many affected individuals and their families.

PMID: 32304785 [PubMed – as supplied by publisher]

Potential benefits of salvage intratympanic dexamethasone injection in profound idiopathic sudden sensorineural hearing loss

https://link.springer.com/article/10.1007%2Fs00405-020-05967-z

https://www.ncbi.nlm.nih.gov/pubmed/32296977?dopt=Abstract

Related Articles

Potential benefits of salvage intratympanic dexamethasone injection in profound idiopathic sudden sensorineural hearing loss.

Eur Arch Otorhinolaryngol. 2020 Apr 15;:

Authors: Choi JW, Lee CK, Kim SB, Lee DY, Ko SC, Park KH, Choi SJ

Abstract

PURPOSES: To compare hearing recovery levels after initial treatment or salvage intratympanic dexamethasone injection (ITDI), and to find the prognostic factor on salvage ITDI therapy in profound ISSNHL.

METHODS: We retrospectively reviewed 115 patients with profound ISSNHL. All patients were treated with combination or systemic steroid therapy as the initial treatment. Next, we used salvage ITDI therapy on patients who showed slight or no improvement according to Siegel’s criteria. To find the prognostic factors for the effectiveness of salvage ITDI therapy, we analyzed clinical data, such as, age, sex, vertigo, symptom duration, diabetes, hypertension, initial PTA, pre-salvage PTA, and treatment methods, using multiple regression analyses.

RESULTS: The rate of serviceable hearing recovery were 10.4% (12/115) in the initial-treatment group and 20.4% (21/103) in the salvage group. The difference was statistically significant (p = 0.041). Pre-salvage PTA, diabetes mellitus, and symptom duration were affective factors for the effectiveness of salvage ITDI therapy in profound ISSNHL refractory to initial treatment, with odds ratios of 1.169 (95% confidence interval, 1.088-1.256), 0.069 (95% confidence interval, 0.005-0.889), and 9.242 (95% confidence interval, 1.079-79.146).

CONCLUSIONS: Salvage therapy should be considered for profound ISSNHL, which is expected to result in poor prognosis or hearing recovery: ITSI therapy might be an effective treatment as salvage therapy.

PMID: 32296977 [PubMed – as supplied by publisher]

Otoprotective Effects of α-lipoic Acid on A/J Mice With Age-related Hearing Loss

https://journals.lww.com/otology-neurotology/Abstract/publishahead/Otoprotective_Effects_of___lipoic_Acid_on_A_J_Mice.96143.aspx

https://www.ncbi.nlm.nih.gov/pubmed/32282782?dopt=Abstract

Otoprotective Effects of α-lipoic Acid on A/J Mice With Age-related Hearing Loss.

Otol Neurotol. 2020 Apr 10;:

Authors: Huang S, Xu A, Sun X, Shang W, Zhou B, Xie Y, Zhao M, Li P, Lu P, Liu T, Han F

Abstract

OBJECTIVE: A/J mice are a mouse model of age-related hearing loss (AHL) with progressive degeneration of outer hair cells (OHCs), spiral ganglion neurons (SGNs), and stria vascularis. This study was carried out to observe the otoprotective effects of α-lipoic acid on A/J mice.

METHODS: A/J mouse pups at postnatal day 7 were randomly distributed into the untreated group, the dimethyl sulfoxide (DMSO) group, and the α-lipoic acid + DMSO group. α-lipoic acid was given to the mice intraperitoneally at a dosage of 50 μg/g body weight every other day. Time course auditory-evoked brainstem response (ABR) thresholds were tested. OHC loss was counted and the densities of SGNs and the width of stria vascularis were measured at 4 and 8 weeks of age.

RESULTS: Measurement of the ABR thresholds revealed that hearing loss in A/J mice was attenuated by α-lipoic acid at age from 3 to 8 weeks. Moreover, preservation effects of OHCs, SGNs, and stria vascularis by α-lipoic acid were observed in the cochleae of A/J mice at 4 and 8 weeks of age.

CONCLUSION: Hearing loss in A/J mice can be attenuated by α-lipoic acid. The otoprotective effects of α-lipoic acid on A/J mice may be obtained by preserving OHCs, SGNs, and stria vascularis in the cochleae. The oxidative damage related to gene mutations may be a potential target for AHL prevention and therapy.

PMID: 32282782 [PubMed – as supplied by publisher]

FGF22 promotes generation of cochlear ribbon synapses through downregulating MEF2D

https://www.aging-us.com/article/103042/text

ribbon synapses may be regulated by FGF22/calcium/CalN/MEF2D signaling, which implied novel therapeutic targets for hearing loss.

FGF22 promotes generation of ribbon synapses through downregulating MEF2D
Shuna Li1 , Jingchun He1 , Yupeng Liu1 , Jun Yang1
1 Department of Otolaryngology-Head and Neck Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China
Received: January 22, 2020       Accepted: March 10, 2020       Published: April 9, 2020https://doi.org/10.18632/aging.103042

Regulation of Noise-Induced Loss of Serotonin Transporters with Resveratrol in a Rat Model: Resveratrol has protective effects against noise-induced loss of SERT

https://www.mdpi.com/1420-3049/24/7/1344

https://www.ncbi.nlm.nih.gov/pubmed/30959762?dopt=Abstract

Related Articles

Regulation of Noise-Induced Loss of Serotonin Transporters with Resveratrol in a Rat Model Using 4-[18F]-ADAM/Small-Animal Positron Emission Tomography.

Molecules. 2019 Apr 05;24(7):

Authors: Li IH, Shih JH, Jhao YT, Chen HC, Chiu CH, Chen CF, Huang YS, Shiue CY, Ma KH

Abstract

Serotonin (5-HT) plays a crucial role in modulating the afferent fiber discharge rate in the inferior colliculus, auditory cortex, and other nuclei of the ascending auditory system. Resveratrol, a natural polyphenol phytoalexin, can inhibit serotonin transporters (SERT) to increase synaptic 5-HT levels. In this study, we investigated the effects of resveratrol on noise-induced damage in the serotonergic system. Male Sprague-Dawley rats were anaesthetized and exposed to an 8-kHz tone at 116 dB for 3.5 h. Resveratrol (30 mg/kg, intraperitoneal injection [IP]) and citalopram (20 mg/kg, IP), a specific SERT inhibitor used as a positive control, were administered once a day for four consecutive days, with the first treatment occurring 2 days before noise exposure. Auditory brainstem response testing and positron emission tomography (PET) with N,N-dimethyl-2-(2-amino-4-[18F]fluorophenylthio)benzylamine (4-[18F]-ADAM, a specific radioligand for SERT) were used to evaluate functionality of the auditory system and integrity of the serotonergic system, respectively, before and after noise exposure. Finally, immunohistochemistry was performed 1 day after the last PET scan. Our results indicate that noise-induced serotonergic fiber loss occurred in multiple brain regions including the midbrain, thalamus, hypothalamus, striatum, auditory cortex, and frontal cortex. This noise-induced damage to the serotonergic system was ameliorated in response to treatment with resveratrol and citalopram. However, noise exposure increased the hearing threshold in the rats regardless of drug treatment status. We conclude that resveratrol has protective effects against noise-induced loss of SERT.

PMID: 30959762 [PubMed – in process]

Neurotrophin gene therapy to promote survival of spiral ganglion neurons after deafness

https://www.sciencedirect.com/science/article/abs/pii/S0378595519304563?via%3Dihub

https://www.ncbi.nlm.nih.gov/pubmed/32331858?dopt=Abstract

Related Articles

Neurotrophin gene therapy to promote survival of spiral ganglion neurons after deafness.

Hear Res. 2020 Apr 05;:107955

Authors: Leake PA, Akil O, Lang H

Abstract

Hearing impairment is a major health and economic concern worldwide. Currently, the cochlear implant (CI) is the standard of care for remediation of severe to profound hearing loss, and in general, contemporary CIs are highly successful. But there is great variability in outcomes among individuals, especially in children, with many CI users deriving much less or even marginal benefit. Much of this variability is related to differences in auditory nerve survival, and there has been substantial interest in recent years in exploring potential therapies to improve survival of the cochlear spiral ganglion neurons (SGN) after deafness. Preclinical studies using osmotic pumps and other approaches in deafened animal models to deliver neurotrophic factors (NTs) directly to the cochlea have shown promising results, especially with Brain-Derived Neurotrophic Factor (BDNF). More recent studies have focused on the use of NT gene therapy to force expression of NTs by target cells within the cochlea. This could provide the means for a one-time treatment to promote long-term NT expression and improve neural survival after deafness. This review summarizes the evidence for the efficacy of exogenous NTs in preventing SGN degeneration after hearing loss and reviews the animal research to date suggesting that NT gene therapy can elicit long-term NT expression in the cochlea, resulting in significantly improved SGN and radial nerve fiber survival after deafness. In addition, we discuss NT gene therapy in other non-auditory applications and consider some of the remaining issues with regard to selecting optimal vectors, timing of treatment, and place/method of delivery, etc. that must be resolved prior to considering clinical application.

PMID: 32331858 [PubMed – as supplied by publisher]

Lin28 reprograms inner ear glia to a neuronal fate: possibility of a new avenue for regeneration that could replace dying neurons in auditory neuropathy

https://stemcellsjournals.onlinelibrary.wiley.com/doi/abs/10.1002/stem.3181

https://www.ncbi.nlm.nih.gov/pubmed/32246510?dopt=Abstract

Related Articles

Lin28 reprograms inner ear glia to a neuronal fate.

Stem Cells. 2020 Apr 03;:

Authors: Kempfle JS, Luu NC, Petrillo M, Al-Asad R, Zhang A, Edge ASB

Abstract

Sensorineural hearing loss is irreversible and can be caused by loss of auditory neurons. Regeneration of neural cells from endogenous cells may offer a future tool to restore the auditory circuit and to enhance the performance of implantable hearing devices. Neurons and glial cells in the peripheral nervous system are closely related and originate from a common progenitor. Prior work in our lab indicated that in the early postnatal mouse inner ear, proteolipid protein 1 (Plp1) expressing glial cells could act as progenitor cells for neurons in vitro. Here we used a transgenic mouse model to transiently overexpress Lin28, a neural stem cell regulator, in Plp1-positive glial cells. Lin28 promoted proliferation and conversion of auditory glial cells into neurons in vitro. To study the effects of Lin28 on endogenous glial cells after loss of auditory neurons in vivo, we produced a model of auditory neuropathy by selectively damaging auditory neurons with ouabain. After neural damage was confirmed by the auditory brainstem response, we briefly upregulated Lin28 in Plp1-expressing inner ear glial cells. One month later, we analyzed the cochlea for neural marker expression by quantitative RT-PCR and immunohistochemistry. We found that transient Lin28 overexpression in Plp1-expressing glial cells induced expression of neural stem cell markers and subsequent conversion into neurons. This suggests the potential for inner ear glia to be converted into neurons as a regeneration therapy for neural replacement in auditory neuropathy. © AlphaMed Press 2020 SIGNIFICANCE STATEMENT: Loss or damage of auditory neurons is associated with sensorineural hearing loss and deafness. To date, no cure is available and amplification, as well as cochlear implants, rely on surviving neurons to convey the auditory signal to the brain. Regeneration strategies focusing on endogenous cell therapy may offer a future treatment option for replacement of lost neurons to restore the auditory circuit. We show here that in a transgenic mouse model, Plp1-positive glial cells of the inner ear have a capacity for regeneration and differentiate into neurons after transient activation of neural stem cell regulator Lin28 in vitro and in vivo. We present evidence that Lin28 acts through stem cell regulatory genes, Sox2 and Hmga2, to stimulate proliferation and reprogramming of inner ear glia to neurons raising the possibility of a new avenue for regeneration that could replace dying neurons in auditory neuropathy.

PMID: 32246510 [PubMed – as supplied by publisher]

Both vitamin D deficiency and hypocalcemia were found to be independently associated with sensorineural hearing loss (SNHL) in children

https://journals.lww.com/otology-neurotology/Abstract/2020/08000/Vitamin_D_Deficiency,_Hypocalcemia,_and_Hearing.24.aspx

https://www.ncbi.nlm.nih.gov/pubmed/32658400?dopt=Abstract

Vitamin D Deficiency, Hypocalcemia, and Hearing Loss in Children.

Otol Neurotol. 2020 Aug;41(7):940-947

Authors: Mehta CH, Close MF, Dornhoffer JR, Liu YF, Nguyen SA, McRackan TR, Meyer TA

Abstract

OBJECTIVE: Characterize relations between vitamin D deficiency (VDD), hypocalcemia, and hearing loss (HL) in children.

STUDY DESIGN: Retrospective review.

SETTING: Tertiary referral hospital.

PATIENTS: Children in the Audiological and Genetic Database with a diagnosis of VDD, rickets, or osteomalacia.

INTERVENTION: None.

MAIN OUTCOME MEASURES: Prevalence, type, severity (4-tone pure-tone average, PTA), and progression of HL. HL was defined as greater than 15 dB HL at any threshold by pure tone, greater than 20 dB HL by sound field audiometry, or greater than 25 dB in infants less than 1 year of age.

RESULTS: Of 888 children with VDD, 474 (53.4%) had HL, with 17% having moderate-profound HL. Compared with an age-matched cohort of 13,320 children drawn from the same database, children with VDD were significantly more likely to have sensorineural HL (SNHL) (adjusted odds ratios [aOR] 1.26 [95% confidence interval [CI] 1.01-1.58]). Among children with VDD, children with femur fracture had a significantly higher rate of HL (81% versus 53%, p = 0.008) and children with hypocalcemia had a significantly higher rate of moderate-profound HL (36% versus 18%, p = 0.016). Additionally, hypocalcemia with and without VDD was associated with SNHL (aOR 2.30 [1.07-4.56]).

CONCLUSIONS: Both vitamin D deficiency and hypocalcemia were found to be independently associated with SNHL, a type of HL that is less likely to improve over time. Recognition of VDD and hypocalcemia as independent risk factors for the development of SNHL could allow for better evaluation and treatment of this patient population. Routine audiological evaluation should be considered in this population.

PMID: 32658400 [PubMed – as supplied by publisher]

Sesamum indicum L. Oil and Sesamin Induce Auditory-Protective Effects Through Changes in Hearing Loss-Related Gene Expression

https://www.liebertpub.com/doi/10.1089/jmf.2019.4542

https://www.ncbi.nlm.nih.gov/pubmed/32186941?dopt=Abstract

Sesamum indicum L. Oil and Sesamin Induce Auditory-Protective Effects Through Changes in Hearing Loss-Related Gene Expression.

J Med Food. 2020 Mar 18;:

Authors: Kim YH, Kim EY, Rodriguez I, Nam YH, Jeong SY, Hong BN, Choung SY, Kang TH

Abstract

Changing consumption patterns and increasing health awareness, especially in Europe, are resulting in an increased demand for sesame seeds. In 2016, Asia imported the highest quantity of sesame seeds, followed by Europe and North America. We examined, for the first time, the effects of treatment with sesame oil and sesamin in hearing impairment models. Sesame oil exhibited an ameliorative effect on auditory impairment in a hair cell line in zebrafish and mice. In ototoxic zebrafish larvae, neuromasts and otic cells increased in numbers because of sesame oil. Furthermore, auditory function in noise-induced hearing loss (NIHL) was studied through auditory brainstem response to evaluate the therapeutic effects of sesame oil. Sesame oil reduced the hearing threshold shift in response to clicks and 8, 16-kHz tone bursts in NIHL mice. Auditory-protective effect of sesame oil was seen in zebrafish and mice; therefore, we used chromatographic analysis to study sesamin, which is the major effective factor in sesame oil. To investigate its effects related to auditory function, we studied the hearing-related gene, Tecta, using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazoliumbromide (MTT) assay. Auditory cell proliferation was induced by treatment with sesame oil and sesamin using Tecta (Tectorin Alpha) regulation. The expression of Tecta increases in the apex area of the cochlear hair cells as they grow, and their activity is enhanced by sesame oil and sesamin. These results provide a novel mechanistic insight into the sesame oil activities and suggest that sesamin, the key constituent in sesame oil, is responsible for its auditory function related benefits, including protection of auditory cells and reversal of their impairments.

PMID: 32186941 [PubMed – as supplied by publisher]

Using Sox2 to alleviate the hallmarks of age-related hearing loss

https://www.sciencedirect.com/science/article/pii/S1568163719304258?via%3Dihub

https://www.ncbi.nlm.nih.gov/pubmed/32173536?dopt=Abstract

Related Articles

Using Sox2 to alleviate the hallmarks of age-related hearing loss.

Ageing Res Rev. 2020 Mar 12;:101042

Authors: Yamoah EN, Li M, Shah A, Elliott KL, Cheah K, Xu PX, Phillips S, Young SM, Eberl DF, Fritzsch B

Abstract

Age-related hearing loss (ARHL) is the most prevalent age-related sensory deficit. ARHL reduces the quality of life of the growing aging population, setting seniors up for the enhanced mental decline. The size of the needy population, the structural deficit, and a likely research strategy for effective treatment of chronic neurosensory hearing in the elderly are needed. Although there has been profound advancement in auditory regenerative research, there remain multiple challenges to restore hearing loss. Thus, additional investigations are required, using novel tools. We propose how the flat epithelium, remaining after the organ of Corti has deteriorated, can be converted to the repaired-sensory epithelium, using Sox2. This will include developing an artificial gene regulatory network transmitted by large viral vectors to the flat epithelium to stimulate remnants of the organ of Corti to restore hair cells. We hope to unite with our proposal toward the common goal, eventually restoring a functional human hearing organ by transforming the flat epithelial cells left after the organ of Corti loss.

PMID: 32173536 [PubMed – as supplied by publisher]

Microenvironment Can Induce Development of Auditory Progenitor Cells from Human Gingival Mesenchymal Stem Cells

https://pubs.acs.org/doi/abs/10.1021/acsbiomaterials.9b01795

Microenvironment Can Induce Development of Auditory Progenitor Cells from Human Gingival Mesenchymal Stem Cells
Sevda Pouraghaei, Fathollah Moztarzadeh*, Chider Chen, Sahar Ansari, and Alireza Moshaverinia*
Cite this: ACS Biomater. Sci. Eng. 2020, 6, 4, 2263–2273
Publication Date:March 10, 2020
https://doi.org/10.1021/acsbiomaterials.9b01795

Relieving ferroptosis may partially reverse neurodegeneration of the auditory cortex

https://febs.onlinelibrary.wiley.com/doi/abs/10.1111/febs.15266

https://www.ncbi.nlm.nih.gov/pubmed/32112499?dopt=Abstract

Related Articles

Relieving ferroptosis may partially reverse neurodegeneration of the auditory cortex.

FEBS J. 2020 Feb 28;:

Authors: Chen X, Li D, Sun HY, Wang WW, Wu H, Kong W, Kong WJ

Abstract

Central presbycusis is caused by degradation of the auditory centre during ageing. Its main characteristics are difficulties in understanding language and localizing sound. Presbycusis is an increasingly critical public health problem, but the underlying molecular mechanism has not been fully elucidated. Ferroptosis is a form of regulated cell death caused by iron- and reactive oxygen species-induced lipid peroxidation. Ferroptosis is related to many pathological processes, but whether it participates in the degeneration of the auditory system remains unclear. To investigate this, we measured iron levels in a simulated ageing model established by the addition of D-galactose (D-gal). We found, for the first time that iron accumulated within cells and that the ultrastructural features of ferroptosis appeared in the auditory cortex with ageing. These changes were accompanied by upregulation of iron regulatory protein 2 (IRP-2), which led to an increase in transferrin receptor 1 (TfR-1), thus increasing iron entry into cells and potentially leading to ferroptosis. In addition, the malondialdehyde (MDA) content and the occurrence of mitochondrial DNA common deletions (CDs) increased, neuron degeneration appeared, and glutathione (GSH) and superoxide dismutase (SOD) activity decreased. Furthermore, we found that treatment with the iron chelator deferoxamine (DFO) and knockdown of IRP-2 both relieved ferroptosis during the simulated ageing process, thus achieving a partial protective effect to delay ageing. In summary, we describe here the first discovery that age-related iron deposition and ferroptosis may be associated with auditory cortex neurodegeneration. Relieving ferroptosis might thus be a new intervention strategy for age-related hearing loss.

PMID: 32112499 [PubMed – as supplied by publisher]

rAAV-Mediated Cochlear Gene Therapy: Prospects and Challenges for Clinical Application

https://www.mdpi.com/2077-0383/9/2/589

https://www.ncbi.nlm.nih.gov/pubmed/32098144?dopt=Abstract

Related Articles

rAAV-Mediated Cochlear Gene Therapy: Prospects and Challenges for Clinical Application.

J Clin Med. 2020 Feb 21;9(2):

Authors: Blanc F, Mondain M, Bemelmans AP, Affortit C, Puel JL, Wang J

Abstract

Over the last decade, pioneering molecular gene therapy for inner-ear disorders have achieved experimental hearing improvements after a single local or systemic injection of adeno-associated, virus-derived vectors (rAAV for recombinant AAV) encoding an extra copy of a normal gene, or ribozymes used to modify a genome. These results hold promise for treating congenital or later-onset hearing loss resulting from monogenic disorders with gene therapy approaches in patients. In this review, we summarize the current state of rAAV-mediated inner-ear gene therapies including the choice of vectors and delivery routes, and discuss the prospects and obstacles for the future development of efficient clinical rAAV-mediated cochlear gene medicine therapy.

PMID: 32098144 [PubMed]

EGF and a GSK3 Inhibitor Deplete Junctional E-cadherin and Stimulate Proliferation in the Mature Mammalian Ear

https://www.jneurosci.org/content/early/2020/02/18/JNEUROSCI.2630-19.2020

https://www.ncbi.nlm.nih.gov/pubmed/32079647?dopt=Abstract

Related Articles

EGF and a GSK3 Inhibitor Deplete Junctional E-cadherin and Stimulate Proliferation in the Mature Mammalian Ear.

J Neurosci. 2020 Feb 19;:

Authors: Kozlowski MM, Rudolf MA, Corwin JT

Abstract

Sensory hair cell losses underlie the vast majority of permanent hearing and balance deficits in humans, but many non-mammalian vertebrates can fully recover from hearing impairments and balance dysfunctions, because supporting cells (SCs) in their ears retain lifelong regenerative capacities that depend on proliferation and differentiation as replacement hair cells. Most SCs in vertebrate ears stop dividing during embryogenesis, and soon after birth vestibular SCs in mammals transition to lasting quiescence as they develop massively thickened circumferential F-actin bands at their E-cadherin-rich adherens junctions. Here, we report that treatment with EGF and a GSK3 inhibitor thinned the circumferential F-actin bands throughout the sensory epithelium of cultured utricles that were isolated from adult mice of either sex. That treatment also caused decreases in E-cadherin, β-catenin, and YAP in the striola, and stimulated robust proliferation of mature, normally quiescent striolar SCs. The findings suggest that E-cadherin-rich junctions, which are not present in the SCs of the fish, amphibians, and birds which readily regenerate hair cells, are responsible in part for the mammalian ear’s vulnerability to permanent balance and hearing deficits.SIGNIFICANCE STATEMENTMillions of people are affected by hearing and balance deficits that arise when loud sounds, ototoxic drugs, infections, and aging cause hair cell losses. Such deficits are permanent for humans and other mammals, but non-mammals can recover hearing and balance after supporting cells regenerate replacement hair cells. Mammalian supporting cells lose the capacity to proliferate around the time they develop unique, exceptionally reinforced, E-cadherin-rich intercellular junctions. Here, we report the discovery of a pharmacological treatment that thins F-actin bands, depletes E-cadherin, and stimulates proliferation in long-quiescent supporting cells within a balance epithelium from adult mice. The findings suggest that high E-cadherin in those supporting cell junctions may be responsible, in part, for the permanence of hair cell loss in mammals.

PMID: 32079647 [PubMed – as supplied by publisher]

Role of melatonin in prevention of age-related hearing loss

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0228943

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7010238/

https://www.ncbi.nlm.nih.gov/pubmed/32040524?dopt=Abstract

Related Articles

Role of melatonin in prevention of age-related hearing loss.

PLoS One. 2020;15(2):e0228943

Authors: Serra LSM, Araújo JG, Vieira ALS, Silva EMD, Andrade RR, Kückelhaus SAS, Sampaio ALL

Abstract

INTRODUCTION: Age-related hearing loss (ARHL) is a consequence of aging of the auditory system. The best known mechanism of cell death in ARHL is apoptosis due to increased production of reactive oxygen species. In this context, it is hypothesized that melatonin, owing to its high antioxidant potential and its action in the mitochondria, helps prevent or delay outer hair cell dysfunction (HCD).

AIMS: To evaluate the effect of melatonin on the prevention of HCD dysfunction in the ARHL process in a susceptible murine C57BL/6J model.

METHOD: C57BL/6J animals were divided into two groups: control (CG) and melatonin (MG). The CG received a saline and ethanol solution and the MG, melatonin (10 mg/kg/day). The solutions were offered daily (50 μl) orally over a 10-month period. Distortion Product Otoacoustic Emissions (DPOAE) measurements were conducted once a month.

RESULTS: There was a decrease in DPOAE values in both groups over time and a differentiation between them from the 10th month of life onwards. At 10 months, the MG maintained higher DPOAE values than the CG at all frequencies tested.

CONCLUSION: The use of melatonin has otoprotective effects on HCD in the ARHL process in the C57BL/6J model.

PMID: 32040524 [PubMed – indexed for MEDLINE]

Exosomes mediate sensory hair cell protection in the inner ear

https://www.jci.org/articles/view/128867

https://www.ncbi.nlm.nih.gov/pubmed/32027617?dopt=Abstract

Exosomes mediate sensory hair cell protection in the inner ear.

J Clin Invest. 2020 Feb 06;:

Authors: Breglio AM, May LA, Barzik M, Welsh NC, Francis SP, Costain TQ, Wang L, Anderson DE, Petralia RS, Wang YX, Friedman TB, Wood MJ, Cunningham LL

Abstract

Hair cells are the mechanosensory receptors of the inner ear, responsible for hearing and balance. Hair cell death and consequent hearing loss are common results of treatment with ototoxic drugs, including the widely-used aminoglycoside antibiotics. Induction of heat shock proteins (HSPs) confers protection against aminoglycoside-induced hair cell death via paracrine signaling that requires extracellular HSP70 (Heat Shock 70 kDa Protein). We investigated the mechanisms underlying this non-cell-autonomous protective signaling in the inner ear. In response to heat stress, inner ear tissue releases exosomes that carry HSP70 in addition to canonical exosome markers and other proteins. Isolated exosomes from heat-shocked utricles were sufficient to improve survival of hair cells exposed to the aminoglycoside antibiotic neomycin, while inhibition or depletion of exosomes from the extracellular environment abolished the protective effect of heat shock. Hair-cell specific expression of the known HSP70 receptor, Toll-like receptor 4 (TLR4), was required for the protective effect of exosomes, and exosomal HSP70 interacted with TLR4 on hair cells. Our results indicate that exosomes are a previously undescribed mechanism of intercellular communication in the inner ear that can mediate non-autonomous hair cell survival. Exosomes may represent a novel class of nano-carriers for delivery of therapeutics against hearing loss.

PMID: 32027617 [PubMed – as supplied by publisher]

Understanding hormone and hormone therapies’ impact on the auditory system

https://onlinelibrary.wiley.com/doi/abs/10.1002/jnr.24588

https://www.ncbi.nlm.nih.gov/pubmed/32026519?dopt=Abstract

Related Articles

Understanding hormone and hormone therapies’ impact on the auditory system.

J Neurosci Res. 2020 Feb 05;:

Authors: Williamson TT, Zhu X, Pineros J, Ding B, Frisina RD

Abstract

Hormones such as estrogen, progesterone, and aldosterone all demonstrate vital roles in sustaining auditory function through either the maintenance of cochlear neurons, up/down regulation of critical molecules (i.e., IGF-1, BDNF, etc.), or generation of the endocochlear potential. With disease and/or age, hormone expression begins to decline drastically, which ultimately affects cochlear structures and the integrity of cochlear cells. The following review explores the latest findings as well as realistic outcomes for hormone therapy treatment in the auditory system. This information could serve as a potential guide for patients considering hormone therapy as a medicinal choice to alleviate the signs of onset of presbycusis-age-related hearing loss. Additional scientific investigations could also be carried out to further enhance recent findings.

PMID: 32026519 [PubMed – as supplied by publisher]

Prostaglandin E1 effects on CD62p and PAC-1 in patients with sudden sensorineural hearing loss

https://www.thrombosisresearch.com/article/S0049-3848(20)30032-3/fulltext

https://www.ncbi.nlm.nih.gov/pubmed/32044505?dopt=Abstract

Related Articles

Prostaglandin E1 effects on CD62p and PAC-1 in patients with sudden sensorineural hearing loss.

Thromb Res. 2020 Jan 23;188:31-38

Authors: Xi J, Liu H, Wang X

Abstract

PERSPECTIVES: To evaluate the treatment outcome of vasodilator prostaglandin E1 (PGE1) in treating sudden sensorineural hearing loss (SSNHL) and to determine its effects on platelet activation, as reflected by changes in CD62p and PAC-1.

METHODS: We prospectively enrolled 60 patients with confirmed SSNHL and randomly divided them into two groups: the SSNHL group received regular therapy, and the SSNHL-PGE1 group received additional intravenous injection of PGE1. After 14 days of treatment, we measured clinical improvement and CD62p-positive and PAC-1-positive platelets. 30 healthy medical staff members were included as a control group.

RESULTS: The SSNHL patients had significantly higher levels of CD62p-positive or PAC-1 positive platelets than the healthy subjects. The ratios of CD62p positive or PAC-1 positive platelets significantly decreased after the two treatments. The average pure tone (PTA) hearing thresholds decreased to 26.51 ± 12.65 dB in SSNHL-PGE1 group after treatment, which was significantly lower than that of the SSNHL group (34.46 ± 10.35 dB). Patients with initial severe or profound hearing loss (PTA ≥ 71 dB) had better hearing improvement on PGE1 than on the regular treatment. Patients in the SSNHL-PGE1 treatment group had significantly lower CD62p and PAC-1 levels than those in the SSNHL group. Patients with higher initial positive CD62p and PAC-1 ratios tended to have higher potential of clinical improvement and hearing gains after PGE1 treatment. Initial CD62p and PAC-1 levels were significantly correlated with hearing thresholds in patients with SSNHL.

CONCLUSION: PGE1 application could improve treatment efficacy and suppress excessive platelet activation in patients with SSNHL.

PMID: 32044505 [PubMed – as supplied by publisher]

The role of Yamamoto new scalp acupuncture as an independent treatment for sudden sensorineural hearing loss: a case report

https://journals.sagepub.com/doi/10.1177/0964528419894594

https://www.ncbi.nlm.nih.gov/pubmed/31968987?dopt=Abstract

Related Articles

The role of Yamamoto new scalp acupuncture (YNSA) as an independent treatment for sudden sensorineural hearing loss: a case report.

Acupunct Med. 2020 Jan 22;:964528419894594

Authors: Kao TC, Yang CM

PMID: 31968987 [PubMed – as supplied by publisher]

Auditory brainstem response results demonstrate that transplantation of UC-MSCs is an efficient therapy for sensorineural hearing loss (SNHL) in pig model

https://anatomypubs.onlinelibrary.wiley.com/doi/abs/10.1002/ar.24346

https://pubmed.ncbi.nlm.nih.gov/31943852-transplantation-and-tracking-of-the-human-umbilical-cord-mesenchymal-stem-cell-labeled-with-superparamagnetic-iron-oxide-in-deaf-pigs/

Transplantation and Tracking of the Human Umbilical Cord Mesenchymal Stem Cell Labeled With Superparamagnetic Iron Oxide in Deaf Pigs

Abstract

The purpose of this study was to establish a safe and effective approach to label the human umbilical cord mesenchymal stem cells (UC-MSCs) derived from the Wharton’s Jelly with superparamagnetic iron oxide (SPIO) nanoparticles as a cell tracer. The cytotoxicity of the SPIO was screened in vitro by cytochemical experiments. The results showed the new infection protocol of SPIO-Lip2000 mixture had high efficiency and the optimal labeling concentration was a 50 μg/ml SPIO suspension. Transmission electron microscope (TEM) confirmed the distribution of the intracellular SPIO. We transplanted the labeled UC-MSCs into the sensorineural hearing loss (SNHL) minipigs at 1 week after noise exposure. Auditory brainstem response results demonstrated the transplantation of UC-MSCs was an efficient therapy for SNHL. The positive sediments in cochlear blood vessels, the bony wall of scala tympani, and spiral ganglion nerve fibers were found in the stem cell recipients’ cochlea. We did not detect iron elements in the inner/outer hair cells’ stereocilia, cuticular plate, or pillar cells from the basal to apex turns of the stem cell recipients’ cochlea. In addition, TEM found SPIO in the medulla oblongata and the cerebrum in the SNHL minipigs after stem cell transplantation. In conclusion, we established a safe and effective approach to labeled human UC-MSCs derived from Wharton’s Jelly by using SPIO nanoparticles as a cell tracer in vitro and in vivo. This protocol showed a wide promising application in stem cell therapy and tracing in vivo for experiments with large mammals. Anat Rec, 2020. © 2020 American Association for Anatomy.

AAV9-PHP.B vector drives gene expression in inner ear hair cells and could serve as a gene therapy vehicle for treatment of inner ear dysfunction in humans

https://www.ncbi.nlm.nih.gov/pubmed/31980281?dopt=Abstract

https://www.sciencedirect.com/science/article/pii/S0378595519305246?via%3Dihub

Lastly, we report here that alternate promoters, Syn and Gfap, can be used in combination with AAV9-PHP.B capsids to drive selective expression in subsets of cochlear cell types, such as neurons and supporting cells. We conclude that the AAV9-PHP.B capsid is a powerful vector for driving exogenous gene expression in pre-clinical mouse models of hearing and balance disorders and may be well-suited for further development and perhaps translation to clinical application as a gene therapy vehicle for treatment of inner ear dysfunction in humans.

Related Articles

Efficient viral transduction in mouse inner ear hair cells with utricle injection and AAV9-PHP.B.

Hear Res. 2020 Jan 13;:107882

Authors: Lee J, Nist-Lund C, Solanes P, Goldberg H, Wu J, Pan B, Schneider BL, Holt JR

Abstract

Viral delivery of exogenous coding sequences into the inner ear has the potential for therapeutic benefit for patients suffering genetic or acquired hearing loss. To devise improved strategies for viral delivery, we investigated two injection techniques, round window membrane injection or a novel utricle injection method, for their ability to safely and efficiently transduce sensory hair cells and neurons of the mouse inner ear. In addition, we evaluated three synthetic AAV vectors (Anc80L65, AAV9-PHP.B, AAV2.7m8) encoding enhanced green fluorescent protein (eGFP) and three promoters (Cmv, Synapsin, Gfap) for their ability to transduce and drive expression in desired cell types. We found the utricle injection method with AAV9-PHP.B and a Cmv promoter was the most efficient combination for driving robust eGFP expression in both inner and outer hair cells. We found eGFP expression levels rose over 3-5 days post-injection, a viral dose of 1.5 × 109 gc yielded half maximal eGFP expression and that the utricle injection method yielded transduced hair cells even when delivered as late as postnatal day 16. Sensory transduction and auditory thresholds were unaltered in injected mice relative to uninjected wild-type controls. Vestibular end organs were also transduced without affecting balance behavior. The Synapsin promoter and the Gfap promoter drove strong eGFP expression in inner ear neurons and supporting cells, respectively. We conclude the AAV9-PHP.B vector and the utricle injection method are well-suited for delivery of exogenous gene constructs into inner ears of mouse models of auditory and vestibular dysfunction.

PMID: 31980281 [PubMed – as supplied by publisher]

Possibility of using human dental pulp stem cells (DPSCs) and SHEDs as an autologous stem cell-based therapy for sensorineural hearing loss patients

https://anatomypubs.onlinelibrary.wiley.com/doi/abs/10.1002/ar.24368

https://pubmed.ncbi.nlm.nih.gov/31930687-neuronal-differentiation-of-dental-pulp-stem-cells-from-human-permanent-and-deciduous-teeth-following-coculture-with-rat-auditory-brainstem-slices/

Neuronal Differentiation of Dental Pulp Stem Cells From Human Permanent and Deciduous Teeth Following Coculture With Rat Auditory Brainstem Slices

Abstract

Sensorineural hearing loss is a common disability found worldwide which is associated with a degeneration of spiral ganglion neurons (SGN). It is a challenge to restore SGN due to the permanent degeneration and viability of SGN is requisite for patients to receive an advantage from hearing aid devices. Human dental pulp stem cells (DPSC) and stem cells from human exfoliated deciduous teeth (SHED) are self-renewing stem cells that originate from the neural crest during development. These stem cells have a high potential for neuronal differentiation. This is primarily due to their multilineage differentiation potential and their relative ease of access. Previously, we have shown the ability of these stem cell types to differentiate into spiral ganglion neuron-like cells. In this study, we induced the cells into neural precursor cells (NPC) and cocultured with auditory brainstem slice (ABS) encompassing cochlear nucleus by the Stoppini method. We also investigated their ability to differentiate after 2 weeks and 4 weeks in coculture. Neuronal differentiation of DPSC-NPC and SHED-NPC was higher expression of specific markers to SGN, TrkB, and Gata3, compared to monoculture. The cells also highly expressed synaptic vesicle protein (SV2A) and exhibited intracellular calcium oscillations. Our findings demonstrated the possibility of using DPSCs and SHEDs as an autologous stem cell-based therapy for sensorineural hearing loss patients.

Repeated Moderate Sound Exposure Causes Accumulated Trauma to Cochlear Ribbon Synapses in Mice

https://www.sciencedirect.com/science/article/abs/pii/S0306452220300075?via%3Dihub

https://pubmed.ncbi.nlm.nih.gov/31935490/

Repeated Moderate Sound Exposure Causes Accumulated Trauma to Cochlear Ribbon Synapses in Mice
Yangtuo Luo 1, Tengfei Qu 2, Qingling Song 2, Yue Qi 2, Shukui Yu 2, Shusheng Gong 2, Ke Liu 3, Xuejun Jiang 4
Affiliations expand
PMID: 31935490 DOI: 10.1016/j.neuroscience.2019.12.049

Short-term NAD+ supplementation prevents hearing loss in mouse models of Cockayne syndrome

https://www.nature.com/articles/s41514-019-0040-z

Short-term NAD+ supplementation prevents hearing loss in mouse models of Cockayne syndrome
Mustafa N. Okur, Beatrice Mao, Risako Kimura, Scott Haraczy, Tracy Fitzgerald, Kamren Edwards-Hollingsworth, Jane Tian, Wasif Osmani, Deborah L. Croteau, Matthew W. Kelley & Vilhelm A. Bohr
npj Aging and Mechanisms of Disease volume 6, Article number: 1 (2020) Cite this article

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Novel Oral Multifunctional Antioxidant HK-2 Prevents Noise-Induced Hearing Loss and Hair Cell Loss

https://pubmed.ncbi.nlm.nih.gov/31945692-novel-oral-multifunctional-antioxidant-prevents-noise-induced-hearing-loss-and-hair-cell-loss/

https://www.sciencedirect.com/science/article/pii/S0378595519304125?via%3Dihub

Novel Oral Multifunctional Antioxidant Prevents Noise-Induced Hearing Loss and Hair Cell Loss

G D Chen 1, D M Daszynski 2, D Ding 1, H Jiang 1, T Woolman 2, K Blessing 3, P F Kador 3, R Salvi 4

PMID: 31945692 DOI: 10.1016/j.heares.2019.107880

Abstract

Oxidative stress is a major contributor to noise-induced hearing loss, the most common cause of hearing loss among military personnel and young adults. HK-2 is a potent, orally-active, multifunctional, redox-modulating drug that has been shown to protect against a wide range of neurological disorders with no observed side effects. HK-2 protected cochlear HEI-OC1 cells against various forms of experimentally-induced oxidative stressors similar to those observed during and after intense noise exposure. The mechanisms by which HK-2 protects cells is twofold, first by its ability to reduce oxidative stress generated by free radicals, and second, by its ability to complex biologically active transition metals such as Fe+2, thus reducing their availability to participate in the Fenton reaction where highly toxic hydroxyl radicals are generated. For the rat in vivo studies, HK-2 provided significant protection against noise-induced hearing loss and hair cell loss. Noise-induced hearing loss was induced by an 8-16 kHz octave band noises presented for 8 h/d for 21 days at an intensity of 95 dB SPL. In the Prevention study, HK-2 was administered orally beginning 5 days before the start of the noise and ending 10 days after the noise. Treatment with HK-2 dose-dependently reduced the amount of noise-induced hearing impairment, reflected in the cochlear compound action potential, and noise-induced hair cell loss. In a subsequent Rescue experiment in which HK-2 was administered for 10 days starting after the noise was turned off, HK-2 also significantly reduced the amount of hearing impairment, but the effect size was substantially less than in the Prevention studies. HK-2 alone did not adversely affect HEI-OC1 cell viability, nor did it cause any adverse changes in rat body weight, behavior, cochlear function or hair cell integrity. Thus, HK-2 is a novel, safe, orally-deliverable and highly effective otoprotective compound with considerable potential for preventing hearing loss from noise and other hearing disorders linked to excessive oxidative stress.

TRPV4 and TRPV3 in cochlear hair cells (HCs) protect hearing in mice

https://www.frontiersin.org/articles/10.3389/fnmol.2019.00296/full

https://pubmed.ncbi.nlm.nih.gov/31866822-transient-receptor-potential-cation-channel-subfamily-vanilloid-4-and-3-in-the-inner-ear-protect-hearing-in-mice/

TRPV4 and TRPV3 in cochlear inner hair cells (HCs) protect hearing in mice

Transient Receptor Potential Cation Channel Subfamily Vanilloid 4 and 3 in the Inner Ear Protect Hearing in Mice

Abstract

The transient receptor potential cation channel, vanilloid type (TRPV) 3, is a member of the TRPV subfamily that is expressed predominantly in the skin, hair follicles, and gastrointestinal tract. It is also distributed in the organ of Corti of the inner ear and colocalizes with TRPV1 or TRPV4, but its role in auditory function is unknown. In the present study, we demonstrate that TRPV3 is expressed in inner hair cells (HCs) but mainly in cochlear outer HCs in mice, with expression limited to the cytoplasm and not detected in stereocilia. We compared the number of HCs as well as distortion product otoacoustic emissions (DPOAE) and auditory brainstem response (ABR) thresholds between TRPV3 knockout (V3KO) and wild-type (V3WT) mice and found that although most mutants (72.3%) had normal hearing, a significant proportion (27.7%) showed impaired hearing associated with loss of cochlear HCs. Compensatory upregulation of TRPV4 in HCs prevented HC damage and kanamycin-induced hearing loss and preserved normal auditory function in most of these mice. Thus, TRPV4 and TRPV3 in cochlear HCs protect hearing in mice; moreover, the results suggest some functional redundancy in the functions of TRPV family members. Our findings provide novel insight into the molecular basis of auditory function in mammals that can be applied to the development of strategies to mitigate hearing loss.

Novel insights into inner ear development and regeneration for targeted hearing loss therapies

https://www.ncbi.nlm.nih.gov/pubmed/31810596?dopt=Abstract

https://www.sciencedirect.com/science/article/pii/S037859551930440X?via%3Dihub

Related Articles

Novel insights into inner ear development and regeneration for targeted hearing loss therapies.

Hear Res. 2019 Nov 28;:107859

Authors: Roccio M, Senn P, Heller S

Abstract

Sensorineural hearing loss is the most common sensory deficit in humans. Despite the global scale of the problem, only limited treatment options are available today. The mammalian inner ear is a highly specialized postmitotic organ, which lacks proliferative or regenerative capacity. Since the discovery of hair cell regeneration in non-mammalian species however, much attention has been placed on identifying possible strategies to reactivate similar responses in humans. The development of successful regenerative approaches for hearing loss strongly depends on a detailed understanding of the mechanisms that control human inner ear cellular specification, differentiation and function, as well as on the development of robust in vitro cellular assays, based on human inner ear cells, to study these processes and optimize therapeutic interventions. We summarize here some aspects of inner ear development and strategies to induce regeneration that have been investigated in rodents. Moreover, we discuss recent findings in human inner ear development and compare the results with findings from animal models. Finally, we provide an overview of strategies for in vitro generation of human sensory cells from pluripotent and somatic progenitors that may provide a platform for drug development and validation of therapeutic strategies in vitro.

PMID: 31810596 [PubMed – as supplied by publisher]

The role of diet in vulnerability to noise-induced cochlear injury and hearing loss

https://asa.scitation.org/doi/10.1121/1.5132707

https://pubmed.ncbi.nlm.nih.gov/31795697-the-role-of-diet-in-vulnerability-to-noise-induced-cochlear-injury-and-hearing-loss/

The role of diet in vulnerability to noise-induced cochlear injury and hearing loss

The Journal of the Acoustical Society of America 146, 4033 (2019); https://doi.org/10.1121/1.5132707

Christopher Spankovich1,a) and Colleen G. Le Prell2

Medicines discovery for auditory disorders: Challenges for industry

https://asa.scitation.org/doi/full/10.1121/1.5132706

https://pubmed.ncbi.nlm.nih.gov/31795652/

Medicines discovery for auditory disorders: Challenges for industry
The Journal of the Acoustical Society of America 146, 3652 (2019); https://doi.org/10.1121/1.5132706
Rick P. C. Cousinsb)

Therapeutic effects of metformin for noise induced hearing loss

https://www.sciencedirect.com/science/article/pii/S0196070919309299?via%3Dihub

Therapeutic effects of metformin for noise induced hearing loss

Received 4 October 2019, Available online 30 October 2019.

https://doi.org/10.1016/j.amjoto.2019.102328

Targeting Inflammatory Processes Mediated by TRPVI and TNF-α for Treating Noise-Induced Hearing Loss

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6786284/

https://www.frontiersin.org/articles/10.3389/fncel.2019.00444/full

https://www.ncbi.nlm.nih.gov/pubmed/31632242?dopt=Abstract

TNF-α and TRPV1 are important therapeutic targets for treating NIHL

Targeting Inflammatory Processes Mediated by TRPVI and TNF-α for Treating Noise-Induced Hearing Loss.

Front Cell Neurosci. 2019;13:444

Authors: Dhukhwa A, Bhatta P, Sheth S, Korrapati K, Tieu C, Mamillapalli C, Ramkumar V, Mukherjea D

Abstract

Noise trauma is the most common cause of hearing loss in adults. There are no known FDA approved drugs for prevention or rescue of noise-induced hearing loss (NIHL). In this study, we provide evidence that implicates stress signaling molecules (TRPV1, NOX3, and TNF-α) in NIHL. Furthermore, we provide evidence that inhibiting any one of these moieties can prevent and treat NIHL when administered within a window period. Hearing loss induced by loud noise is associated with the generation of reactive oxygen species (ROS), increased calcium (Ca2+) in the endolymph and hair cells, and increased inflammation in the cochlea. Increased (Ca2+) and ROS activity persists for several days after traumatic noise exposure (NE). Chronic increases in (Ca2+) and ROS have been shown to increase inflammation and apoptosis in various tissue. However, the precise role of Ca2+ up-regulation and the resulting inflammation causing a positive feedback loop in the noise-exposed cochlea to generate sustained toxic amounts of Ca2+ are unknown. Here we show cochlear TRPV1 dysregulation is a key step in NIHL, and that inflammatory TNF-α cytokine-mediated potentiation of TRPV1 induced Ca2+ entry is an essential mechanism of NIHL. In the Wistar rat model, noise produces an acute (within 48 h) and a chronic (within 21 days) increase in cochlear gene expression of TRPV1, NADPH oxidase 3 (NOX3) and pro-inflammatory mediators such as tumor necrosis factor-α (TNF-α) and cyclooxygenase-2 (COX2). Additionally, we also show that H2O2 (100 μM) produces a robust increase in Ca2+ entry in cell cultures which is enhanced by TNF-α via the TRPV1 channel and which involves ERK1/2 phosphorylation. Mitigation of NIHL could be achieved by using capsaicin (TRPV1 agonist that rapidly desensitizes TRPV1. This mechanism is used in the treatment of pain in diabetic peripheral neuropathy) pretreatment or by inhibition of TNF-α with Etanercept (ETA), administered up to 7 days prior to NE or within 24 h of noise. Our results demonstrate the importance of the synergistic interaction between TNF-α and TRPV1 in the cochlea and suggest that these are important therapeutic targets for treating NIHL.

PMID: 31632242 [PubMed]

Genetic therapies for hearing loss: Accomplishments and remaining challenges

https://link.springer.com/article/10.1007%2Fs11306-019-1595-1

https://www.ncbi.nlm.nih.gov/pubmed/31586696?dopt=Abstract

Genetic therapies for hearing loss: Accomplishments and remaining challenges.

Neurosci Lett. 2019 Oct 03;:134527

Authors: Taiber S, Avraham KB

Abstract

More than 15 years have passed since the official completion of the Human Genome Project. Predominantly due to this project, over one hundred genes have now been linked to hearing loss. Although major advancements have been made in the understanding of underlying pathologies in deafness as a consequence of these gene discoveries, biological treatments for these conditions are still not available and current treatments rely on amplification or prosthetics. A promising approach for developing treatments for genetic hearing loss is the most simplistic one, that of gene therapy. Gene therapy would intuitively be ideal for these conditions since it is directed at the very source of the problem. Recent achievements in this field in laboratory models spike hope and optimism among scientists, patients, and industry, and suggest that this approach can mature into clinical trials in the coming years. Here we review the existing literature and discuss the different aspects of developing gene therapy for genetic hearing loss.

PMID: 31586696 [PubMed – as supplied by publisher]

Comparing Steroids and Diuretics in the Treatment of Acute Low-Tone Sensorineural Hearing Loss

https://journals.sagepub.com/doi/10.1177/0145561319869610

https://www.ncbi.nlm.nih.gov/pubmed/31569978?dopt=Abstract

Meta-Analysis Comparing Steroids and Diuretics in the Treatment of Acute Low-Tone Sensorineural Hearing Loss.

Ear Nose Throat J. 2019 Sep 30;:145561319869610

Authors: Zhu Y, Li G, Zhuang H, Yang Z, Sun J, Xiong G, Wang X

Abstract

OBJECTIVE: Our objective was to perform a meta-analysis to compare the effectiveness of steroids and diuretics in the treatment of acute low-tone sensorineural hearing loss (ALHL).

METHODS: PubMed, Google Scholar, and Sci databases were searched for randomized controlled trials (RCTs) examining the treatment of ALHL with steroids and diuretics. The Cochrane Reviewer’s Handbook 5.0 evaluation criteria were used to evaluate the quality of the included RCTs. Meta-analysis was performed using Revman 5.3 software to compare the recovery rate of low-tone hearing levels between patients treated with steroids and diuretics.

RESULTS: A total of 3 RCTs were included. There was no heterogeneity between the 3 studies (χ2 = 2.61, P = .27, I 2 = 23%); thus, a fixed-effects model of analysis was used. Meta-analysis showed there was no significant difference in the recovery rate of patients treated with steroids and those treated with diuretics (odds ratio = 1.48, 95% confidence interval: 0.64-3.40, P = .36).

CONCLUSION: Steroids and diuretics are equally effective for the treatment of ALHL.

PMID: 31569978 [PubMed – as supplied by publisher]

Effect of Specific Retinoic Acid Receptor Agonists on Noise-Induced Hearing Loss

https://www.mdpi.com/1660-4601/16/18/3428

Effect of Specific Retinoic Acid Receptor Agonists on Noise-Induced Hearing Loss
by Sang Hyun Kwak 1,Gi-Sung Nam 2,Seong Hoon Bae 1 andJinsei Jung 1,*OrcID
1
Department of Otorhinolaryngology, Yonsei University College of Medicine, Seoul 03722, Korea
2
Department of Otorhinolaryngology, Chonbuk National University College of Medicine, Jeonju 54907, Korea
*
Author to whom correspondence should be addressed.
Int. J. Environ. Res. Public Health 2019, 16(18), 3428; https://doi.org/10.3390/ijerph16183428
Received: 3 July 2019 / Revised: 10 September 2019 / Accepted: 11 September 2019 / Published: 16 September 2019
(This article belongs to the Special Issue Environmental Exposures and Hearing Loss)

β-secretase BACE1 is required for normal cochlear function and essential for the processing of auditory signals in the inner ear

https://www.jneurosci.org/content/early/2019/09/13/JNEUROSCI.0028-19.2019

https://www.ncbi.nlm.nih.gov/pubmed/31527119?dopt=Abstract

Related Articles

β-secretase BACE1 is required for normal cochlear function.

J Neurosci. 2019 Sep 16;:

Authors: Dierich M, Hartmann S, Dietrich N, Moeser P, Brede F, Johnson Chacko L, Tziridis K, Schilling A, Krauss P, Hessler S, Karch S, Schrott-Fischer A, Blumer M, Birchmeier C, Oliver D, Moser T, Schulze H, Alzheimer C, Leitner MG, Huth T

Abstract

Cleavage of amyloid precursor protein (APP) by β-secretase BACE1 initiates the production and accumulation of neurotoxic amyloid-β peptides, which is widely considered an essential pathogenic mechanism in Alzheimer’s disease (AD). Here, we report that BACE1 is essential for normal auditory function. Compared to wild type littermates, BACE1-/- mice of either sex exhibit significant hearing deficits, as indicated by increased thresholds and reduced amplitudes in auditory brainstem responses (ABRs), and decreased distortion product otoacoustic emissions (DPOAEs). In these mice immunohistochemistry revealed aberrant synaptic organization in the cochlea and hypomyelination of auditory nerve fibers as predominant neuropathological substrates of hearing loss in BACE1-/- mice. In particular, we found that fibers of spiral ganglion neurons (SGN) close to the organ of Corti are disorganized and abnormally swollen. BACE1-deficiency also engenders organization defects in the postsynaptic compartment of SGN fibers with ectopic over-expression of PSD95 far outside the synaptic region. During postnatal development, auditory fiber myelination in BACE1-/- mice lags behind dramatically and remains incomplete into adulthood. We relate the marked hypomyelination to the impaired processing of Neuregulin-1 when BACE1 is absent. To determine whether the cochlea of adult wild type mice is susceptible to AD treatment-like suppression of BACE1, we administered the established BACE1 inhibitor NB-360 for 6 weeks. The drug suppressed BACE1 activity in the brain, but did not impair hearing performance and, upon neuropathological examination, did not produce the characteristic cochlear abnormalities of BACE1-/- mice. Together, these data strongly suggest that the hearing loss of BACE1-knockout mice represents a developmental phenotype.SIGNIFICANCE STATEMENTGiven its crucial role in the pathogenesis of Alzheimer’s disease (AD), BACE1 is a prime pharmacological target for AD prevention and therapy. However, the safe and long-term administration of BACE1-inhibitors as envisioned in AD requires a comprehensive understanding of the various physiological functions of BACE1. Here, we report that BACE1 is essential for the processing of auditory signals in the inner ear, as BACE1-deficient mice exhibit significant hearing loss. We relate this deficit to impaired myelination and aberrant synapse formation in the cochlea, which manifest during postnatal development. By contrast, prolonged pharmacological suppression of BACE1 activity in adult wild type mice did not reproduce the hearing deficit or the cochlear abnormalities of BACE1 null mice.

PMID: 31527119 [PubMed – as supplied by publisher]

Protective role of estrogen towards acquired forms of hearing loss

https://link.springer.com/article/10.1007%2Fs00018-019-03295-y

https://www.ncbi.nlm.nih.gov/pubmed/31522250?dopt=Abstract

Experimental evidence supporting a protective role of estrogen towards acquired forms of hearing loss

Auditory function and dysfunction: estrogen makes a difference.

Cell Mol Life Sci. 2019 Sep 14;:

Authors: Delhez A, Lefebvre P, Péqueux C, Malgrange B, Delacroix L

Abstract

Estrogen is the major female hormone involved in reproductive functions, but it also exerts a variety of additional roles in non-reproductive organs. In this review, we highlight the preclinical and clinical studies that have pointed out sex differences and estrogenic influence on audition. We also describe the experimental evidences supporting a protective role of estrogen towards acquired forms of hearing loss. Although a high level of endogenous estrogen is associated with a better hearing function, hormonal treatments at menopause have provided contradictory outcomes. The various factors that are likely to explain these discrepancies include the treatment regimen as well as the hormonal status and responsiveness of the patients. The complexity of estrogen signaling is being untangled and many downstream effectors of its genomic and non-genomic actions have been identified in other systems. Based on these advances and on the common physio-pathological events that underlie age-related, drug or noise-induced hearing loss, we discuss potential mechanisms for their protective actions in the cochlea.

PMID: 31522250 [PubMed – as supplied by publisher]

Pleiotrophin (PTN) may be a novel candidate to improve sensorineural hearing loss treatment

https://link.springer.com/article/10.1007%2Fs00221-019-05644-6

https://www.ncbi.nlm.nih.gov/pubmed/31515588?dopt=Abstract

Related Articles

Pleiotrophin increases neurite length and number of spiral ganglion neurons in vitro.

Exp Brain Res. 2019 Sep 12;:

Authors: Bertram S, Roll L, Reinhard J, Groß K, Dazert S, Faissner A, Volkenstein S

Abstract

Acoustic trauma, aging, genetic defects or ototoxic drugs are causes for sensorineural hearing loss involving sensory hair cell death and secondary degeneration of spiral ganglion neurons. Auditory implants are the only available therapy for severe to profound sensorineural hearing loss when hearing aids do not provide a sufficient speech discrimination anymore. Neurotrophic factors represent potential therapeutic candidates to improve the performance of cochlear implants (CIs) by the support of spiral ganglion neurons (SGNs). Here, we investigated the effect of pleiotrophin (PTN), a well-described neurotrophic factor for different types of neurons that is expressed in the postnatal mouse cochlea. PTN knockout mice exhibit severe deficits in auditory brainstem responses, which indicates the importance of PTN in inner ear development and function and makes it a promising candidate to support SGNs. Using organotypic explants and dissociated SGN cultures, we investigated the influence of PTN on the number of neurons, neurite number and neurite length. PTN significantly increased the number and neurite length of dissociated SGNs. We further verified the expression of important PTN-associated receptors in the SG. mRNA of anaplastic lymphoma kinase, αv integrin, β3 integrin, receptor protein tyrosine phosphatase β/ζ, neuroglycan C, low-density lipoprotein receptor-related protein 1 and syndecan 3 was detected in the inner ear. These results suggest that PTN may be a novel candidate to improve sensorineural hearing loss treatment in the future.

PMID: 31515588 [PubMed – as supplied by publisher]

Review and analysis of existing pharmacologic therapies in patients with idiopathic sudden sensorineural hearing loss

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0221713

https://www.ncbi.nlm.nih.gov/pubmed/31498809?dopt=Abstract

A systematic review and network meta-analysis of existing pharmacologic therapies in patients with idiopathic sudden sensorineural hearing loss.

PLoS One. 2019;14(9):e0221713

Authors: Ahmadzai N, Kilty S, Cheng W, Esmaeilisaraji L, Wolfe D, Bonaparte JP, Schramm D, Fitzpatrick E, Lin V, Skidmore B, Moher D, Hutton B

Abstract

BACKGROUND: Hearing loss is one of the leading causes of disability worldwide. Patients with hearing loss experience impaired quality of life, as well as emotional and financial consequences that affect both themselves and their families. Idiopathic sudden sensorineural hearing loss (ISSNHL) is a common but difficult to treat condition that has a sudden onset of ≤ 72 hour associated with various etiologies, with the majority of cases being idiopathic. There exists a wide range of therapeutic options, however, the uncertainty surrounding their comparative efficacy and safety makes selection of treatment difficult. This systematic review and network meta-analysis (NMA) assessed the relative effects of competing treatments for management of ISSNHL.

METHODS: A protocol for this review was registered with PROSPERO (CRD42017073756). A detailed search of MEDLINE, Embase and the Cochrane Library from inception to February 8th, 2018 was carried out by an experienced information specialist. Grey literature was also searched. Screening full-text records, and risk of bias assessment were carried out independently by two reviewers, and disagreements were resolved through consensus or third party adjudication, while data was collected by one reviewer and verified by a second reviewer. Bayesian network meta-analyses (NMA) were performed to inform comparisons between interventions for a priori specified outcomes that included pure tone average (PTA) improvement and hearing recovery.

RESULTS: The search identified a total of 1,138 citations, of which 613 remained for review after removal of duplicates. Of these, 23 publications describing 19 unique studies (total sample size of 1,527) met our a priori eligibility criteria, that were assessed to be at unclear or high risk of bias on several domains. We identified data on several interventions for ISSNHL therapy and were able to construct treatment networks consisting of six intervention groups that included placebo; intratympanic (IT) steroid; IT plus systemic steroid; per oral (PO) steroid; intravenous (IV) steroid; and IV plus PO steroid for our NMAs. IT plus systemic steroids demonstrated the largest difference in PTA improvement compared to placebo (25.85 dB, 95% CrI 7.18-40.58), followed by IV plus PO steroids (22.06 dB, 95% CrI 1.24-39.17), IT steroids (18.24 dB, 95% CrI 3.00-29.81). We observed that the difference of PTA improvement between each intervention and placebo diminished over time, attributed to spontaneous recovery. The binary outcomes of hearing recovery demonstrated similar relative ordering of interventions but were less sensitive than PTA improvement to capture the significant differences between interventions and placebo.

CONCLUSION: Unclear to high risk of bias trials rated IT plus systemic steroid treatment as the best among the six interventions compared, and all active treatments were better than placebo in improving PTA. However, it should be noted that certain comparisons were based on indirect evidence only or few studies of small sample size, and analyses were unable to control for steroid type and dosage. Given these limitations, further data originating from methodologically sound and rigorous trials with adequate reporting are needed to confirm our findings.

PMID: 31498809 [PubMed – in process]

High Dose of Intratympanic Steroids for Sudden Sensorineural Hearing Loss Salvage

https://journals.lww.com/otology-neurotology/Abstract/publishahead/High_Dose_of_Intratympanic_Steroids_for_Sudden.96374.aspx

https://www.ncbi.nlm.nih.gov/pubmed/31498293?dopt=Abstract

High Dose of Intratympanic Steroids for Sudden Sensorineural Hearing Loss Salvage.

Otol Neurotol. 2019 Sep 06;:

Authors: Taha A, Shlamkovitch N, Abu-Eta R, Yeheskeli E, Muallem-Kalmovich L, Gavriel H, Pitaro J

Abstract

OBJECTIVE: Intratympanic (IT) steroid administration for sudden sensorineural hearing loss is offered as salvage to patients who failed systemic steroid treatment. Our objective was to study the audiometric and clinical outcomes of patients given salvage therapy with high-dose IT steroids instilled via ventilation tube.

STUDY DESIGN: Retrospective case review.

SETTING: Academic secondary medical center.

PATIENTS: One hundred three patients >18 years of age with sudden sensorineural hearing loss who failed systemic steroids and received IT treatment between 2010 and 2018.

INTERVENTION: Following ventilation tube insertion, 1 ml of 10 mg/ml dexamethasone was instilled, twice daily, for 7 days.

OUTCOME MEASURES: Hearing assessment immediately before and after treatment. Tinnitus and vertigo complaints and risk factors were also retrieved.

RESULTS: Tinnitus had improved in 53 (52%) patients, vertigo in 4 (4%), and aural fullness sensation in 56 (55%) (p < 0.001, p = 0.344, p < 0.001, respectively). The mean pure-tone threshold difference across frequencies following treatment was between 0 and 6 dB. A significant improvement was observed at 250, 500, 1000 Hz (p < 0.001 in all), and at 2000 Hz (p = 0.035). No significant difference was found at 4000 and 8000 Hz (p = 0.055, p = 0.983 respectively). Mean pure-tone average improvement of 4.5 dB was detected in 61 (59%) patients (p = 0.001). The mean speech discrimination score improved by 7% (p = 0.001). Four (22%) diabetic and nine (20%) hypertensive patients had pure-tone average ≥10 dB improvement (p = 0.759, p = 0.852 respectively). CONCLUSION: Although more than half of the patients improved clinically, the significance of the slight audiometric improvement should be weighed against the treatment protocol's complications. PMID: 31498293 [PubMed - as supplied by publisher]

Canalostomy is an ideal option for inner ear gene delivery for hearing loss

https://www.tandfonline.com/doi/abs/10.1080/00016489.2019.1654130?journalCode=ioto20

https://www.ncbi.nlm.nih.gov/pubmed/31486693?dopt=Abstract

Related Articles

Canalostomy is an ideal surgery route for inner ear gene delivery in big animal model.

Acta Otolaryngol. 2019 Sep 05;:1-9

Authors: Ji XJ, Chen W, Wang X, Zhang Y, Liu Q, Guo WW, Zhao JG, Yang SM

Abstract

Background: Inner gene therapy offers great promises as a potential treatment for hearing loss. Aims/objectives: One of the critical determinants of the success of inner ear gene therapy is to find a delivery method which results in consistent transduction efficiency of targeted cell types while minimizing hearing loss. Material and methods: Surgery was performed only in the right ear of each Bama miniature pig, and the left ear served as a control. The gene delivery to inner ear via round window membrane (RWM) and posterior semicircular canal (PSC) approach was performed with the viral vector AAV1-CMV-GFP. Results: The gene delivery through RWM and the PSC (canalostomy) is able to perfuse the inner ear. Conclusions and significance: The easy anatomic identification of the PSC, as to RWM, as well as minimal manipulation of the temporal bone required, make this surgical approach an attractive option for inner ear gene delivery in big animal model.

PMID: 31486693 [PubMed – as supplied by publisher]

Progenitor Cells from the Adult Human Inner Ear

https://anatomypubs.onlinelibrary.wiley.com/doi/full/10.1002/ar.24228

https://www.ncbi.nlm.nih.gov/pubmed/31489779?dopt=Abstract

Related Articles

Progenitor Cells from the Adult Human Inner Ear.

Anat Rec (Hoboken). 2019 Sep 05;:

Authors: Senn P, Mina A, Volkenstein S, Kranebitter V, Oshima K, Heller S

Abstract

Loss of inner ear hair cells leads to incurable balance and hearing disorders because these sensory cells do not effectively regenerate in humans. A potential starting point for therapy would be the stimulation of quiescent progenitor cells within the damaged inner ear. Inner ear progenitor/stem cells, which have been described in rodent inner ears, would be principal candidates for such an approach. Despite the identification of progenitor cell populations in the human fetal cochlea and in the adult human spiral ganglion, no proliferative cell populations with the capacity to generate hair cells have been reported in vestibular and cochlear tissues of adult humans. The present study aimed at filling this gap by isolating colony-forming progenitor cells from surgery- and autopsy-derived adult human temporal bones in order to generate inner ear cell types in vitro. Sphere-forming and mitogen-responding progenitor cells were isolated from vestibular and cochlear tissues. Clonal spheres grown from adult human utricle and cochlear duct were propagated for a limited number of generations. When differentiated in absence of mitogens, the utricle-derived spheres robustly gave rise to hair cell-like cells, as well as to cells expressing supporting cell-, neuron-, and glial markers, indicating that the adult human utricle harbors multipotent progenitor cells. Spheres derived from the adult human cochlear duct did not give rise to hair cell-like or neuronal cell types, which is an indication that human cochlear cells have limited proliferative potential but lack the ability to differentiate into major inner ear cell types. Anat Rec, 2019. © 2019 The Authors. The Anatomical Record published by Wiley Periodicals, Inc. on behalf of American Association for Anatomy.

PMID: 31489779 [PubMed – as supplied by publisher]

Comparison of Timing of Dexamethasone Administration on Noise-induced Hearing Loss (Before/After Acoustic Trauma)

https://www.nature.com/articles/s41598-019-49133-w

https://www.ncbi.nlm.nih.gov/pubmed/31477769?dopt=Abstract

Related Articles

Cochlear Glucocorticoid Receptor and Serum Corticosterone Expression in a Rodent Model of Noise-induced Hearing Loss: Comparison of Timing of Dexamethasone Administration.

Sci Rep. 2019 Sep 02;9(1):12646

Authors: Lee SH, Lyu AR, Shin SA, Jeong SH, Lee SA, Park MJ, Park YH

Abstract

Glucocorticoid (GC) is a steroid hormone secreted from the adrenal cortex in response to stress, which acts by binding to cytoplasmic glucocorticoid receptors (GRs). Dexamethasone (DEX) is a synthetic GC exhibiting immunosuppressive effects in both human and rodent models of hearing loss. While clinical evidence has shown the effectiveness of DEX for treatment of various inner ear diseases, its mechanisms of action and the optimal timing of treatment are not well understood. In the present study, intergroup comparisons were conducted based on the time point of treatment with DEX: (1) pretreatment; (2) posttreatment; and (3) pre&post-noise. The pre&post DEX treatment group showed a significant improvement in threshold shift at 1 day post-noise exposure as compared to the TTS (transient threshold shift)-only group at 8 and 16 kHz. Both TTS and PTS (permanent threshold shift) significantly reduced cochlear GR mRNA expression and increased serum corticosterone and cochlear inflammatory cytokines. The pre&post DEX treatment group showed a significant decrease in serum corticosterone level as compared to other DEX treatment groups and TTS-treated group at 3 days after acoustic trauma. Our results suggest that the timing of DEX administration differentially modulates systemic steroid levels, GR expression and cochlear cytokine expression.

PMID: 31477769 [PubMed – in process]

Inner ear organoids: new tools to understand neurosensory cell development, degeneration and regeneration

https://dev.biologists.org/content/146/17/dev177188

https://www.ncbi.nlm.nih.gov/pubmed/31477580?dopt=Abstract

Related Articles

Inner ear organoids: new tools to understand neurosensory cell development, degeneration and regeneration.

Development. 2019 09 02;146(17):

Authors: Roccio M, Edge ASB

Abstract

The development of therapeutic interventions for hearing loss requires fundamental knowledge about the signaling pathways controlling tissue development as well as the establishment of human cell-based assays to validate therapeutic strategies ex vivo Recent advances in the field of stem cell biology and organoid culture systems allow the expansion and differentiation of tissue-specific progenitors and pluripotent stem cells in vitro into functional hair cells and otic-like neurons. We discuss how inner ear organoids have been developed and how they offer for the first time the opportunity to validate drug-based therapies, gene-targeting approaches and cell replacement strategies.

PMID: 31477580 [PubMed – indexed for MEDLINE]

PKHD1L1 is a coat protein of hair-cell stereocilia and is required for normal hearing

https://www.nature.com/articles/s41467-019-11712-w

https://www.ncbi.nlm.nih.gov/pubmed/31444330?dopt=Abstract

Related Articles

PKHD1L1 is a coat protein of hair-cell stereocilia and is required for normal hearing.

Nat Commun. 2019 Aug 23;10(1):3801

Authors: Wu X, Ivanchenko MV, Al Jandal H, Cicconet M, Indzhykulian AA, Corey DP

Abstract

The bundle of stereocilia on inner ear hair cells responds to subnanometer deflections produced by sound or head movement. Stereocilia are interconnected by a variety of links and also carry an electron-dense surface coat. The coat may contribute to stereocilia adhesion or protect from stereocilia fusion, but its molecular identity remains unknown. From a database of hair-cell-enriched translated proteins, we identify Polycystic Kidney and Hepatic Disease 1-Like 1 (PKHD1L1), a large, mostly extracellular protein of 4249 amino acids with a single transmembrane domain. Using serial immunogold scanning electron microscopy, we show that PKHD1L1 is expressed at the tips of stereocilia, especially in the high-frequency regions of the cochlea. PKHD1L1-deficient mice lack the surface coat at the upper but not lower regions of stereocilia, and they develop progressive hearing loss. We conclude that PKHD1L1 is a component of the surface coat and is required for normal hearing in mice.

PMID: 31444330 [PubMed – in process]

KCNQ activators may treat and prevent hearing loss caused by KCNQ4 gene mutation

https://www.nature.com/articles/s12276-019-0300-9

https://www.ncbi.nlm.nih.gov/pubmed/31434872?dopt=Abstract

Related Articles

Rare KCNQ4 variants found in public databases underlie impaired channel activity that may contribute to hearing impairment.

Exp Mol Med. 2019 Aug 21;51(8):99

Authors: Jung J, Lin H, Koh YI, Ryu K, Lee JS, Rim JH, Choi HJ, Lee HJ, Kim HY, Yu S, Jin H, Lee JH, Lee MG, Namkung W, Choi JY, Gee HY

Abstract

KCNQ4 is frequently mutated in autosomal dominant non-syndromic hearing loss (NSHL), a typically late-onset, initially high-frequency loss that progresses over time (DFNA2). Most KCNQ4 mutations linked to hearing loss are clustered around the pore region of the protein and lead to loss of KCNQ4-mediated potassium currents. To understand the contribution of KCNQ4 variants to NSHL, we surveyed public databases and found 17 loss-of-function and six missense KCNQ4 variants affecting amino acids around the pore region. The missense variants have not been reported as pathogenic and are present at a low frequency (minor allele frequency < 0.0005) in the population. We examined the functional impact of these variants, which, interestingly, induced a reduction in potassium channel activity without altering expression or trafficking of the channel protein, being functionally similar to DFNA2-associated KCNQ4 mutations. Therefore, these variants may be risk factors for late-onset hearing loss, and individuals harboring any one of these variants may develop hearing loss during adulthood. Reduced channel activity could be rescued by KCNQ activators, suggesting the possibility of medical intervention. These findings indicate that KCNQ4 variants may contribute more to late-onset NSHL than expected, and therefore, genetic screening for this gene is important for the prevention and treatment of NSHL. PMID: 31434872 [PubMed - in process]

Cochlear histopathology in human genetic hearing loss: State of the science and future prospects

https://www.sciencedirect.com/science/article/pii/S0378595519301893?via%3Dihub

https://www.ncbi.nlm.nih.gov/pubmed/31493568?dopt=Abstract

Cochlear histopathology in human genetic hearing loss: State of the science and future prospects.

Hear Res. 2019 Aug 19;382:107785

Authors: Bommakanti K, Iyer JS, Stankovic KM

Abstract

Sensorineural hearing loss (SNHL) is an extraordinarily common disability, affecting 466 million people across the globe. Half of these incidents are attributed to genetic mutations that disrupt the structure and function of the cochlea. The human cochlea’s interior cannot be imaged or biopsied without damaging hearing; thus, everything known about the morphologic correlates of hereditary human deafness comes from histopathologic studies conducted in either cadaveric human temporal bone specimens or animal models of genetic deafness. The purpose of the present review is to a) summarize the findings from all published histopathologic studies conducted in human temporal bones with known SNHL-causing genetic mutations, and b) compare the reported phenotypes of human vs. mouse SNHL caused by the same genetic mutation. The fact that human temporal bone histopathologic analysis has been reported for only 22 of the nearly 200 identified deafness-causing genes suggests a great need for alternative and improved techniques for studying human hereditary deafness; in light of this, the present review concludes with a summary of promising future directions, specifically in the fields of high resolution cochlear imaging, intracochlear fluid biopsy, and gene therapy.

PMID: 31493568 [PubMed – as supplied by publisher]

Heparin therapy as adjuvant treatment for profound idiopathic sudden sensorineural hearing loss

https://onlinelibrary.wiley.com/doi/abs/10.1002/lary.28231

https://www.ncbi.nlm.nih.gov/pubmed/31397902?dopt=Abstract

Heparin therapy as adjuvant treatment for profound idiopathic sudden sensorineural hearing loss.

Laryngoscope. 2019 Aug 09;:

Authors: Kim J, Jeong J, Ha R, Sunwoo W

Abstract

OBJECTIVES/HYPOTHESIS: This study aimed to provide evidence of whether unfractionated heparin used as adjuvant therapy in conjunction with systemic corticosteroid therapy improves hearing recovery in patients with profound idiopathic sudden sensorineural hearing loss (ISSNHL), and to compare the effect of this treatment with those of additional intratympanic corticosteroid therapy.

STUDY DESIGN: Retrospective chart review.

METHODS: Eighty-seven patients with profound ISSNHL (≥90 dB) and who had been admitted at a tertiary referral center between 2010 and 2018 were retrospectively reviewed, 67 patients for additional intratympanic corticosteroid injection (ITSI) (ITSI group) and 21 for adjuvant heparin therapy (heparin group). Hearing recovery was evaluated by grade assessment according to the American Academy of Otolaryngology-Head and Neck Surgery criteria.

RESULTS: Of the patients in the heparin group, 42.8% recovered serviceable hearing, which was significantly higher than the recovery rates (19.7%) of those in the ITSI group. Particularly, in patients with pretreatment hearing level of 90 to 100 dB, adjuvant heparin therapy enhanced therapeutic effects with a significant hearing recovery rate of 80%. However, in patients with initial hearing level >100 dB, the rates of significant hearing recovery in the two groups were roughly equal and remained unsatisfactory (8.1% in the ITSI group and 9.1% in the heparin group).

CONCLUSIONS: The results of this study suggest that the treatment of profound ISSNHL with adjuvant heparin therapy, in combination with systemic steroid therapy, results in higher hearing recovery rates when compared to combined local and systemic corticosteroid therapy, without serious complications.

LEVEL OF EVIDENCE: 3b Laryngoscope, 2019.

PMID: 31397902 [PubMed – as supplied by publisher]

Effects of D-methionine in mice with noise-induced hearing loss mice

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6726779/

https://www.ncbi.nlm.nih.gov/pubmed/31327277?dopt=Abstract

Related Articles

Effects of D-methionine in mice with noise-induced hearing loss mice.

J Int Med Res. 2019 Aug;47(8):3874-3885

Authors: Wang Y, Qu Y, Chen X, Zhang P, Su D, Wang L, Yang F, Yang J

PMID: 31327277 [PubMed – indexed for MEDLINE]

Hearing regeneration and regenerative medicine: present and future approaches

https://www.termedia.pl/Hearing-regeneration-and-regenerative-medicine-present-and-future-approaches,19,36991,1,1.html

https://www.ncbi.nlm.nih.gov/pubmed/31360190?dopt=Abstract

Hearing regeneration and regenerative medicine: present and future approaches.

Arch Med Sci. 2019 Jul;15(4):957-967

Authors: Nacher-Soler G, Garrido JM, Rodríguez-Serrano F

Abstract

More than 5% of the world population lives with a hearing impairment. The main factors responsible for hearing degeneration are ototoxic drugs, aging, continued exposure to excessive noise and infections. The pool of adult stem cells in the inner ear drops dramatically after birth, and therefore an endogenous cellular source for regeneration is absent. Hearing loss can emerge after the degeneration of different cochlear components, so there are multiple targets to be reached, such as hair cells (HCs), spiral ganglion neurons (SGNs), supporting cells (SCs) and ribbon synapses. Important discoveries in the hearing regeneration field have been reported regarding stem cell transplantation, migration and survival; genetic systems for cell fate monitoring; and stem cell differentiation to HCs, SGNs and SCs using adult stem cells, embryonic stem cells and induced pluripotent stem cells. Moreover, some molecular mediators that affect the establishment of functional synapses have been identified. In this review, we will focus on reporting the state of the art in the regenerative medicine field for hearing recovery. Stem cell research has enabled remarkable advances in regeneration, particularly in neuronal cells and synapses. Despite the progress achieved, there are certain issues that need a deeper development to improve the results already obtained, or to develop new approaches aiming for the clinical application.

PMID: 31360190 [PubMed]

Avenanthramide-C (AVN-C) prevents noise- and drug-induced hearing loss while protecting auditory hair cells from oxidative stress

https://www.nature.com/articles/s41420-019-0195-1

https://www.ncbi.nlm.nih.gov/pubmed/31312524?dopt=Abstract

Avenanthramide-C prevents noise- and drug-induced hearing loss while protecting auditory hair cells from oxidative stress.

Cell Death Discov. 2019;5:115

Authors: Umugire A, Lee S, Kim D, Choi M, Kim HS, Cho HH

Abstract

Noise exposure or ototoxic drugs instigate various types of damage to the cochlea, resulting in hearing loss (HL). While the incidence of HL is growing continuously, there are, so far, no adequate drugs to prevent or treat HL. Avenanthramide (AVN), a natural product extracted from oats, has been reported to possess anti-oxidant/inflammatory properties, and protect several types of cells. In this study, we investigated whether AVN-C can protect auditory hair cells, and preserve hearing from noise trauma and ototoxic drugs. Wild-type C57BL/6 mice were used to generate several HL models. Serum and perilymphatic fluid samples were analyzed using mass spectrophotometry to detect AVN-C. AVN-C crossed the blood-labyrinth barrier, and was detected in the perilymph after systemic injection. Pretreatment by AVN-C 24โ€‰h before exposure to temporary threshold shift noise contributed to the preserving hearing. Moreover, in the case of permanent threshold shift, AVN-C provided significant protection from noise. AVN-C also strongly protected against deterioration in hearing due to kanamycin and furosemide (Kโ€‰+โ€‰F). According to the results of our scanning electron microscopy analysis, many outer hair cells (OHCs) were destroyed by noise trauma, while AVN-C prevented these losses. OHC loss due to Kโ€‰+โ€‰F was even more severe, even affecting the apex. Strikingly, AVN-C treatment maintained OHCs at a level comparable to normal cochlea. AVN-C reduced the dichlorofluorescin (DCF)-positive population in gentamicin-treated HEI-OC1 in vitro. The expressions of TNF-a, BAK, IL-1b, and Bcl-2 were attenuated by AVN-C, revealing its antioxidant effects. The results of this study show that AVN-C crosses the blood-labyrinth barrier and provide a significant protection against noise- and drug-induced ototoxicity. Hence, AVN-C is a good candidate for future therapy aimed at protecting against sensorineural HL.

PMID: 31312524 [PubMed]

Divergent auditory-nerve encoding deficits between two common etiologies of sensorineural hearing loss

https://www.ncbi.nlm.nih.gov/pubmed/31285299?dopt=Abstract

Divergent auditory-nerve encoding deficits between two common etiologies of sensorineural hearing loss.

J Neurosci. 2019 Jul 08;:

Authors: Henry KS, Sayles M, Hickox AE, Heinz MG

Abstract

Speech intelligibility can vary dramatically between individuals with similar clinically defined severity of hearing loss based on the audiogram. These perceptual differences, despite equal audiometric-threshold elevation, are often assumed to reflect central-processing variations. Here, we compared peripheral-processing in auditory-nerve fibers of male chinchillas between two prevalent hearing-loss etiologies: metabolic hearing loss (MHL) and noise-induced hearing loss (NIHL). MHL results from age-related reduction of the endocochlear potential due to atrophy of the stria vascularis. MHL in the present study was induced using furosemide, which provides a validated model of age-related MHL in young animals by reversibly inhibiting the endocochlear potential. Effects of MHL on peripheral processing were assessed using Wiener-kernel (system-identification) analyses of single auditory-nerve fiber responses to broadband noise, for direct comparison to previously published auditory-nerve responses from animals with NIHL. Wiener-kernel analyses show that even mild NIHL causes grossly abnormal coding of low-frequency stimulus components. In contrast, for MHL the same abnormal coding was only observed with moderate-severe loss. For equal sensitivity loss, coding impairment was substantially less severe with MHL than with NIHL, probably due to greater preservation of the tip-to-tail ratio of cochlear frequency tuning with MHL compared to NIHL rather than different intrinsic auditory-nerve properties. Differences in peripheral neural coding between these two pathologies [sbond] the more severe of which, NIHL, is preventable [sbond] likely contribute to individual speech-perception differences. Our results underscore the need to minimize noise overexposure and for strategies to personalize diagnosis and treatment for individuals with sensorineural hearing loss.SIGNIFICANCE STATEMENTDifferences in speech perception ability between individuals with similar clinically defined severity of hearing loss are often assumed to reflect central neural processing differences. Here, we demonstrate for the first time that peripheral neural processing of complex sounds differs dramatically between the two most common etiologies of hearing loss. Greater processing impairment with noise-induced compared to an age-related (metabolic) hearing-loss etiology may explain heightened speech-perception difficulties in people overexposed to loud environments. These results highlight the need for public policies to prevent noise-induced hearing loss – an entirely avoidable hearing-loss etiology – and for personalized strategies to diagnose and treat sensorineural hearing loss.

PMID: 31285299 [PubMed – as supplied by publisher]

Gene therapy for sensorineural hearing loss (SNHL)

https://academic.oup.com/hmg/advance-article-abstract/doi/10.1093/hmg/ddz129/5520925?redirectedFrom=fulltext

https://www.ncbi.nlm.nih.gov/pubmed/31227837?dopt=Abstract

Related Articles

Gene therapy for hearing loss.

Hum Mol Genet. 2019 Jun 22;:

Authors: Omichi R, Shibata SB, Morton CC, Smith RJH

Abstract

Sensorineural hearing loss (SNHL) is the most common sensory disorder. Its underlying etiologies include a broad spectrum of genetic and environmental factors that can lead to hearing loss that is congenital or late onset, stable or progressive, drug-related, noise-induced, age-related, traumatic or post-infectious. Habilitation options typically focus on amplification using wearable or implantable devices, however exciting new gene-therapy based strategies to restore and prevent SNHL are actively under investigation. Recent proof-of-principle studies demonstrate the potential therapeutic potential of molecular agents delivered to the inner ear to ameliorate different types of SNHL. Correcting or preventing underlying genetic forms of hearing loss is poised to become a reality. Herein, we review molecular therapies for hearing loss such as gene replacement, antisense oligonucleotides, RNA interference and CRISPR-based gene editing. We discuss delivery methods, techniques and viral vectors employed for inner ear gene therapy, and the advancements in this field that are paving the way for basic science research discoveries to transition to clinical trials.

PMID: 31227837 [PubMed – as supplied by publisher]

Role of estrogen signaling in hearing: hormonal modulation of hearing may lead to the development of therapeutics for sensorineural hearing loss

https://asa.scitation.org/doi/10.1121/1.5111870

https://www.ncbi.nlm.nih.gov/pubmed/31255106?dopt=Abstract

Sex differences in hearing: Probing the role of estrogen signaling.

J Acoust Soc Am. 2019 Jun;145(6):3656

Authors: Shuster BZ, Depireux DA, Mong JA, Hertzano R

Abstract

Hearing loss is the most common form of sensory impairment in humans, with an anticipated rise in incidence as the result of recreational noise exposures. Hearing loss is also the second most common health issue afflicting military veterans. Currently, there are no approved therapeutics to treat sensorineural hearing loss in humans. While hearing loss affects both men and women, sexual dimorphism is documented with respect to peripheral and central auditory physiology, as well as susceptibility to age-related and noise-induced hearing loss. Physiological differences between the sexes are often hormone-driven, and an increasing body of literature demonstrates that the hormone estrogen and its related signaling pathways may in part, modulate the aforementioned differences in hearing. From a mechanistic perspective, understanding the underpinnings of the hormonal modulation of hearing may lead to the development of therapeutics for age related and noise induced hearing loss. Here the authors review a number of studies that range from human populations to animal models, which have begun to provide a framework for understanding the functional role of estrogen signaling in hearing, particularly in normal and aberrant peripheral auditory physiology.

PMID: 31255106 [PubMed – in process]

Applications of photobiomodulation in hearing research: from bench to clinic

https://link.springer.com/article/10.1007%2Fs13534-019-00114-y

Applications of photobiomodulation in hearing research: from bench to clinic

Biomedical Engineering Letters

pp 1–8 | Cite as

Applications of photobiomodulation in hearing research: from bench to clinic

Authors
Jae-Hun LeeSehwan KimJae Yun JungMin Young LeeEmail author

Review Article
First Online: 18 June 2019

Abstract
Hearing loss is very common and economically burdensome. No accepted therapeutic modality for sensorineural hearing loss is yet available; most clinicians emphasize rehabilitation, placing hearing aids and cochlear implants. Photobiomodulation (PBM) employs light energy to enhance or modulate the activities of specific organs, and is a popular non-invasive therapy used to treat skin lesions and neurodegenerative disorders. Efforts to use PBM to improve hearing have been ongoing for several decades. Initial in vitro studies using cell lines and ex vivo culture techniques have now been supplanted by in vivo studies in animals; PBM protects the sensory epithelium and triggers neural regeneration. Many reports have used PBM to treat tinnitus. In this brief review, we introduce PBM applications in hearing research, helpful protocols, and relevant background literature.

Intratympanic Triamcinolone Acetonide as Treatment Option for Idiopathic Sudden Sensorineural Hearing Loss

https://journals.lww.com/otology-neurotology/Abstract/2019/07000/Intratympanic_Triamcinolone_Acetonide_as_Treatment.4.aspx

https://www.ncbi.nlm.nih.gov/pubmed/31192900?dopt=Abstract

Intratympanic Triamcinolone Acetonide as Treatment Option for Idiopathic Sudden Sensorineural Hearing Loss.

Otol Neurotol. 2019 Jul;40(6):720-727

Authors: Dahm V, Nieratschker M, Riss D, Kaider A, Auinger A, Honeder C, Arnoldner C

Abstract

INTRODUCTION: Corticosteroids represent the most commonly used treatment option for patients with idiopathic sudden sensorineural hearing loss. In the past, these compounds were mainly formulated and tested for intravenous or oral administration. Intratympanic application is increasingly being used, often as salvage treatment. The most suitable corticosteroid for local application has yet to be identified. Trials have suggested that triamcinolone acetonide has superior molecular properties for this treatment modality.

METHODS: The main aim of this study was to retrospectively assess the first audiometric results of patients diagnosed with idiopathic sudden sensorineural hearing loss and treated simultaneously with systemic prednisolone and intratympanic triamcinolone acetonide. This data was then compared to systemic treatment only, as well as to historic cohorts treated intratympanically with widely used corticosteroids, namely dexamethasone or methylprednisolone.

RESULTS: 90 patients received intravenous prednisolone only, and 89 individuals underwent intravenous treatment combined with three to four simultaneous intratympanic applications of triamcinolone. Eight patients received intratympanic triamcinolone as first-line treatment. After adjusting data for sex, time since onset, age, and severity of hearing loss, no statistically significant difference between the two main treatment groups could be identified. No major adverse events were observed, specifically no otitis media or persistent vertigo. Two perforated tympanic membranes healed spontaneously within several days.

CONCLUSION: While the exact role of intratympanic injections requires additional trials, triamcinolone resulted in similar outcomes compared to studies using dexamethasone or methylprednisolone. Due to favorable pharmacological properties, triamcinolone represents a safe and efficacious alternative for intratympanic treatment in idiopathic sensorineural hearing loss.

PMID: 31192900 [PubMed – in process]

Gene Editing Based Hearing Impairment Research and Therapeutics

https://www.ncbi.nlm.nih.gov/pubmed/31195050?dopt=Abstract

Gene Editing Based Hearing Impairment Research and Therapeutics.

Neurosci Lett. 2019 Jun 10;:134326

Authors: Kang W, Sun Z, Zhao X, Wang X, Tao Y, Wu H

Abstract

Hearing impairment affects 1 in 500 newborns worldwide and nearly one out of three people over the age of 65 (WHO, 2019). Hereditary hearing loss is the most common type of congenital deafness; genetic factors also affect deafness susceptibility. Gene therapies may preserve or restore natural sound perception, and have rescued deafness in multiple hereditary murine models. CRISPR-Cas9 and base editors (BEs) are newly developed gene-editing technologies that can facilitate gene studies in the inner ear and provide therapeutic approaches for hearing impairment. Here, we present recent applications of gene editing in the inner ear.

PMID: 31195050 [PubMed – as supplied by publisher]

Dextromethorphan (DXM) could be a potential agent in alleviating noise-induced hearing loss (NIHL)

https://www.sciencedirect.com/science/article/pii/S0041008X19302066?via%3Dihub

https://www.ncbi.nlm.nih.gov/pubmed/31153898?dopt=Abstract

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Evaluation of brain SERT with 4-[18F]-ADAM/micro-PET and hearing protective effects of dextromethorphan in hearing loss rat model.

Toxicol Appl Pharmacol. 2019 May 30;:114604

Authors: Liu CT, Huang YS, Chen HC, Ma KH, Wang CH, Chiu CH, Shih JH, Kang HH, Shiue CY, Li IH

Abstract

This study investigated the protective effects of dextromethorphan (DXM) on noise-induced hearing loss (NIHL) in rats. This study aimed to improve the auditory threshold and to understand the protective effects of DXM against N-methyl-d-aspartate (NMDA)-induced neurite degeneration of serotonergic neurons. The animals were exposed to 8-kHz narrowband noise at a 118-dB sound pressure level for 3.5 h. The hearing thresholds were determined by measuring the auditory brainstem response to click stimuli. Serotonin transporter (SERT) expression was determined through micro-positron emission tomography (PET) using N,N-dimethyl-2-(2-amino-4-18F-fluorophenylthio)benzylamine (4-[18F]-ADAM). We also investigated the effects of DXM on NMDA-induced morphological changes in the primary cultures of rat serotonergic neurons. NIHL significantly improved after prophylactic treatment with DXM (p < .05). SERT density in DXM-treated rats was significantly higher than that in non-DXM-treated rats. Because prophylactic medication restored the NMDA-inhibited neurite length of serotonergic neurons and presented SERT density, DXM could be a potential agent in alleviating NIHL. PMID: 31153898 [PubMed - as supplied by publisher]

Role of viral infection in sudden hearing loss: the viral hypothesis of SSNHL

https://journals.sagepub.com/doi/10.1177/0300060519847860

https://www.ncbi.nlm.nih.gov/pubmed/31130031?dopt=Abstract

Related Articles

Role of viral infection in sudden hearing loss.

J Int Med Res. 2019 May 27;:300060519847860

Authors: Chen X, Fu YY, Zhang TY

Abstract

According to a recent epidemiological survey, the incidence of sudden sensorineural hearing loss (SSNHL) is increasing yearly. The cause of SSNHL is of great interest in research. To date, viral infection, vascular occlusion, abnormal cellular stress responses within the cochlea, and immune-mediated mechanisms are considered the most likely etiologies of this disease. Among these etiologies, the relationship between viral infection and sudden deafness has been unclear. In this review, we mainly discuss the viral hypothesis of SSNHL. There is little research proving or clearly indicating the pathogenesis of this disease. Further research is needed to elucidate the precise etiopathogenesis to better understand SSNHL and establish more suitable treatment to help restore hearing in affected patients.

PMID: 31130031 [PubMed – as supplied by publisher]

Mesenchymal stem cells for sensorineural hearing loss: protocol for a systematic review of preclinical studies

https://systematicreviewsjournal.biomedcentral.com/articles/10.1186/s13643-019-1015-7

https://www.ncbi.nlm.nih.gov/pubmed/31128597?dopt=Abstract

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Mesenchymal stem cells for sensorineural hearing loss: protocol for a systematic review of preclinical studies.

Syst Rev. 2019 May 25;8(1):126

Authors: Chorath KT, Willis MJ, Morton-Gonzaba N, Humann WJ, Moreira A

Abstract

BACKGROUND: Sensorineural hearing loss (SNHL) is the most common form of hearing impairment and is characterized by a loss of receptor hair cells and/or spiral ganglion neurons. Regenerative stem cell therapy could potentially restore normal hearing and slow the progression of hearing loss in patients. Preclinical animal studies have demonstrated that mesenchymal stem cells (MSCs) could be a promising new therapy for this condition. These findings have prompted investigators to begin human clinical trials to assess the safety and efficacy of MSCs for the treatment of SNHL. The objective of the proposed systematic review is to examine the efficacy of MSCs as a therapy for SNHL in animal models.

METHODS: We will include preclinical animal studies of SNHL in which MSCs are administered, and outcomes are compared against MSC-naïve controls. The primary outcome will include audiologic tests that are routinely used in experimental studies of hearing loss, such as auditory brainstem response (ABR) and distortion product otoacoustic emissions testing (DPOAE). Secondary outcomes will include histology, microscopy, gene protein expression, and behavioral responses of animals. Electronic searches of MEDLINE via PubMed, Scopus, ScienceDirect, and Cumulative Index to Nursing and Allied Health Literature (CINAHL) will be performed. Search results will be screened independently and in duplicate. Data from eligible studies will be extracted, pooled, and analyzed using random effects models. Risk of bias and publication bias will be assessed using the Systematic Review Center for Laboratory Animal Experimentation (SYRCLE) risk of bias tool and Funnel Plots/Egger’s regression tests, respectively.

DISCUSSION: This systematic review will provide a summary of the efficacy of MSC therapy in animal models of SNHL, utilizing functional hearing assessment as a primary outcome. Findings from this review are important because they can elucidate research gaps that should be addressed in future preclinical studies and in turn can be translated into clinical studies.

SYSTEMATIC REVIEW REGISTRATION: CAMARADES ( http://www.dcn.ed.ac.uk/camarades/ ).

PMID: 31128597 [PubMed – in process]

Intratympanic steroids for combined treatment of idiopathic sudden hearing loss: when is it too late?

https://www.tandfonline.com/doi/abs/10.1080/00016489.2019.1614222?journalCode=ioto20

https://www.ncbi.nlm.nih.gov/pubmed/31124732?dopt=Abstract

Related Articles

Intratympanic steroids for combined treatment of idiopathic sudden hearing loss: when is it too late?

Acta Otolaryngol. 2019 May 24;:1-4

Authors: Amarillo E, Navarro A, Hernández-García E, Plaza G

Abstract

Background: Idiopathic sudden sensorineural hearing loss (ISSNHL) requires early treatment. Objective: To describe our experience on intratympanic steroid treatment (ITS) of ISSNHL analyzing the delay to start therapy as prognostic factor. Material and methods: We perform a retrospective study on ISSNHL treated with systemic steroids without full recovery on PTA (pure tone average) according to Siegel criteria. They were divided into two different groups: one group that additionally received ITS as combined therapy (treatment group), and another without it (control group). We analyzed the hearing recovery at 6 months and 2 years, and the influence of the delay to start ITS in the recovery. Results: After ITS was added, further complete recovery was achieved in 10 patients of the treatment group. After 6 months, PTA improvement in the treatment group was 10.84 dB, compared to 1.13 dB in the control group (p<.0001). Nevertheless, patients starting such combination of oral steroids and ITS within 8 days of diagnosis had an additional gain of 15 dB in the first 6 months, that increased to 19.17 dB after 24 months (p<.022). Conclusions: When ITS was added within the first 8 days, a significantly better and more stable response was obtained. PMID: 31124732 [PubMed - as supplied by publisher]

Association of anemia with sensorineural hearing loss: a systematic review and meta-analysis

https://www.ncbi.nlm.nih.gov/pubmed/31122277?dopt=Abstract

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Association of anemia with sensorineural hearing loss: a systematic review and meta-analysis.

BMC Res Notes. 2019 May 23;12(1):283

Authors: Mohammed SH, Shab-Bidar S, Abuzerr S, Habtewold TD, Alizadeh S, Djafarian K

Abstract

OBJECTIVE: Evidence shows that anemic individuals are at a higher risk of hearing loss. However, there is no systematic review and meta-analysis study. Thus, we aimed to meta-analyze the existing evidence on the association of iron deficiency anemia (IDA) with sensorineural hearing loss (SNHL). We searched PubMed, MEDLINE, Embase, Scopus, and Google Scholar from inception through October 30, 2017, for studies done on the association of the IDA with SNHL. Pooled odds ratio (OR) was calculated by random effect meta-analysis method. Heterogeneity was assessed by I2 metrics.

RESULT: Four studies, covering a total of 344,080 adults and children, were included. The odds of SNHL was higher by 55% in individuals with IDA, compared with individuals without IDA (OR = 1.55, 95% CI 1.17-2.06; P = 0.03). The age-specific ORs were 1.36 (95% CI 1.15-1.61; P = 0.27) and 3.67 (95% CI 1.72-7.84) for adults and children, respectively. IDA may be a contributing factor to hearing loss. Further studies are warranted, including whether IDA treatment reduces the risk of hearing loss. Meanwhile, hearing loss screening in anemic individuals, or vice versa, may represent an important consideration. PROSPERO registration CRD42017082108.

PMID: 31122277 [PubMed – in process]

The use of hyperbaric oxygen therapy in acute hearing loss: a narrative review

https://link.springer.com/article/10.1007%2Fs00405-019-05469-7

https://www.ncbi.nlm.nih.gov/pubmed/31111252?dopt=Abstract

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The use of hyperbaric oxygen therapy in acute hearing loss: a narrative review.

Eur Arch Otorhinolaryngol. 2019 May 20;:

Authors: Bayoumy AB, de Ru JA

Abstract

INTRODUCTION: Acute hearing loss can have a major impact on a patient’s life. This holds true for both acute acoustic trauma (AAT) and idiopathic sudden sensorineural hearing loss (ISSHL), two devastating conditions for which no highly effective treatment options exist. This narrative review provides the rationale and evidence for HBOT in AAT and ISSHL.

METHODS: Narrative review of all the literature available on HBOT in acute hearing loss, studies were retrieved from systematic searches on PubMed and by cross referencing.

DISCUSSION: First, the etiological mechanisms of acute hearing loss and the mechanism of action of HBOT were discussed. Furthermore, we have provided an overview of 68 studies that clinically investigated the effect of HBOT in the last couple of decades. For future studies, it is recommend to start as early as possible with therapy, preferably within 48 h and to use combination therapy consisting of HBOT and corticosteroids.

IMPLICATIONS FOR PRACTICE: HBOT has been used quite extensively for acute hearing loss in the last couple of decades. Based on the amount of studies showing a positive effect, HBOT should be discussed with patients (shared decision making) as optional therapy in case of AAT and ISSHL.

PMID: 31111252 [PubMed – as supplied by publisher]

The effect of intratympanic oxytocin treatment on rats exposed to acoustic trauma

https://www.cambridge.org/core/journals/journal-of-laryngology-and-otology/article/effect-of-intratympanic-oxytocin-treatment-on-rats-exposed-to-acoustic-trauma/DE3B7A3BDBC0086FA738A1D40592FCFA

The effect of intratympanic oxytocin treatment on rats exposed to acoustic trauma
F C Akin Ocal (a1), G G Kesici (a2), S G Gurgen (a3), R Ocal (a2) …
DOI: https://doi.org/10.1017/S0022215119001014Published online by Cambridge University Press: 17 May 2019

Unconventional secretory pathway activation restores hair cell mechanotransduction in an USH3A model

https://www.pnas.org/content/early/2019/05/14/1817500116

https://www.ncbi.nlm.nih.gov/pubmed/31097578?dopt=Abstract

Related Articles

Unconventional secretory pathway activation restores hair cell mechanotransduction in an USH3A model.

Proc Natl Acad Sci U S A. 2019 May 16;:

Authors: Gopal SR, Lee YT, Stepanyan R, McDermott BM, Alagramam KN

Abstract

The pathogenic variant c.144T>G (p.N48K) in the clarin1 gene (CLRN1) results in progressive loss of vision and hearing in Usher syndrome IIIA (USH3A) patients. CLRN1 is predicted to be an essential protein in hair bundles, the mechanosensory structure of hair cells critical for hearing and balance. When expressed in animal models, CLRN1 localizes to the hair bundle, whereas glycosylation-deficient CLRN1N48K aggregates in the endoplasmic reticulum, with only a fraction reaching the bundle. We hypothesized that the small amount of CLRN1N48K that reaches the hair bundle does so via an unconventional secretory pathway and that activation of this pathway could be therapeutic. Using genetic and pharmacological approaches, we find that clarin1 knockout (clrn1 KO/KO ) zebrafish that express the CLRN1 c.144T>G pathogenic variant display progressive hair cell dysfunction, and that CLRN1N48K is trafficked to the hair bundle via the GRASP55 cargo-dependent unconventional secretory pathway (GCUSP). On expression of GRASP55 mRNA, or on exposure to the drug artemisinin (which activates GCUSP), the localization of CLRN1N48K to the hair bundles was enhanced. Artemisinin treatment also effectively restored hair cell mechanotransduction and attenuated progressive hair cell dysfunction in clrn1 KO/KO larvae that express CLRN1 c.144T>G , highlighting the potential of artemisinin to prevent sensory loss in CLRN1 c.144T>G patients.

PMID: 31097578 [PubMed – as supplied by publisher]

Hearing Protection, Restoration, and Regeneration: An Overview of Emerging Therapeutics for Inner Ear and Central Hearing Disorders

https://journals.lww.com/otology-neurotology/Abstract/2019/06000/Hearing_Protection,_Restoration,_and_Regeneration_.2.aspx

https://www.ncbi.nlm.nih.gov/pubmed/31083073?dopt=Abstract

Hearing Protection, Restoration, and Regeneration: An Overview of Emerging Therapeutics for Inner Ear and Central Hearing Disorders.

Otol Neurotol

Related Articles

Hearing Protection, Restoration, and Regeneration: An Overview of Emerging Therapeutics for Inner Ear and Central Hearing Disorders.

Otol Neurotol. 2019 Jun;40(5):559-570

Authors: Schilder AGM, Su MP, Blackshaw H, Lustig L, Staecker H, Lenarz T, Safieddine S, Gomes-Santos CS, Holme R, Warnecke A

Abstract

OBJECTIVE: To provide an overview of biotechnology and pharmaceutical companies active in the field of inner ear and central hearing disorders and their therapeutic approaches.

METHODS: Scientific and grey literature was searched using broad search terms to identify companies and their hearing-related therapeutic approaches. For each approach its lead indication, product, therapeutic modality, target, mechanism of action and current phase of clinical development was collated.

RESULTS: A total of 43 biotechnology and pharmaceutical companies have been identified that are developing therapeutics for inner ear and central hearing disorders. Their therapeutics include drug-, cell- and gene-based approaches to prevent hearing loss or its progression, restore hearing, and regenerate the inner ear. Their therapeutic targets and specific mechanisms of action are wide-ranging, reflecting the complexity of the hearing pathways and the diversity of mechanisms underlying inner ear disorders. While none of the novel products under investigation have yet made it to the clinical market, and a large proportion are still at preclinical phase, many therapeutics have already entered clinical testing with more expected to do so in the next few years.

CONCLUSION: A wide range of novel therapeutics targeting different hearing, balance and tinnitus pathways, and patient populations are approaching the clinical domain. It is important that clinicians involved in the care of patients with hearing loss prepare for what may become a radically different approach to the management of hearing disorders, and develop a true understanding of the new therapies’ mechanisms of action, applications, and indications.

PMID: 31083073 [PubMed – in process]

PubMed:31083073

Efficacy and Safety of AM-111 in the Treatment of Acute Unilateral Sudden Deafness

https://journals.lww.com/otology-neurotology/fulltext/2019/06000/Efficacy_and_Safety_of_AM_111_in_the_Treatment_of.6.aspx

https://www.ncbi.nlm.nih.gov/pubmed/31083077?dopt=Abstract

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Efficacy and Safety of AM-111 in the Treatment of Acute Unilateral Sudden Deafness-A Double-blind, Randomized, Placebo-controlled Phase 3 Study.

Otol Neurotol. 2019 Jun;40(5):584-594

Authors: Staecker H, Jokovic G, Karpishchenko S, Kienle-Gogolok A, Krzyzaniak A, Lin CD, Navratil P, Tzvetkov V, Wright N, Meyer T

Abstract

OBJECTIVE: To confirm the efficacy and safety of AM-111 (brimapitide), a cell-penetrating c-Jun N-terminal Kinase (JNK) inhibitor, in patients suffering from severe to profound acute unilateral idiopathic sudden sensorineural hearing loss (ISSNHL).

STUDY DESIGN: Prospective, double-blind, randomized, placebo-controlled phase 3 study with follow-up visits on Days 3, 7, 28, and 91.

SETTING: Fifty-one European and Asian sites (tertiary referral centers, private ENT practices).

PATIENTS: Two hundred fifty-six patients aged 18 to 65 years presenting within 72 hours following ISSNHL onset with mean hearing loss ≥ 40 dB and mean threshold ≥ 60 dB at the 3 worst affected contiguous test frequencies.

INTERVENTIONS: Single-dose intratympanic injection of AM-111 (0.4 or 0.8 mg/ml) or placebo; oral prednisolone as reserve therapy if hearing improvement < 10 dB at Day 7. MAIN OUTCOME MEASURES: Hearing improvement to Day 28 was the primary efficacy endpoint; complete hearing recovery, frequency of reserve therapy used, complete tinnitus remission, improvement in word recognition were secondary endpoints. Safety was evaluated by the frequency of clinically relevant hearing deterioration and adverse events. RESULTS: While the primary efficacy endpoint was not met in the overall study population, post-hoc analysis showed a clinically relevant and nominally significant treatment effect for AM-111 0.4 mg/ml in patients with profound ISSNHL. The study drug and the administration procedure were well tolerated. CONCLUSIONS: AM-111 provides effective otoprotection in case of profound ISSNHL. Activation of the JNK stress kinase, AM-111's pharmacologic target, seems to set in only following pronounced acute cochlear injury associated with large hearing threshold shifts. PMID: 31083077 [PubMed - in process]

Intratympanically Delivered Steroids Impact Thousands More Inner Ear Genes Than Systemic Delivery

https://journals.sagepub.com/doi/abs/10.1177/0003489419837562?journalCode=aora

https://www.ncbi.nlm.nih.gov/pubmed/31092042?dopt=Abstract

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Intratympanically Delivered Steroids Impact Thousands More Inner Ear Genes Than Systemic Delivery.

Ann Otol Rhinol Laryngol. 2019 Jun;128(6_suppl):134S-138S

Authors: Trune DR, Shives KD, Hausman F, Kempton JB, MacArthur CJ, Choi D

Abstract

OBJECTIVES: Glucocorticoids are given for sensorineural hearing loss, but little is known of their molecular impact on the inner ear. Furthermore, in spite of claims of improved hearing recovery with intratympanic delivery of steroids, no studies have actually documented the inner ear molecular functions that are enhanced with this delivery method.

METHODS: To assess steroid-driven processes in the inner ear, gene chip analyses were conducted on mice treated systemically with the glucocorticoids prednisolone or dexamethasone or the mineralocorticoid aldosterone. Other mice were given the same steroids intratympanically. Inner ears were harvested at 6 hours and processed on the Affymetrix 430 2.0 Gene Chip for expression of its 34 000 genes. Results were statistically analyzed for up or down expression of each gene against control (untreated) mice.

RESULTS: Analyses showed approximately 17 500 genes are normally expressed in the inner ear and steroids alter expression of 55% to 82% of these. Dexamethasone changed expression of 9424 (53.9%) inner ear genes following systemic injection but 14 899 ear genes (85%) if given intratympanically. A similar pattern was seen with prednisolone, as 7560 genes were impacted by oral delivery and 11 164 genes (63.8%) when given intratympanically. The mineralocorticoid aldosterone changed expression of only 268 inner ear genes if given orally, but this increased to 10 124 genes (57.9%) if injected intratympanically. Furthermore, the glucocorticoids given actually impacted more inner ear genes via the mineralocorticoid receptor than the glucocorticoid receptor.

CONCLUSIONS: Thousands of inner ear genes were affected by steroids, and this number increased significantly if steroids were delivered intratympanically. Also, the impact of glucocorticoids on inner ear mineralocorticoid functions is more substantial than previously known. Thus, the application of therapeutic steroids for hearing loss needs to be reassessed in light of their more comprehensive impact on inner ear genes. Furthermore, simply ascribing the efficacy of steroids to immunosuppression no longer appears to be warranted.

PMID: 31092042 [PubMed – in process]

Recovery From Sudden Sensorineural Hearing Loss May Be Linked to Chronic Stress Levels and Steroid Treatment Resistance

https://pubs.asha.org/doi/10.1044/2019_AJA-18-0127

https://www.ncbi.nlm.nih.gov/pubmed/31084569?dopt=Abstract

Related Articles

Recovery From Sudden Sensorineural Hearing Loss May Be Linked to Chronic Stress Levels and Steroid Treatment Resistance.

Am J Audiol. 2019 May 14;:1-7

Authors: Ajduk J, Košec A, Kelava I, Ries M, Gregurić T, Kalogjera L

Abstract

Purpose This article investigates the possible connections between the level of chronic stress and success of steroid therapy in patients with sudden sensorineural hearing loss (SSNHL). Method A single-center, retrospective, longitudinal cohort study on 55 patients in a tertiary referral otology center was examined. Patients diagnosed with SSNHL between 2014 and 2017 were asked to complete a Measure of Perceived Stress (Brajac, Tkalcic, Dragojević, & Gruber, 2003 ) questionnaire. Inclusion criteria were patients > 18 years of age, SSNHL diagnosed within 4 previous weeks, completed steroid treatment, and complete documentation. Results There were 30 patients (55%) that showed significant improvement in their pure-tone audiogram (PTA) hearing threshold average (≥ 15 dB) after steroid treatment. Two-step cluster analysis identified 3 clusters based on average PTA hearing threshold recovery and average Measure of Perceived Stress scores. The difference between pretreatment and posttreatment hearing levels was significantly higher in the cluster with moderate stress compared to clusters with mild and high stress levels (Kruskal-Wallis test, Friedman test, p < .001). There were no significant differences in average PTA hearing threshold recovery after steroid therapy between groups of patients with mild and severe stress. Conclusion Patients with moderate stress levels show significantly better results after steroid treatment for SSNHL than patients with low or high stress levels. PMID: 31084569 [PubMed - as supplied by publisher]

Stem Cell Based Drug Delivery for Protection of Auditory Neurons

https://www.frontiersin.org/articles/10.3389/fncel.2019.00177/full

https://www.ncbi.nlm.nih.gov/pubmed/31139049?dopt=Abstract

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Stem Cell Based Drug Delivery for Protection of Auditory Neurons in a Guinea Pig Model of Cochlear Implantation.

Front Cell Neurosci. 2019;13:177

Authors: Scheper V, Hoffmann A, Gepp MM, Schulz A, Hamm A, Pannier C, Hubka P, Lenarz T, Schwieger J

Abstract

Background: The success of a cochlear implant (CI), which is the standard therapy for patients suffering from severe to profound sensorineural hearing loss, depends on the number and excitability of spiral ganglion neurons (SGNs). Brain-derived neurotrophic factor (BDNF) has a protective effect on SGNs but should be applied chronically to guarantee their lifelong survival. Long-term administration of BDNF could be achieved using genetically modified mesenchymal stem cells (MSCs), but these cells should be protected – by ultra-high viscous (UHV-) alginate (‘alginate-MSCs’) – from the recipient immune system and from uncontrolled migration. Methods: Brain-derived neurotrophic factor-producing MSCs were encapsulated in UHV-alginate. Four experimental groups were investigated using guinea pigs as an animal model. Three of them were systemically deafened and (unilaterally) received one of the following: (I) a CI; (II) an alginate-MSC-coated CI; (III) an injection of alginate-embedded MSCs into the scala tympani followed by CI insertion and alginate polymerization. Group IV was normal hearing, with CI insertion in both ears and a unilateral injection of alginate-MSCs. Using acoustically evoked auditory brainstem response measurements, hearing thresholds were determined before implantation and before sacrificing the animals. Electrode impedance was measured weekly. Four weeks after implantation, the animals were sacrificed and the SGN density and degree of fibrosis were evaluated. Results: The MSCs survived being implanted for 4 weeks in vivo. Neither the alginate-MSC injection nor the coating affected electrode impedance or fibrosis. CI insertion with and without previous alginate injection in normal-hearing animals resulted in increased hearing thresholds within the high-frequency range. Low-frequency hearing loss was additionally observed in the alginate-injected and implanted cochleae, but not in those treated only with a CI. In deafened animals, the alginate-MSC coating of the CI significantly prevented SGN from degeneration, but the injection of alginate-MSCs did not. Conclusion: Brain-derived neurotrophic factor-producing MSCs encapsulated in UHV-alginate prevent SGNs from degeneration in the form of coating on the CI surface, but not in the form of an injection. No increase in fibrosis or impedance was detected. Further research and development aimed at verifying long-term mechanical and biological properties of coated electrodes in vitro and in vivo, in combination with chronic electrical stimulation, is needed before the current concept can be tested in clinical trials.

PMID: 31139049 [PubMed]

New molecular therapies for the treatment of hearing loss

https://www.sciencedirect.com/science/article/pii/S0163725819300774?via%3Dihub

https://www.ncbi.nlm.nih.gov/pubmed/31075354?dopt=Abstract

New molecular therapies for the treatment of hearing loss.

Pharmacol Ther. 2019 May 07;:

Authors: Ma Y, Wise AK, Shepherd RK, Richardson RT

Abstract

An estimated 466 million people suffer from hearing loss worldwide. Sensorineural hearing loss is characterized by degeneration of key structures of the sensory pathway in the cochlea such as the sensory hair cells, the primary auditory neurons and their synaptic connection to the hair cells – the ribbon synapse. Various strategies to protect or regenerate these sensory cells and structures are the subject of intensive research. Yet despite recent advances in our understandings of the capacity of the cochlea for repair and regeneration there are currently no pharmacological or biological interventions for hearing loss. Current research focusses on localized cochlear drug, gene and cell-based therapies. One of the more promising drug-based therapies is based on neurotrophic factors for the repair of the ribbon synapse after noise exposure, as well as preventing loss of primary auditory neurons and regrowth of the auditory neuron fibers after severe hearing loss. Drug therapy delivery technologies are being employed to address the specific needs of neurotrophin and other therapies for hearing loss that include the need for high doses, long-term delivery, localised or cell-specific targeting and techniques for their safe and efficacious delivery to the cochlea. Novel biomaterials are enabling high payloads of drugs to be administered to the cochlea with subsequent slow-release properties that are proving to be beneficial for treating hearing loss. In parallel, new gene therapy technologies are addressing the need for cell specificity and high efficacy for the treatment of both genetic and acquired hearing loss with promising reports of hearing recovery. Some biomaterials and cell therapies are being used in conjunction with the cochlear implant ensuring therapeutic benefit to the primary neurons during electrical stimulation. This review will introduce the auditory system, hearing loss and the potential for repair and regeneration in the cochlea. Drug delivery to the cochlea will then be reviewed, with a focus on new biomaterials, gene therapy technologies, cell therapy and the use of the cochlear implant as a vehicle for drug delivery. With the current pre-clinical research effort into therapies for hearing loss, including clinical trials for gene therapy, the future for the treatment for hearing loss is looking bright.

PMID: 31075354 [PubMed – as supplied by publisher]

The TLR-4/NF-κB signaling pathway activation in cochlear inflammation of rats with noise-induced hearing loss

https://www.sciencedirect.com/science/article/abs/pii/S0378595518305367?via%3Dihub

https://www.ncbi.nlm.nih.gov/pubmed/31096078?dopt=Abstract

Related Articles

The TLR-4/NF-κB signaling pathway activation in cochlear inflammation of rats with noise-induced hearing loss.

Hear Res. 2019 08;379:59-68

Authors: Zhang G, Zheng H, Pyykko I, Zou J

Abstract

The TLR-4/NF-κB signaling pathway is involved in innate immunity and inflammation induced by trauma. The present study aimed to investigate possible TLR-4/NF-κB signaling pathway activation in the cochlea associated with acoustic trauma that might induce cochlear inflammation. A total of 72 rats were exposed to white noise at 120 dB SPL for 8 h per day repeated over 2 successive days. Auditory brainstem responses (ABR) were measured in animals before noise exposure and 0 d (PE0), 1 d (PE1), 3 d (PE3), 7 d (PE7), and 14 d (PE14) after noise exposure. At each defined time point, animals were sacrificed, and cochleae were collected to evaluate the expression levels of TLR4, MyD88, cytoplasmic NF-κB p65, IκBα, TNF-α, and IL-1β using western blotting and NF-κB p65 transcriptional activity using an NF-κB p65 Transcription Factor Assay Kit. Cochlear localizations of TLR-4, TNF-α and IL-1β were analyzed using immunohistochemistry in paraffin-embedded slices. The nuclear translocation of NF-κB p65 was evaluated using immunofluorescence staining in paraffin-embedded slices. DNA fragmentation was measured with a TUNEL assay in paraffin-embedded slices. We found a stable permanent threshold shift after noise exposure. After noise exposure, expression levels of TLR-4, MyD88, IκBα, TNF-α, and IL-1β were significantly upregulated (PE3); DNA binding activity of NF-κB p65 was also significantly enhanced (PE3), while the cytoplasmic NF-κB p65 levels were unchanged. TLR-4, TNF-α, and IL-1β immunostaining intensities were substantially enhanced in spiral ganglion cells and spiral ligament fibrocytes after noise exposure (PE3). In conclusion, the results of this study indicate that the TLR-4/NF-κB signaling pathway is activated in noise-exposed cochleae and that it participates in noise-induced cochlear inflammation.

PMID: 31096078 [PubMed – indexed for MEDLINE]

Otoprotectants: From Research to Clinical Application

https://www.thieme-connect.de/products/ejournals/abstract/10.1055/s-0039-1684045

https://www.ncbi.nlm.nih.gov/pubmed/31036993?dopt=Abstract

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Otoprotectants: From Research to Clinical Application.

Semin Hear. 2019 May;40(2):162-176

Authors: Le Prell CG

Abstract

There is an urgent need for otoprotective drug agents. Prevention of noise-induced hearing loss continues to be a major challenge for military personnel and workers in a variety of industries despite the requirements that at-risk individuals use hearing protection devices such as ear plugs or ear muffs. Drug-induced hearing loss is also a major quality-of-life issue with many patients experiencing clinically significant hearing loss as a side effect of treatment with life-saving drug agents such as cisplatin and aminoglycoside antibiotics. There are no pharmaceutical agents approved by the United States Food and Drug Administration for the purpose of protecting the inner ear against damage, and preventing associated hearing loss (otoprotection). However, a variety of preclinical studies have suggested promise, with some supporting data from clinical trials now being available as well. Additional research within this promising area is urgently needed.

PMID: 31036993 [PubMed]

Cav3.2 T-Type Calcium Channels Are Potential Pharmacological Targets for Hearing Loss

https://www.ncbi.nlm.nih.gov/pubmed/31029730?dopt=Abstract

https://www.sciencedirect.com/science/article/pii/S0306452219302714?via%3Dihub

Cav3.2 T-Type Calcium Channels Are Physiologically Mandatory For The Auditory System.

Neuroscience. 2019 Apr 25;:

Authors: Lundt A, Seidel R, Soós J, Henseler C, Müller R, Bakki M, Arshaad MI, Ehninger D, Hescheler J, Sachinidis A, Broich K, Wormuth C, Papazoglou A, Weiergräber M

Abstract

Voltage-gated Ca2+ channels (VGCCs) play key roles in auditory perception and information processing within the inner ear and brainstem. Pharmacological inhibition of low voltage-activated (LVA) T-type Ca2+ channels is related to both age- and noise induced hearing loss in experimental animals and may represent a promising approach to the treatment of auditory impairment of various etiologies. Within the LVA Ca2+ channel subgroup, Cav3.2 is the most prominently expressed T-type channel entity in the cochlea and auditory brainstem. Thus, we performed a complete gender specific click and tone burst based auditory brainstem response (ABR) analysis of Cav3.2+/- and Cav3.2-/- mice, including i.a. temporal progression in hearing loss, amplitude growth function and wave latency analysis as well as a cochlear qPCR based evaluation of other VGCCs transcripts. Our results, based on a self-programmed automated wavelet approach, demonstrate that both heterozygous and Cav3.2 null mutant mice exhibit age-dependent increases in hearing thresholds at 5 months of age. In addition, complex alterations in WI-IV amplitudes and latencies were detected that were not attributable to alterations in the expression of other VGCCs in the auditory tract. Our results clearly demonstrate the important physiological role of Cav3.2 VGCCs in the spatiotemporal organization of auditory processing in young adult mice and suggest potential pharmacological targets for interventions in the future.

PMID: 31029730 [PubMed – as supplied by publisher]

Mitochondria-Targeted Antioxidants for Treatment of Hearing Loss: A Systematic Review

https://www.mdpi.com/2076-3921/8/4/109

https://www.ncbi.nlm.nih.gov/pubmed/31022870?dopt=Abstract

Related Articles

Mitochondria-Targeted Antioxidants for Treatment of Hearing Loss: A Systematic Review.

Antioxidants (Basel). 2019 Apr 24;8(4):

Authors: Fujimoto C, Yamasoba T

Abstract

Mitochondrial dysfunction is associated with the etiologies of sensorineural hearing loss, such as age-related hearing loss, noise- and ototoxic drug-induced hearing loss, as well as hearing loss due to mitochondrial gene mutation. Mitochondria are the main sources of reactive oxygen species (ROS) and ROS-induced oxidative stress is involved in cochlear damage. Moreover, the release of ROS causes further damage to mitochondrial components. Antioxidants are thought to counteract the deleterious effects of ROS and thus, may be effective for the treatment of oxidative stress-related diseases. The administration of mitochondria-targeted antioxidants is one of the drug delivery systems targeted to mitochondria. Mitochondria-targeted antioxidants are expected to help in the prevention and/or treatment of diseases associated with mitochondrial dysfunction. Of the various mitochondria-targeted antioxidants, the protective effects of MitoQ and SkQR1 against ototoxicity have been previously evaluated in animal models and/or mouse auditory cell lines. MitoQ protects against both gentamicin- and cisplatin-induced ototoxicity. SkQR1 also provides auditory protective effects against gentamicin-induced ototoxicity. On the other hand, decreasing effect of MitoQ on gentamicin-induced cell apoptosis in auditory cell lines has been controversial. No clinical studies have been reported for otoprotection using mitochondrial-targeted antioxidants. High-quality clinical trials are required to reveal the therapeutic effect of mitochondria-targeted antioxidants in terms of otoprotection in patients.

PMID: 31022870 [PubMed]

Antisense Oligonucleotides for the Treatment of Inner Ear Dysfunction

https://link.springer.com/article/10.1007%2Fs13311-019-00729-0

https://www.ncbi.nlm.nih.gov/pubmed/30972560?dopt=Abstract

Related Articles

Antisense Oligonucleotides for the Treatment of Inner Ear Dysfunction.

Neurotherapeutics. 2019 Apr 10;:

Authors: Hastings ML, Jones TA

Abstract

Antisense oligonucleotides (ASOs) have shown potential as therapeutic molecules for the treatment of inner ear dysfunction. The peripheral sensory organs responsible for both hearing and equilibrium are housed within the inner ear. Hearing loss and vestibular balance problems affect a large portion of the population and limited treatment options exist. Targeting ASOs to the inner ear as a therapeutic strategy has unique pharmacokinetic and drug delivery opportunities and challenges. Here, we review ASO technology, delivery, disease targets, and other key considerations for development of this therapeutic approach.

PMID: 30972560 [PubMed – as supplied by publisher]

Protective and therapeutic effects of milrinone on acoustic trauma in rat cochlea

https://link.springer.com/article/10.1007%2Fs00405-019-05417-5

https://www.ncbi.nlm.nih.gov/pubmed/30955065?dopt=Abstract

Protective and therapeutic effects of milrinone on acoustic trauma in rat cochlea.

Eur Arch Otorhinolaryngol. 2019 Apr 06;:

Authors: Ceylan SM, Uysal E, Altinay S, Sezgin E, Bilal N, Petekkaya E, Dokur M, Kanmaz MA, Gulbagci ME

Abstract

OBJECTIVE: The aim of this study was to investigate the potential protective and therapeutic effects of milrinone, a specific phosphodiesterase (PDE) III inhibitor, on acoustic trauma-induced cochlear injury and apoptosis.

METHODS: A total number of 30 healthy Wistar albino rats were evenly divided into five groups as follows: group 1 was assigned as control group; group 2 and 3 were assigned as low-dosage groups (0.25 mg/kg) in which milrinone was administered 1 h before acoustic trauma (AT) and 2 h after AT, respectively; group 4 and 5 were assigned as high-dosage groups (0.50 mg/kg) in which the drug was administered 1 h before AT and 2 h after AT, respectively. Except control group, all treatment groups received a single dosage of milrinone for 5 days. Distortion product otoacoustic emissions (DPOAE) measurements were recorded before AT as well as at second and fifth post-traumatic days. At the end of fifth day, all rats were sacrificed and the cochlea of the rats was removed for histopathological evaluation. In addition, the groups were compared in terms of apoptotic index via caspase-3 staining.

RESULTS: In terms of signal-to-noise ratio (SNR), there was no statistically significant difference among the groups following AT (p > 0.05). After 5 days of milrinone treatment, the best SNR values were found in group 5, though all groups did not statistically differ (p > 0.05). In histopathological evaluation, vacuolization, inflammation, and edema scores in all treatment groups were statistically lower than those of the control group (p < 0.05). In group 2 and 4 where the drug was administered before AT, the inflammation and apoptosis index was lower than those of group 3 and 5 where the drug was administered after AT (p < 0.0001).

CONCLUSION: We reveal that milrinone has a protective effect on cochlear damage in the experimental acoustic model of rats. This protective effect was more apparent following the pre-traumatic milrinone administration, and is associated with its effect on decreasing inflammation and apoptosis. Based on DPOAE measurements following AT, especially in the group 5 (high-dosage group), milrinone may also have a therapeutic effect.

PMID: 30955065 [PubMed – as supplied by publisher]