RESUMO
Mangiferin(MGF) exhibits crucial biological roles, including antioxidant and anti-inflammatory functions. However, how to clearly elucidate the functioning mechanism of MGF for inhibiting cisplatin-induced hearing loss requires in-depth investigation. In this work, we aimed at gaining insight into how MGF functions as the protective agent against cisplatin-triggered ototoxicity using various assays. The variation for reactive oxygen species (ROS) concentrations was determined with MitoSOX-Red and 2',7'-Dichlorodihydrofluorescein diacetate staining (DCFH-DA). The protective function and corresponding mechanism of MGF in hair cell survival in the House Ear Institute-Organ of Corti (HEI-OC1) cell line were assessed using RNA sequencing (RNA-Seq). Our findings demonstrated that MGF significantly alleviated cisplatin-induced injury to hair cells in vitro, encompassing cell lines and cochlear explants, as well as in vivo models, including C57BL/6â¯J mice and zebrafish larvae. Mechanistic studies revealed that MGF reversed the increased accumulation of ROS and inhibited cell apoptosis through mitochondrial-mediated intrinsic pathway. Moreover, real-time quantitative polymerase chain reaction (RT-qPCR) and western blotting data indicated MGF protected against cisplatin-mediated ototoxicity via the mitogen-activated protein kinase pathway (MAPK). These findings demonstrated MGF has significant potential promise in combating cisplatin-induced ototoxicity, offering a foundation for expanded investigation into therapeutic approaches for auditory protection.
Assuntos
Apoptose , Cisplatino , Células Ciliadas Auditivas , Perda Auditiva Neurossensorial , Camundongos Endogâmicos C57BL , Ototoxicidade , Espécies Reativas de Oxigênio , Xantonas , Peixe-Zebra , Cisplatino/toxicidade , Cisplatino/efeitos adversos , Animais , Ototoxicidade/prevenção & controle , Espécies Reativas de Oxigênio/metabolismo , Camundongos , Perda Auditiva Neurossensorial/induzido quimicamente , Perda Auditiva Neurossensorial/tratamento farmacológico , Perda Auditiva Neurossensorial/metabolismo , Perda Auditiva Neurossensorial/prevenção & controle , Perda Auditiva Neurossensorial/patologia , Apoptose/efeitos dos fármacos , Xantonas/farmacologia , Xantonas/uso terapêutico , Células Ciliadas Auditivas/efeitos dos fármacos , Células Ciliadas Auditivas/metabolismo , Células Ciliadas Auditivas/patologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Antioxidantes/farmacologiaRESUMO
Sensorineural hearing loss (SNHL), often stemming from reactive oxygen species (ROS) generation due to various factors such as ototoxic drugs, acoustic trauma, and aging, remains a significant health concern. Oxidative stress-induced damage to the sensory cells of the inner ear, particularly the non-regenerating hair cells, is a critical pathologic mechanism leading to SNHL. Despite the proven efficacy of antioxidants in mitigating oxidative stress, their clinical application for otoprotection is hindered by the limitations of conventional drug delivery methods. This review highlights the challenges associated with systemic and intratympanic administration of antioxidants, including the blood-labyrinthine barrier, restricted permeability of the round window membrane, and inadequate blood flow to the inner ear. To overcome these hurdles, the application of nanoparticles as a delivery platform for antioxidants emerges as a promising solution. Nanocarriers facilitate indirect drug delivery to the cochlea through the round and oval window membrane, optimising drug absorption while reducing dosage, Eustachian tube clearance, and associated side effects. Furthermore, the development of nanoparticles carrying antioxidants tailored to the intracochlear environment holds immense potential. This literature research aimed to critically examine the root causes of SNHL and ROS overproduction in the inner ear, offering insights into the application of nanoparticle-based drug delivery systems for safeguarding sensorineural hair cells. By focusing on the intricate interplay between oxidative stress and hearing loss, this research aims to contribute to the advancement of innovative therapeutic strategies for the prevention of SNHL.
Assuntos
Antioxidantes , Sistemas de Liberação de Medicamentos , Perda Auditiva Neurossensorial , Nanopartículas , Estresse Oxidativo , Antioxidantes/administração & dosagem , Antioxidantes/farmacologia , Humanos , Perda Auditiva Neurossensorial/tratamento farmacológico , Perda Auditiva Neurossensorial/prevenção & controle , Animais , Estresse Oxidativo/efeitos dos fármacos , Sistemas de Liberação de Medicamentos/métodos , Espécies Reativas de Oxigênio/metabolismo , Portadores de Fármacos/química , Orelha Interna/efeitos dos fármacos , Orelha Interna/metabolismoRESUMO
Sensorineural hearing loss (SNHL) induced by noise has increased in recent years due to personal headphone use and noisy urban environments. The study shows a novel model of gradually progressive SNHL induced by repeated exposure to moderate noise (8-kHz octave band noise, 90-dB sound pressure level) for 1 hr exposure per day in BALB/cCr mice. The results showed that the repeated exposure led to gradually progressive SNHL, which was dependent on the number of exposures, and resulted in permanent hearing loss after 5 exposures. Repeated exposure to noise causes a loss of synapses between the inner hair cells and the peripheral terminals of the auditory nerve fibers. Additionally, there is a reduction in the expression levels of c-fos and Arc, both of which are indicators of cochlear nerve responses to noise exposure. Oral administration of resveratrol (RSV, 50 mg/kg/day) during the noise exposure period significantly prevented the noise exposure-induced synapse loss and SNHL. Furthermore, the study found that RSV treatment prevented the noise-induced increase in the gene expression levels of the proinflammatory cytokine interleukin-1ß in the cochlea. These results demonstrated the potential usefulness of RSV in preventing noise-induced SNHL in the animal model established as gradually progressive SNHL.
Assuntos
Perda Auditiva Provocada por Ruído , Perda Auditiva Neurossensorial , Doenças dos Roedores , Camundongos , Animais , Resveratrol/uso terapêutico , Ruído/efeitos adversos , Perda Auditiva Neurossensorial/prevenção & controle , Perda Auditiva Neurossensorial/complicações , Perda Auditiva Neurossensorial/veterinária , Perda Auditiva Provocada por Ruído/prevenção & controle , Perda Auditiva Provocada por Ruído/etiologia , Perda Auditiva Provocada por Ruído/veterinária , CócleaRESUMO
INTRODUCTION: Sensorineural hearing loss results in irreversible loss of inner ear hair cells and spiral ganglion neurons. Reduced sound detection and speech discrimination can span all ages, and sensorineural hearing rehabilitation is limited to amplification with hearing aids or cochlear implants. Recent insights into experimental drug treatments for inner ear regeneration and otoprotection have paved the way for clinical trials in order to restore a more physiological hearing experience. Paired with the development of innovative minimally invasive approaches for drug delivery to the inner ear, new, emerging treatments for hearing protection and restoration are within reach. AREAS COVERED: This expert opinion provides an overview of the latest experimental drug therapies to protect from and to restore sensorineural hearing loss. EXPERT OPINION: The degree and type of cellular damage to the cochlea, the responsiveness of remaining, endogenous cells to regenerative treatments, and the duration of drug availability within cochlear fluids will determine the success of hearing protection or restoration.
Assuntos
Perda Auditiva Neurossensorial , Humanos , Perda Auditiva Neurossensorial/tratamento farmacológico , Perda Auditiva Neurossensorial/prevenção & controle , Células Ciliadas Auditivas Internas/fisiologia , Gânglio Espiral da Cóclea , Preparações Farmacêuticas , Drogas em InvestigaçãoRESUMO
Background: Sensorineural hearing loss has been associated with oxidative stress. However, an antioxidant that passes effectively through the ear remains elusive. Method: Probucol (PB)-based nanoparticles were formed using a spray-drying encapsulation technique, characterized and tested in vitro. Results: Uniform, spherical nanoparticles were produced. The addition of lithocholic acid to PB formulations did not affect drug content or production yield, but it did modify capsule size, surface tension, electrokinetic stability and drug release. Cell viability, bioenergetics and inflammatory profiles were improved when auditory cells were exposed to PB-based nanoparticles, which showed antioxidant properties (p < 0.05). Conclusion: PB-based nanoparticles can potentially protect the auditory cell line from oxidative stress and could be used in future in vivo studies as a potential new therapeutic agent for sensorineural hearing loss.
Oxidative stress is an imbalance of cellular processes in which the production of free radicals outweighs the cellular defense mechanism. The association of oxidative stress with the pathophysiology of sensorineural hearing loss (SHL) is well established. SHL development is associated with chronic damage in the structure of the inner ear or auditory nerve. Therefore, potent antioxidants such as probucol could be one way to prevent or treat SHL. However, due to its isolated position, SHL is challenging to treat, imposing a desperate need for refining existing therapeutic methods; one way to do this is by optimizing the formulation using nanoparticles. We aimed to design a novel, stable formulation of PB using polymers and excipients to develop nanoparticles and examine the efficiency of these formulations on the HEI-OC1 stress cell line. We found that the prepared nanoparticle is robust and stable and protects HEI-OC1 from cellular toxicity and oxidative stress. It could be a novel therapeutic agent to treat or prevent SHL.
Assuntos
Perda Auditiva Neurossensorial , Nanopartículas , Humanos , Probucol/farmacologia , Antioxidantes/farmacologia , Ácidos e Sais Biliares/farmacologia , Estresse Oxidativo , Perda Auditiva Neurossensorial/tratamento farmacológico , Perda Auditiva Neurossensorial/prevenção & controle , Audição , Preparações FarmacêuticasRESUMO
Mitochondrial dysfunction has been implicated in numerous common diseases as well as aging and plays an important role in the pathogenesis of sensorineural hearing loss (SNHL). In the current study, we showed that supplementation with germanium dioxide (GeO2) in CBA/J mice resulted in SNHL due to the degeneration of the stria vascularis and spiral ganglion, which were associated with down-regulation of mitochondrial respiratory chain associated genes and up-regulation in apoptosis associated genes in the cochlea. Supplementation with taurine, coenzyme Q10, or hydrogen-rich water, attenuated the cochlear degeneration and associated SNHL induced by GeO2. These results suggest that daily supplements or consumption of antioxidants, such as taurine, coenzyme Q10, and hydrogen-rich water, may be a promising intervention to slow SNHL associated with mitochondrial dysfunction.
Assuntos
Perda Auditiva Neurossensorial , Ubiquinona , Camundongos , Animais , Ubiquinona/farmacologia , Taurina/farmacologia , Camundongos Endogâmicos CBA , Perda Auditiva Neurossensorial/induzido quimicamente , Perda Auditiva Neurossensorial/genética , Perda Auditiva Neurossensorial/prevenção & controle , Cóclea , MitocôndriasRESUMO
The Food and Drug Administrationapproved drug sirolimus, which inhibits mechanistic target of rapamycin (mTOR), is the leading candidate for targeting aging in rodents and humans. We previously demonstrated that sirolimus could treat ARHL in mice. In this study, we further demonstrate that sirolimus protects mice against cocaine-induced hearing loss. However, using efficacy and safety tests, we discovered that mice developed substantial hearing loss when administered high doses of sirolimus. Using pharmacological and genetic interventions in murine models, we demonstrate that the inactivation of mTORC2 is the major driver underlying hearing loss. Mechanistically, mTORC2 exerts its effects primarily through phosphorylating in the AKT/PKB signaling pathway, and ablation of P53 activity greatly attenuated the severity of the hearing phenotype in mTORC2-deficient mice. We also found that the selective activation of mTORC2 could protect mice from acoustic trauma and cisplatin-induced ototoxicity. Thus, in this study, we discover a function of mTORC2 and suggest that its therapeutic activation could represent a potentially effective and promising strategy to prevent sensorineural hearing loss. More importantly, we elucidate the side effects of sirolimus and provide an evaluation criterion for the rational use of this drug in a clinical setting.
Assuntos
Perda Auditiva Neurossensorial/metabolismo , Alvo Mecanístico do Complexo 2 de Rapamicina/metabolismo , Proteína Companheira de mTOR Insensível à Rapamicina/metabolismo , Transdução de Sinais , Animais , Modelos Animais de Doenças , Perda Auditiva Neurossensorial/induzido quimicamente , Perda Auditiva Neurossensorial/genética , Perda Auditiva Neurossensorial/prevenção & controle , Alvo Mecanístico do Complexo 2 de Rapamicina/genética , Camundongos , Camundongos Knockout , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteína Companheira de mTOR Insensível à Rapamicina/genética , Sirolimo/efeitos adversos , Sirolimo/farmacologia , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismoRESUMO
BACKGROUND: Hearing loss can have a major impact on children's language development, academic success and hearing comprehension. The aim of the present study was to determinate risk factors for severe and profound hearing loss in child candidates for cochlear implantation in southeast of Iran during 2014-2020. MATERIALS AND METHODS: This case-control study consisted of 400 children referring to a cochlear implant center (in southeastern Iran) from Bandar Abbas, Zahedan and Kerman during the years 2014-2020 as cases. The subjects were selected using the random sampling method; 200 children hospitalized in Shafa and Afzalipour hospitals were selected as controls. RESULTS: Based on the results of the multivariate logistic regression, weight less than 1500 g (OR = 4.40: p < 0.05), hospitalization in NICU (OR = 7.21: p < 0.05), family history of hearing loss (OR = 11.47: p < 0.05), Gestational age over 35 (OR = 9.63: p < 0.05), intracranial hemorrhage (OR = 5.18: p < 0.05), consanguineous marriage (OR = 12.48: p < 0.05) and high fever and seizures (OR = 3.02: p < 0.05) were recognized as risk factors for sensorineural deafness in children. CONCLUSION: Most of the risk factors for deafness are preventable, and hereditary factors play an important role in congenital deafness in children. Therefore, genetic counseling before consanguineous marriage, early diagnosis, timely intervention can prevent many cases of hearing loss in children.
Assuntos
Implante Coclear , Perda Auditiva Neurossensorial , Estudos de Casos e Controles , Criança , Surdez/epidemiologia , Surdez/etiologia , Surdez/prevenção & controle , Surdez/cirurgia , Perda Auditiva Neurossensorial/epidemiologia , Perda Auditiva Neurossensorial/etiologia , Perda Auditiva Neurossensorial/prevenção & controle , Perda Auditiva Neurossensorial/cirurgia , Humanos , Irã (Geográfico)/epidemiologia , Fatores de RiscoRESUMO
Hearing loss is a debilitating disease that affects 10% of adults worldwide. Most sensorineural hearing loss is caused by the loss of mechanosensitive hair cells in the cochlea, often due to aging, noise, and ototoxic drugs. The identification of genes that can be targeted to slow aging and reduce the vulnerability of hair cells to insults is critical for the prevention of sensorineural hearing loss. Our previous cell-specific transcriptome analysis of adult cochlear hair cells and supporting cells showed that Clu, encoding a secreted chaperone that is involved in several basic biological events, such as cell death, tumor progression, and neurodegenerative disorders, is expressed in hair cells and supporting cells. We generated Clu-null mice (C57BL/6) to investigate its role in the organ of Corti, the sensory epithelium responsible for hearing in the mammalian cochlea. We showed that the deletion of Clu did not affect the development of hair cells and supporting cells; hair cells and supporting cells appeared normal at 1 month of age. Auditory function tests showed that Clu-null mice had hearing thresholds comparable to those of wild-type littermates before 3 months of age. Interestingly, Clu-null mice displayed less hair cell and hearing loss compared to their wildtype littermates after 3 months. Furthermore, the deletion of Clu is protected against aminoglycoside-induced hair cell loss in both in vivo and in vitro models. Our findings suggested that the inhibition of Clu expression could represent a potential therapeutic strategy for the alleviation of age-related and ototoxic drug-induced hearing loss.
Assuntos
Clusterina/deficiência , Células Ciliadas Auditivas/fisiologia , Perda Auditiva Neurossensorial/prevenção & controle , Presbiacusia/prevenção & controle , Animais , Limiar Auditivo , Sequência de Bases , Sistemas CRISPR-Cas , Senescência Celular , Clusterina/biossíntese , Clusterina/genética , Clusterina/fisiologia , Sinergismo Farmacológico , Potenciais Evocados Auditivos do Tronco Encefálico , Furosemida/administração & dosagem , Furosemida/toxicidade , Células Ciliadas Auditivas/efeitos dos fármacos , Perda Auditiva Neurossensorial/induzido quimicamente , Canamicina/administração & dosagem , Canamicina/toxicidade , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Técnicas de Cultura de Órgãos , Órgão Espiral/patologia , Emissões Otoacústicas Espontâneas , RNA Mensageiro/biossíntese , RNA Mensageiro/genéticaRESUMO
As a general sensory disorder, hearing loss was a major concern worldwide. Autophagy is a common cellular reaction to stress that degrades cytoplasmic waste through the lysosome pathway. Autophagy not only plays major roles in maintaining intracellular homeostasis but is also involved in the development and pathogenesis of many diseases. In the auditory system, several studies revealed the link between autophagy and hearing protection. In this review, we aimed to establish the correlation between autophagy and hair cells (HCs) from the aspects of ototoxic drugs, aging, and acoustic trauma and discussed whether autophagy could serve as a potential measure in the protection of HCs.
Assuntos
Autofagia , Perda Auditiva Neurossensorial/prevenção & controle , Envelhecimento/genética , Envelhecimento/fisiologia , Animais , Autofagia/efeitos dos fármacos , Cisplatino/toxicidade , Cóclea/irrigação sanguínea , Cóclea/crescimento & desenvolvimento , Células Ciliadas Auditivas/metabolismo , Células Ciliadas Auditivas/patologia , Perda Auditiva Provocada por Ruído , Perda Auditiva Neurossensorial/etiologia , Perda Auditiva Neurossensorial/genética , Perda Auditiva Neurossensorial/metabolismo , Humanos , Fator de Crescimento Insulin-Like I/fisiologia , Isquemia/fisiopatologia , Camundongos , Camundongos Knockout , MicroRNAs/genética , Estresse Oxidativo , Resveratrol/uso terapêutico , Privação do Sono/complicaçõesRESUMO
Megalin has been proposed as an endocytic receptor for aminoglycosides as well as estrogen and androgen. We aimed to investigate the otoprotective effects of antiandrogens (flutamide, FM) on kanamycin (KM)-induced hearing loss in rats. Rats were divided into four groups. The KM group was administered KM (20 mg/kg/day) for 5 days, while the FM group received FM (15 mg/kg/day) for 10 days. In the KM + FM group, KM and FM (15 mg/kg/day) were simultaneously injected for 5 days and then FM was injected for 5 days. Auditory brainstem responses were measured. Western blotting and/or quantitative reverse transcriptase-polymerase chain reaction were performed for megalin, cytochrome P450 1A1 (Cyp1a1), Cyp1b1, metallothionein 1A (MT1A), MT2A, tumor necrosis factor (TNF)-α, caspase 3, and cleaved caspase 3. The FM + KM group showed attenuated auditory thresholds when compared with the KM group at 4, 8, 16, and 32 kHz (all p < 0.05). The KM + FM group showed lower megalin and Cyp1b1 levels than the KM group (all p < 0.05). The KM + FM group revealed lower MT1A, TNFα, and caspase 3 protein levels, compared with those in the KM group (all p < 0.05). Androgen receptor inhibition protects against cochlear injuries in KM-induced hearing loss rats by attenuating megalin expression, revealing anti-inflammatory and anti-apoptotic effects.
Assuntos
Antagonistas de Receptores de Andrógenos/farmacologia , Perda Auditiva Neurossensorial/prevenção & controle , Animais , Antibacterianos/toxicidade , Limiar Auditivo/efeitos dos fármacos , Cóclea/efeitos dos fármacos , Cóclea/patologia , Cóclea/fisiopatologia , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1A1/metabolismo , Citocromo P-450 CYP1B1/genética , Citocromo P-450 CYP1B1/metabolismo , Potenciais Evocados Auditivos do Tronco Encefálico/efeitos dos fármacos , Flutamida/farmacologia , Expressão Gênica/efeitos dos fármacos , Perda Auditiva Neurossensorial/induzido quimicamente , Perda Auditiva Neurossensorial/fisiopatologia , Canamicina/toxicidade , Proteína-2 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Proteína-2 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Masculino , Metalotioneína/genética , Metalotioneína/metabolismo , Substâncias Protetoras/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Cisplatin is an efficacious anticancer agent, but its use is limited by ototoxicity and resultant irreversible sensorineural hearing loss. Cisplatin ototoxicity is associated with cochlear cell oxidative stress and mitochondrial damage. However, mitophagy is vital for maintaining mitochondrial quality and cellular metabolism. Accordingly, we investigated the role of mitophagy in regulating cisplatin-induced ototoxicity using the auditory cell line HEI-OC1. In this study, HEI-OC1 cells were treated with either cisplatin alone (10 µM, 0, 8, 16, and 24 h); cisplatin (10 µM, 24 h) post transfection with small-interfering (si)RNAs targeting mitophagy-associated mRNAs; cisplatin (10 µM, 24 h) succeeding pretreatment with the mitophagy suppressor, 3-methyladenine (3-MA; 5 or 10 mM, 6 h); or cisplatin (30 µM, 24 h) following pretreatment with the mitophagy promoter, carbonyl cyanide m-chlorophenylhydrazone (CCCP; 1 or 2 µM, 2 h). The viability of cells, expression of mitophagy marker, and mitochondrial functions were then assessed in these cells. Cell viability was determined by a water-soluble tetrazolium assay; expression of mitophagy-associated proteins PINK1, Parkin, BNIP3, FUNDC1, p62, and LC3B was analyzed by Western blotting, mitochondrial membrane potential by flow cytometry, intracellular ATP by spectrophotometry, and mitochondrial degradation by dual staining for mitochondria and autophagosomes or lysosomes. Our results showed that cisplatin gradually reduced the viable cell number over time, induced mitochondrial depolarization, decreased intracellular ATP concentration, and enhanced the expression of PINK1, Parkin, BNIP3, p62, and LC3B. In addition, Parkin and BNIP3 knockdown accelerated cisplatin-induced loss of cell viability, mitochondrial membrane potential, mitophagosome/lysosome formation, and reduction in intracellular ATP production. Pretreatment with 3-MA aggravated the cisplatin-induced cytotoxicity, while that with CCCP reversed this effect. Overall, our findings indicate that mitophagy protects HEI-OC1 cells against cisplatin-induced cell death. Consequently, we strongly believe that targeted promotion of mitophagy may confer protection against cisplatin-induced ototoxicity.
Assuntos
Cisplatino/efeitos adversos , Mitofagia/fisiologia , Ototoxicidade/fisiopatologia , Apoptose/efeitos dos fármacos , Autofagossomos/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cisplatino/farmacologia , Perda Auditiva Neurossensorial/prevenção & controle , Humanos , Potencial da Membrana Mitocondrial/fisiologia , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Mitocôndrias/metabolismo , Ototoxicidade/metabolismo , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismoRESUMO
BACKGROUND: The previous 30 years have provided information on the mechanisms of cell death in the inner ear after noise exposure, ototoxic drug injury, and during aging, and clinical trials have emerged for all of these acquired forms of hearing loss. Sudden hearing loss is less well understood, but restoration of hearing after sudden hearing loss is also a long-standing drug target, typically using steroids as an intervention but with other agents of interest as well. PURPOSE: The purpose of this review was to describe the state of the science regarding clinical testing of investigational medicinal products for the inner ear with respect to treatment or prevention of acquired hearing loss. DATA COLLECTION AND ANALYSIS: Comprehensive search and summary of clinical trials listed in the National Library of Medicine (www. CLINICALTRIALS: gov) database identified 61 clinical trials. RESULTS: Study phase, status, intervention, and primary, secondary, and other outcomes are summarized for studies assessing prevention of noise-induced hearing loss, prevention of drug-induced hearing loss, treatment of stable sensorineural hearing loss, and treatment of sudden sensorineural hearing loss. CONCLUSION: This review provides a comprehensive summary of the state of the science with respect to investigational medicinal products for the inner ear evaluated in human clinical trials, and the current challenges for the field.
Assuntos
Morte Celular/fisiologia , Surdez/prevenção & controle , Orelha Interna/patologia , Perda Auditiva Provocada por Ruído/tratamento farmacológico , Perda Auditiva Neurossensorial/tratamento farmacológico , Perda Auditiva Súbita/tratamento farmacológico , Morte Celular/efeitos dos fármacos , Surdez/induzido quimicamente , Surdez/tratamento farmacológico , Perda Auditiva Provocada por Ruído/patologia , Perda Auditiva Provocada por Ruído/prevenção & controle , Perda Auditiva Neurossensorial/induzido quimicamente , Perda Auditiva Neurossensorial/patologia , Perda Auditiva Neurossensorial/prevenção & controle , Perda Auditiva Súbita/induzido quimicamente , Perda Auditiva Súbita/patologia , Perda Auditiva Súbita/prevenção & controle , Humanos , Estados UnidosRESUMO
OBJECTIVES: To determine the prevalence of Sensorineural Hearing Loss (SNHL) attributable to Sickle Cell Disease (SCD) in the global pediatric population and to identify factors contributing to its severity. STUDY DESIGN: Meta-analysis. METHODS: We performed a comprehensive literature search for scientific articles in PubMed, Scopus, CINAHL, Web of Science, and the Cochrane Library that reported the incidence of hearing loss in populations under 18 years of age with excluding studies analyzing patients on iron chelation therapy, adults, or those without objective audiological analysis. RESULTS: We identified 138 initial studies with 17 selected for analysis after applying the exclusion criteria. A total of 1,282 SCD patients and 553 controls were included in the meta-analysis. There was a statistically significant increase in the prevalence of SNHL in children with SCD compared to the general population with a cumulative risk ratio of 3.33. CONCLUSION: This is the first systematic investigation of the relationship between SCD and SNHL in pediatric patients across the globe. The increased prevalence of SNHL in the pediatric SCD population warrants future research into the predictors of SNHL severity and merits routine audiometric monitoring of SCD patients to reduce the social and developmental morbidity of hearing loss at a young age. PROSPERO Registration #: CRD42019132601. Laryngoscope, 131:1147-1156, 2021.
Assuntos
Anemia Falciforme/complicações , Audiometria , Carga Global da Doença , Perda Auditiva Neurossensorial/epidemiologia , Programas de Rastreamento/métodos , Anemia Falciforme/terapia , Criança , Perda Auditiva Neurossensorial/diagnóstico , Perda Auditiva Neurossensorial/etiologia , Perda Auditiva Neurossensorial/prevenção & controle , Humanos , Incidência , Prevalência , Índice de Gravidade de DoençaRESUMO
We and others have previously identified signalling pathways associated with the adenosine A1 receptor (A1R) as important regulators of cellular responses to injury in the cochlea. We have shown that the "post-exposure" treatment with adenosine A1R agonists confers partial protection against acoustic trauma and other forms of sensorineural hearing loss (SNHL). The aim of this study was to determine if increasing A1R responsiveness to endogenous adenosine would have the same otoprotective effect. This was achieved by pharmacological targeting of the Regulator of G protein Signalling 4 (RGS4). RGS proteins inhibit signal transduction pathways initiated by G protein-coupled receptors (GPCR) by enhancing GPCR deactivation and receptor desensitisation. A molecular complex between RGS4 and neurabin, an intracellular scaffolding protein expressed in neural and cochlear tissues, is the key negative regulator of A1R activity in the brain. In this study, Wistar rats (6-8 weeks) were exposed to traumatic noise (110 dBSPL, 8-16 kHz) for 2 h and a small molecule RGS4 inhibitor CCG-4986 was delivered intratympanically in a Poloxamer-407 gel formulation for sustained drug release 24 or 48 h after noise exposure. Intratympanic administration of CCG-4986 48 h after noise exposure attenuated noise-induced permanent auditory threshold shifts by up to 19 dB, whilst the earlier drug administration (24 h) led to even better preservation of auditory thresholds (up to 32 dB). Significant improvement of auditory thresholds and suprathreshold responses was linked to improved survival of sensorineural tissues and afferent synapses in the cochlea. Our studies thus demonstrate that intratympanic administration of CCG-4986 can rescue cochlear injury and hearing loss induced by acoustic overexposure. This research represents a novel paradigm for the treatment of various forms of SNHL based on regulation of GPCR.
Assuntos
Perda Auditiva Provocada por Ruído/prevenção & controle , Perda Auditiva Neurossensorial/prevenção & controle , Proteínas RGS/antagonistas & inibidores , Sulfonamidas/farmacologia , Animais , Limiar Auditivo/efeitos dos fármacos , Cóclea/efeitos dos fármacos , Cóclea/metabolismo , Potenciais Evocados Auditivos do Tronco Encefálico/efeitos dos fármacos , Células Ciliadas Auditivas/efeitos dos fármacos , Perda Auditiva Provocada por Ruído/metabolismo , Perda Auditiva Neurossensorial/metabolismo , Masculino , Proteínas dos Microfilamentos/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Proteínas RGS/metabolismo , Ratos Wistar , Receptor A1 de Adenosina/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
Sensorineural hearing loss is prevalent in patients receiving cisplatin therapy. Tetramethylpyrazine (Tet) and tanshinone IIA (Tan IIA) have protective roles against hearing impairment or ototoxicity. The present study aimed to investigate the molecular mechanisms underlying cisplatininduced ototoxicity and the protective effect of Tet and Tan IIA against it. House Ear InstituteOrgan of Corti 1 auditory cells were treated with titrating doses of Tan IIA, Tet, and cisplatin. In a cell viability assay, cisplatin, Tan IIA and Tet had IC50 values of 42.89 µM, 151.80 and 1.04x103 mg/l, respectively. Tan IIA augmented cisplatininduced cytotoxicity. However, Tet concentrations <75 mg/l attenuated cisplatininduced cytotoxicity and apoptosis. Moreover, RNA sequencing analysis was carried out on auditory cells treated for 30 h with 30 µM cisplatin alone for 48 h or combined with 37.5 mg/l Tet for 30 h. Differentially expressed genes (DEGs) induced in these conditions were identified and examined using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis. Cisplatin increased the expression of genes related to the p53 and FoxO pathways, such as Fas, p21/CDKN1A, and Bcl2 binding component 3, but decreased the expression of insulinlike growth factor 1 (IGF1), as well as genes in the histone (Hist)1 and Hist2 clusters. Treatment with Tet downregulated FOXO3 and Bcl2 binding component 3, and increased the expression of IGF1. Moreover, Tet upregulated genes associated with Wnt signaling, but not p53related genes. Thus, the otoprotective properties of Tet might be mediated by activation of Wnt and IGF1 signaling, and inhibition of FoxO signaling.
Assuntos
Abietanos/farmacologia , Perda Auditiva Neurossensorial/metabolismo , Pirazinas/farmacologia , Abietanos/metabolismo , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , China , Cisplatino/efeitos adversos , Cisplatino/farmacologia , Bases de Dados Genéticas , Perfilação da Expressão Gênica/métodos , Perda Auditiva Neurossensorial/genética , Perda Auditiva Neurossensorial/prevenção & controle , Humanos , Camundongos , Ototoxicidade , Pirazinas/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
The effect of dextromethorphan (DXM) use in sensorineural hearing loss (SNHL) has not been fully examined. We conducted an animal model and nationwide retrospective matched-cohort study to explore the association between DXM use and SNHL. Eight-week-old CBA/CaJ hearing loss was induced by a white noise 118 dB sound pressure level for 3 h. DXM (30 mg/kg) was administered intraperitoneally for 5 days and boost once round window DXM socking. In population-based study, we examined the medical records over 40 years old in Taiwan's National Health Insurance Research Database between 2000 and 2015 to establish retrospective matched-cohort to explore the correlation between DXM use and SNHL. Using click auditory brainstem response (ABR), hearing threshold was measured as 48.6 ± 2.9 dB in control mice compared with 42.6 ± 7.0 dB in DXM mice, which differed significantly (p = 0.002) on day 60 after noise exposure with a larger ABR wave I amplitude in DXM mice. In human study, we used a Cox regression hazard model to indicate that a significantly lower percentage individuals developed SNHL compared with and without DXM use (0.44%, 175/39,895 vs. 1.05%, 1675/159,580, p < 0.001). After adjustment for age and other variables [adjusted hazard ratio: 0.725 (95% confidence interval: 0.624-0.803, p < 0.001)], this study also demonstrated that DXM use appeared to reduce the risk of developing SNHL. This animal study demonstrated that DXM significantly attenuated noise-induced hearing loss. In human study, DXM use may have a protective effect against SNHL.
Assuntos
Dextrometorfano , Antagonistas de Aminoácidos Excitatórios , Perda Auditiva Provocada por Ruído , Perda Auditiva Neurossensorial , Adulto , Animais , Estudos de Coortes , Dextrometorfano/farmacologia , Dextrometorfano/uso terapêutico , Antagonistas de Aminoácidos Excitatórios/farmacologia , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Feminino , Perda Auditiva Neurossensorial/tratamento farmacológico , Perda Auditiva Neurossensorial/prevenção & controle , Humanos , Masculino , Camundongos , Camundongos Endogâmicos CBA , Estudos Retrospectivos , TaiwanAssuntos
Controle de Doenças Transmissíveis/métodos , Surtos de Doenças/prevenção & controle , Perda Auditiva Neurossensorial/etiologia , Perda Auditiva Neurossensorial/prevenção & controle , Perda Auditiva Súbita/etiologia , Perda Auditiva Súbita/prevenção & controle , Vacina contra Caxumba , Caxumba/complicações , Caxumba/prevenção & controle , Feminino , Seguimentos , Perda Auditiva Neurossensorial/epidemiologia , Perda Auditiva Súbita/epidemiologia , Humanos , Irlanda/epidemiologia , Masculino , Caxumba/epidemiologia , Estudos Retrospectivos , Índice de Gravidade de Doença , Fatores de TempoRESUMO
BACKGROUND: Stickler syndrome is a collagenopathy caused by mutations in the genes COL2A1 (STL1) or COL11A1 (STL2). Affected patients manifest ocular, auditory, articular, and craniofacial manifestations in varying degrees. Ocular symptoms include myopia, retinal detachment, cataract, and glaucoma. The aim of this systematic review was to evaluate the prevalence of ocular manifestations and the outcome of prophylactic treatment on reducing the risk of retinal detachment. METHOD: A systematic literature search was performed in the PubMed database. Information on the cross-study prevalence of myopia, retinal detachment, cataract, glaucoma, visual impairment, severity and age of onset of myopia and retinal detachments. Studies that reported on the outcome of prophylactic treatment against a control group were explored. RESULTS: 37 articles with 2324 individual patients were included. Myopia was found in 83% of patients, mostly of a moderate to severe degree. Retinal detachments occurred in 45% of patients. Generally, the first detachment occurred in the second decade of life in STL1 patients and later in STL2. Cataracts were more common in STL2 patients, 59% versus 36% in STL1. Glaucoma (10%) and visual impairment (blind: 6%; vision loss in one eye: 10%) were rare. Three studies reported on the effect of prophylactic treatment being protective. CONCLUSION: Ocular manifestations are common in Stickler patients, but the comparison between studies was difficult because of inconsistencies in diagnostic and inclusion criteria by different studies. Sight-threatening complications such as retinal detachments are common but although prophylactic therapy is reported to be effective in retrospective studies, evidence from randomized trials is missing.
Assuntos
Artrite/prevenção & controle , Colágeno Tipo II/genética , Colágeno Tipo XI/deficiência , Doenças do Tecido Conjuntivo/prevenção & controle , Perda Auditiva Neurossensorial/prevenção & controle , Mutação , Descolamento Retiniano/prevenção & controle , Descolamento do Vítreo/prevenção & controle , Artrite/genética , Artrite/patologia , Colágeno Tipo XI/genética , Doenças do Tecido Conjuntivo/genética , Doenças do Tecido Conjuntivo/patologia , Crioterapia , Perda Auditiva Neurossensorial/genética , Perda Auditiva Neurossensorial/patologia , Humanos , Terapia a Laser , Descolamento Retiniano/genética , Descolamento Retiniano/patologia , Descolamento do Vítreo/genética , Descolamento do Vítreo/patologiaRESUMO
Congenital cytomegalovirus (cCMV) infection is a major cause of hearing loss in children. A few cases of cCMV twin pregnancies are reported in the literature. Twins can react differently to maternal infection, but hearing loss is rarely evaluated. Two couples of twins with cCMV infection and different audiologic outcomes are reported. The first couple of twins was composed by two male twins, both affected by cCMV infection. The first born had normal hearing function, and the second born had sensorineural hearing loss (SNHL). In the second couple, a male and a female twin, only the male twin was affected by cCMV infection, and both had normal hearing function. In this case series, an interesting finding was the association between the presence of viral DNA in liquor and hearing loss in one newborn. Further research is needed to better understand the pathophysiology of SNHL caused by cCMV infection.