RESUMEN
Hearing disorders constitute one of the major health concerns in the USA. Decades of basic and clinical studies have identified numerous ototoxic agents and investigated their modes of action on the inner ear, utilizing tissue culture as well as animal and human models. Current preventive and therapeutic approaches are considered unsatisfactory. Therefore, additional modalities should be developed. Many studies suggest that increased levels of oxidative stress, chronic inflammation, and glutamate play an important role in the initiation and progression of damage to the inner ear leading to hearing impairments. To prevent these cellular deficits, antioxidants, anti-inflammatory agents, and antagonists of glutamate receptor have been used individually or in combination with limited success. It is essential, therefore, to simultaneously enhance the levels of antioxidant enzymes by activating the Nrf2 (a nuclear transcriptional factor) pathway, dietary and endogenous antioxidant compounds, and B12-vitamins in order to reduce the levels of oxidative stress, chronic inflammation, and glutamate at the same time. This review presents evidence to show that increased levels of these cellular metabolites, biochemical or factors are involved in the pathogenesis of cochlea leading to hearing impairments. It presents scientific rationale for the use of a mixture of micronutrients that may decrease the levels of oxidative damage, chronic inflammation, and glutamate at the same time. The benefits for using oral administration of proposed micronutrient mixture in humans are presented. Animal and limited human studies indirectly suggest that orally administered micronutrients can accumulate in the inner ear. Therefore, this route of administration may be useful in prevention, and in combination with standard care, in improved management of hearing problems following exposure to well-recognized and studied ototoxic agents, such as noise, cisplatin, aminoglycoside antibiotics, and advanced age.
Asunto(s)
Ácido Glutámico/metabolismo , Trastornos de la Audición , Micronutrientes/farmacología , Estrés Oxidativo/efectos de los fármacos , Animales , Antioxidantes/farmacología , Trastornos de la Audición/inmunología , Trastornos de la Audición/metabolismo , Trastornos de la Audición/prevención & control , Humanos , Inflamación/terapia , Factor 2 Relacionado con NF-E2/metabolismoRESUMEN
Unlike mammalian hair cells, which are essentially unable to regenerate after damage, avian hair cells have a robust capacity for regeneration. The prerequisite for understanding the above difference is knowing the genetic programming of avian hair cell regeneration. Although the major processes have been known, the precise molecular signaling that induces regeneration remains unclear. To address this issue, we performed a high-throughput transcriptomic analysis of gene expression during hair cell regeneration in the chick cochlea after antibiotic injury in vivo. A total of 16,588 genes were found to be expressed in the cochlea, of which about 1000 genes were differentially expressed among the four groups studied, i.e., 2 days (d) or 3â¯d post-treatment with gentamicin or physiological saline. The differentially expressed genes were distributed across approximately one hundred signaling pathways, including the Notch, MAPK (FGF), Wnt and TGF-ß (BMP) pathways that have been shown to play important roles in embryonic development. Some differentially expressed genes (2-3 in each pathway) were further verified by qRT-PCR. After blocking Notch, FGF or BMP signaling, the number of regenerating hair cells and mitotic supporting cells increased. However, the opposite effect was observed after suppressing the Wnt pathway or enhancing BMP signaling. To our knowledge, the present study provided a relatively complete dataset of candidate genes and signaling pathways most likely involved in hair cell regeneration and should be a useful start in deciphering the genetic circuitry for inducing hair cell regeneration in the chick cochlea.
Asunto(s)
Proteínas Morfogenéticas Óseas/genética , Factores de Crecimiento de Fibroblastos/genética , Perfilación de la Expresión Génica/métodos , Gentamicinas , Células Ciliadas Auditivas/patología , Trastornos de la Audición/genética , Trastornos de la Audición/patología , Receptores Notch/genética , Regeneración/genética , Transcriptoma , Proteínas Wnt/genética , Animales , Animales Recién Nacidos , Proteínas Morfogenéticas Óseas/metabolismo , Diferenciación Celular/genética , Proliferación Celular/genética , Pollos , Modelos Animales de Enfermedad , Factores de Crecimiento de Fibroblastos/metabolismo , Células Ciliadas Auditivas/metabolismo , Trastornos de la Audición/inducido químicamente , Trastornos de la Audición/metabolismo , Receptores Notch/metabolismo , Transducción de Señal/genética , Técnicas de Cultivo de Tejidos , Proteínas Wnt/metabolismoRESUMEN
Systemic corticosteroids have been the mainstay of treatment for various hearing disorders for more than 30 yr. Accordingly, numerous studies have described glucocorticoids (GCs) and stressors to be protective in the auditory organ against damage associated with a variety of health conditions, including noise exposure. Conversely, stressors are also predictive risk factors for hearing disorders. How both of these contrasting stress actions are linked has remained elusive. Here, we demonstrate that higher corticosterone levels during acoustic trauma in female rats is highly correlated with a decline of auditory fiber responses in high-frequency cochlear regions, and that hearing thresholds and the outer hair cell functions (distortion products of otoacoustic emissions) are left unaffected. Moreover, when GC receptor (GR) or mineralocorticoid receptor (MR) activation was antagonized by mifepristone or spironolactone, respectively, GR, but not MR, inhibition significantly and permanently attenuated trauma-induced effects on auditory fiber responses, including inner hair cell ribbon loss and related reductions of early and late auditory brainstem responses. These findings strongly imply that higher corticosterone stress levels profoundly impair auditory nerve processing, which may influence central auditory acuity. These changes are likely GR mediated as they are prevented by mifepristone.-Singer, W., Kasini, K., Manthey, M., Eckert, P., Armbruster, P., Vogt, M. A., Jaumann, M., Dotta, M., Yamahara, K., Harasztosi, C., Zimmermann, U., Knipper, M., Rüttiger, L. The glucocorticoid antagonist mifepristone attenuates sound-induced long-term deficits in auditory nerve response and central auditory processing in female rats.
Asunto(s)
Nervio Coclear/fisiopatología , Potenciales Evocados Auditivos del Tronco Encefálico/efectos de los fármacos , Glucocorticoides/antagonistas & inhibidores , Trastornos de la Audición/fisiopatología , Pérdida Auditiva Provocada por Ruido/fisiopatología , Mifepristona/farmacología , Animales , Cóclea/metabolismo , Cóclea/patología , Cóclea/fisiopatología , Nervio Coclear/metabolismo , Nervio Coclear/patología , Femenino , Glucocorticoides/efectos adversos , Glucocorticoides/farmacología , Trastornos de la Audición/inducido químicamente , Trastornos de la Audición/tratamiento farmacológico , Trastornos de la Audición/metabolismo , Pérdida Auditiva Provocada por Ruido/inducido químicamente , Pérdida Auditiva Provocada por Ruido/tratamiento farmacológico , Pérdida Auditiva Provocada por Ruido/metabolismo , Ratas , Ratas Wistar , Receptores de Glucocorticoides/metabolismo , Receptores de Mineralocorticoides/metabolismoRESUMEN
Salicylate is the active ingredient in aspirin, and in high-doses it is used as an experimental tool to induce transient hearing loss, tinnitus, and hyperacusis. These salicylate-induced perceptual disturbances are associated with tonotopic-map reorganization and neural activity modulation, and such neural correlates have been examined in the central auditory pathway, including the auditory cortex (AC). Although previous studies have reported that salicylate induces increases in noise-burst-evoked neural responses and reorganization of tonotopic maps in the primary AC, little is known about the effects of salicylate on other frequency-organized AC subfields such as the anterior auditory, secondary auditory, and dorsomedial fields. Therefore, to examine salicylate-induced spatiotemporal effects on AC subfields, we measured sound-evoked neural activity in mice before and after the administration of sodium salicylate (SS, 200 mg/kg), using flavoprotein auto-fluorescence imaging. SS-treatment gradually reduced responses driven by tone-bursts with lower (≤8 kHz) and higher (≥25 kHz) frequencies over 3 h, whereas evoked responses to tone-bursts within middle-range frequencies (e.g., 12 and 16 kHz) were sustained and unchanged in the four subfields. Additionally, in each of the four subfields, SS-treatment induced similar reorganization of tonotopic maps, and the response areas selectively driven by the middle-range frequencies were profoundly expanded. Our results indicate that the SS-induced tonotopic map reorganizations in each of the four AC subfields were similar, and only the extent of the activated areas responsive to tone-bursts with specific frequencies was subfield-dependent. Thus, we expect that examining cortical reorganization induced by SS may open the possibility of new treatments aimed at altering cortical reorganization into the normative functional organization.
Asunto(s)
Corteza Auditiva/fisiopatología , Mapeo Encefálico/métodos , Potenciales Evocados Auditivos , Trastornos de la Audición/fisiopatología , Imagen Óptica , Salicilato de Sodio , Acúfeno/fisiopatología , Estimulación Acústica , Animales , Corteza Auditiva/metabolismo , Modelos Animales de Enfermedad , Flavoproteínas/metabolismo , Trastornos de la Audición/inducido químicamente , Trastornos de la Audición/diagnóstico por imagen , Trastornos de la Audición/metabolismo , Masculino , Ratones Endogámicos C57BL , Factores de Tiempo , Acúfeno/inducido químicamente , Acúfeno/diagnóstico por imagen , Acúfeno/metabolismoRESUMEN
This study aims to assess whether geranylgeranylacetone (GGA) could reduce ototoxicity induced by cisplatin through upregulation of not only heat shock protein(HSP)-70, but also HSP-27 and HSP-40, and to study if GGA would reduce cisplatin-induced increase in oxidative stress. 48 guinea pigs were used in this study and treated with the following regimen: 0.5% CMC (sodium carboxymethyl cellulose) control for 7days, GGA (600mg/kg/d) for 7days, a combination of GGA (600mg/kg) for 7days and then one dose of 10mg/kg cisplatin (GGA+Cis), and a combination of CMC for 7days and then 10mg/kg cisplatin (cisplatin group). Auditory brainstem response (ABR) measurement was performed in each animal at time before treatment and 7days after the last dose. Additionally, HSPs, nitric oxide (NO), and lipid peroxidation (LPO) levels in cochlear membranous tissues were assessed. The mean ABR thresholds in the cisplatin group were significantly (p<0.05) increased when compared to the other three groups. In guinea pigs receiving both GGA and cisplatin, the mean threshold shift (TS) were smaller (p<0.05) than those of the cisplatin group, but larger (p<0.05) than those of the CMC control or GGA only group with statistical significance. Compared to the GGA only group or the group treated with GGA+Cis, the cisplatin group had the highest (p<0.05) oxidative stress (NO and LPO levels), and the lowest (p<0.05) mean HSPs expression levels. It can be concluded that GGA attenuate ototoxicity induced by cisplatin through upregulation of HSP-27, -40, and -70. Moreover, increased oxidative stress induced by cisplatin in the cochlea membranous tissue could be reduced by pre-treatment of GGA.
Asunto(s)
Cisplatino/toxicidad , Diterpenos/farmacología , Potenciales Evocados Auditivos del Tronco Encefálico/efectos de los fármacos , Trastornos de la Audición/metabolismo , Trastornos de la Audición/fisiopatología , Proteínas de Choque Térmico/metabolismo , Estrés Oxidativo/efectos de los fármacos , Animales , Cisplatino/antagonistas & inhibidores , Cóclea/metabolismo , Cobayas , Trastornos de la Audición/inducido químicamente , Peroxidación de Lípido , Masculino , Óxido Nítrico/metabolismoRESUMEN
IMPORTANCE: Excess free radical-induced oxidative stress and inflammatory processes are increasingly recognized as causative factors in hearing and balance disorders. Antioxidant micronutrients neutralize free radicals and, at adequate doses, reduce inflammation and demonstrate benefits in animal models and human trials. Therefore, it is reasonable to expect that biomarkers of oxidative damage and inflammation are appropriate correlative biological outcome parameters in clinical hearing intervention studies. OBJECTIVE: To provide the otology investigator a selected panel of biomarkers from the large universe of available tests that can be used as reasonable secondary endpoints in hearing and balance research. BACKGROUND SETTING: The tenets of antioxidant science dictate that there are a great variety of free radicals and that they impact different cellular targets. They also demonstrate varying functions in different cellular environments. In addition, oxidative stress and inflammation may cause direct injury to tissues, cell membrane lipids, proteins and mitochondrial, and nuclear DNA. To accommodate these many pathways, the useful categories of potential biomarkers become extensive. The degree of injury is also reflected by separate markers of inflammation and measures of antioxidant levels. Therefore, to provide a reliable indication of oxidative damage, inflammation and antioxidant level, it is necessary to determine a broad spectrum of lipid peroxidation markers, adducts of DNA, oxidation levels of proteins and pro-inflammatory cytokines. CONCLUSION: This report highlights some of the most clinically relevant and well-studied biomarkers in each category of tissue damage. It also includes those markers with which the authors have had direct positive clinical experience. The outcome from these studies is intended to provide a list of adjunctive measures that can be recommended as a relevant biomarker panel in hearing disorder clinical trials.
Asunto(s)
Biomarcadores/análisis , Trastornos de la Audición/diagnóstico , Estrés Oxidativo/fisiología , Animales , Biomarcadores/metabolismo , Trastornos de la Audición/metabolismo , Humanos , Equilibrio PosturalRESUMEN
STUDY OBJECTIVES: The aims of this study were to determine if a correlation exists between the level of hypoxia induced by severe obstructive sleep apnea syndrome (OSAS) and the level of auditory dysfunction when verifying such a relationship using polysomnography (PSG). METHODS: A retrospective review of 41 patients with severe OSAS was performed. Independent risk factors for hearing impairment included parameters of PSG, which were analyzed in two hearing groups at a level ≥ 40 decibels (dB). RESULTS: Oxyhemoglobin saturation, especially the lowest oxyhemoglobin saturation level, showed lower thresholds in the hearing impairment group than in the control group (p = 0.039 at NREM stage; p = 0.029 at REM stage; p = 0.001 at total sleep stage). After adjusting for other risk factors, the sole variable that remained significant was lowest oxyhemoglobin saturation (total; p = 0.046). In the correlation analysis, a decreasing lowest oxyhemoglobin saturation (from all subjects, n = 41) correlated with a greater mean hearing threshold (R(2) = 0.297; p < 0.001). CONCLUSION: Our results indicated that lowest oxyhemoglobin saturation in PSG is the only variable correlated with the hearing threshold. This finding could be predictive of possible hearing alternation in patients with severe OSAS. COMMENTARY: A commentary on this article appears in this issue on page 641.
Asunto(s)
Trastornos de la Audición/complicaciones , Trastornos de la Audición/metabolismo , Oxihemoglobinas/metabolismo , Apnea Obstructiva del Sueño/complicaciones , Apnea Obstructiva del Sueño/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Polisomnografía , Estudios Retrospectivos , Factores de Riesgo , Índice de Severidad de la EnfermedadRESUMEN
The aim of this study was to investigate the effects of intracochlear bleeding during cochleostomy on cochlear inflammatory response and residual hearing in a guinea pig animal model. Auditory brainstem response threshold shifts were greater in blood injected ears (p<0.05). Interleukin-1ß, interleukin-10, tumor necrosis factor-α and nitric oxide synthase 2, cytokines that are related to early stage inflammation, were significantly increased in blood injected ears compared to normal and cochleostomy only ears at 1 day after surgery; with the increased IL-1ß being sustained until 3 days after the surgery (p<0.05). Hair cells were more severely damaged in blood injected ears than in cochleostomy only ears. Histopathologic examination revealed more extensive fibrosis and ossification in blood injected ears than cochleostomy only ears. These results show that intracochlear bleeding enhanced cochlear inflammation resulting in increased fibrosis and ossification in an experimental animal model.
Asunto(s)
Cóclea/cirugía , Implantación Coclear/efectos adversos , Fibrosis/patología , Trastornos de la Audición/patología , Hemorragia/complicaciones , Osificación Heterotópica/patología , Complicaciones Posoperatorias , Animales , Umbral Auditivo , Citocinas/metabolismo , Modelos Animales de Enfermedad , Potenciales Evocados Auditivos del Tronco Encefálico , Fibrosis/etiología , Fibrosis/metabolismo , Cobayas , Células Ciliadas Auditivas/patología , Trastornos de la Audición/etiología , Trastornos de la Audición/metabolismo , Inflamación/etiología , Inflamación/metabolismo , Inflamación/patología , Mediadores de Inflamación/metabolismo , Masculino , Osificación Heterotópica/etiología , Osificación Heterotópica/metabolismoRESUMEN
Hearing impairment is the most common human sensory deficit. Considering the sophisticated anatomy and physiology of the auditory system, disease-related failures frequently occur. To meet the demands of the neuronal circuits responsible for processing auditory information, the synapses of the lower auditory pathway are anatomically and functionally specialized to process acoustic information indefatigably with utmost temporal precision. Despite sharing some functional properties, the afferent synapses of the cochlea and of auditory brainstem differ greatly in their morphology and employ distinct molecular mechanisms for regulating synaptic vesicle release. Calyceal synapses of the endbulb of Held and the calyx of Held profit from a large number of release sites that project onto one principal cell. Cochlear inner hair cell ribbon synapses exhibit a unique one-to-one relation of the presynaptic active zone to the postsynaptic cell and use hair-cell-specific proteins such as otoferlin for vesicle release. The understanding of the molecular physiology of the hair cell ribbon synapse has been advanced by human genetics studies of sensorineural hearing impairment, revealing human auditory synaptopathy as a new nosological entity.
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Percepción Auditiva , Tronco Encefálico/fisiología , Cóclea/inervación , Nervio Coclear/fisiología , Células Ciliadas Auditivas Internas/fisiología , Audición , Transmisión Sináptica , Animales , Vías Auditivas/fisiología , Tronco Encefálico/metabolismo , Nervio Coclear/metabolismo , Potenciales Evocados Auditivos , Células Ciliadas Auditivas Internas/metabolismo , Trastornos de la Audición/metabolismo , Trastornos de la Audición/fisiopatología , Trastornos de la Audición/psicología , Humanos , Proteínas del Tejido Nervioso/metabolismoAsunto(s)
Corteza Auditiva/fisiología , Percepción Auditiva , Trastornos de la Percepción Auditiva/fisiopatología , Tronco Encefálico/fisiología , Células Ciliadas Auditivas/fisiología , Trastornos de la Audición/fisiopatología , Transmisión Sináptica , Animales , Corteza Auditiva/metabolismo , Vías Auditivas/metabolismo , Vías Auditivas/fisiología , Trastornos de la Percepción Auditiva/metabolismo , Trastornos de la Percepción Auditiva/psicología , Tronco Encefálico/metabolismo , Potenciales Evocados Auditivos del Tronco Encefálico , Células Ciliadas Auditivas/metabolismo , Trastornos de la Audición/metabolismo , Trastornos de la Audición/psicología , Humanos , Proteínas del Tejido Nervioso/metabolismoRESUMEN
Kv1.1 subunits of low voltage-activated (Kv) potassium channels are encoded by the Kcna1 gene and crucially determine the synaptic integration window to control the number and temporal precision of action potentials in the auditory brainstem of mammals and birds. Prior electrophysiological studies showed that auditory signaling is compromised in monaural as well as in binaural neurons of the auditory brainstem in Kv1.1 knockout mice (Kcna1(-/-)). Here we examine the behavioral effects of Kcna1 deletion on sensory tasks dependent on either binaural processing (detecting the movement of a sound source across the azimuth), monaural processing (detecting a gap in noise), as well as binaural summation of the acoustic startle reflex (ASR). Hearing thresholds measured by auditory brainstem responses (ABR) do not differ between genotypes, but our data show a much stronger performance of wild type mice (+/+) in each test during binaural hearing which was lost by temporarily inducing a unilateral hearing loss (through short term blocking of one ear) thus remarkably, leaving no significant difference between binaural and monaural hearing in Kcna1(-/-) mice. These data suggest that the behavioral effect of Kv1.1 deletion is primarily to impede binaural integration and thus to mimic monaural hearing.
Asunto(s)
Percepción Auditiva , Conducta Animal , Trastornos de la Audición/metabolismo , Audición , Canal de Potasio Kv.1.1/deficiencia , Estimulación Acústica , Animales , Vías Auditivas/fisiopatología , Percepción Auditiva/genética , Umbral Auditivo , Potenciales Evocados Auditivos del Tronco Encefálico , Femenino , Genotipo , Audición/genética , Trastornos de la Audición/genética , Trastornos de la Audición/fisiopatología , Canal de Potasio Kv.1.1/genética , Masculino , Ratones Endogámicos C3H , Ratones Noqueados , Fenotipo , Psicoacústica , Reflejo de Sobresalto , Detección de Señal Psicológica , Localización de Sonidos , Factores de TiempoRESUMEN
Transmembrane channel-like (TMC) proteins 1 and 2 are necessary for hair cell mechanotransduction but their precise function is controversial. A growing body of evidence supports a direct role for TMC1 and TMC2 as components of the transduction complex. However, a number of important questions remain and alternate hypotheses have been proposed. Here we present an historical overview of the identification and cloning of Tmc genes, a discussion of mutations in TMC1 that cause deafness in mice and humans and a brief review of other members of the Tmc gene superfamily. We also examine expression of Tmc mRNAs and localization of the protein products. The review focuses on potential functions of TMC proteins and the evidence from Beethoven mice that suggests a direct role for TMC1 in hair cell mechanotransduction. Data that support alternate interpretations are also considered. The article concludes with a discussion of outstanding questions and future directions for TMC research. This article is part of a Special Issue entitled
Asunto(s)
Percepción Auditiva , Células Ciliadas Auditivas/metabolismo , Audición , Mecanotransducción Celular , Proteínas de la Membrana/metabolismo , Estimulación Acústica , Secuencia de Aminoácidos , Animales , Modelos Animales de Enfermedad , Trastornos de la Audición/genética , Trastornos de la Audición/metabolismo , Trastornos de la Audición/fisiopatología , Trastornos de la Audición/psicología , Humanos , Potenciales de la Membrana , Proteínas de la Membrana/genética , Ratones , Ratones Mutantes , Datos de Secuencia MolecularRESUMEN
KCNA10 is a voltage gated potassium channel that is expressed in the inner ear. The localization and function of KCNA10 was studied in a mutant mouse, B6-Kcna10(TM45), in which the single protein coding exon of Kcna10 was replaced with a beta-galactosidase reporter cassette. Under the regulatory control of the endogenous Kcna10 promoter and enhancers, beta-galactosidase was expressed in hair cells of the vestibular organs and the organ of Corti. KCNA10 expression develops in opposite tonotopic gradients in the inner and outer hair cells. Kcna10(TM45) homozygotes display only a mild elevation in pure tone hearing thresholds as measured by auditory brainstem response (ABR), while heterozygotes are normal. However, Kcna10(TM45) homozygotes have absent vestibular evoked potentials (VsEPs) or elevated VsEP thresholds with prolonged peak latencies, indicating significant vestibular dysfunction despite the lack of any overt imbalance behaviors. Our results suggest that Kcna10 is expressed primarily in hair cells of the inner ear, with little evidence of expression in other organs. The Kcna10(TM45) targeted allele may be a model of human nonsyndromic vestibulopathy.
Asunto(s)
Células Ciliadas Auditivas/metabolismo , Trastornos de la Audición/genética , Canales de Potasio de la Superfamilia Shaker/genética , Enfermedades Vestibulares/genética , Vestíbulo del Laberinto/metabolismo , Estimulación Acústica , Secuencia de Aminoácidos , Animales , Audiometría de Tonos Puros , Umbral Auditivo , Potenciales Evocados Auditivos del Tronco Encefálico , Predisposición Genética a la Enfermedad , Trastornos de la Audición/metabolismo , Trastornos de la Audición/fisiopatología , Homocigoto , Ratones , Ratones de la Cepa 129 , Ratones Endogámicos C57BL , Ratones Noqueados , Datos de Secuencia Molecular , Mutación , Fenotipo , ARN Mensajero/metabolismo , Tiempo de Reacción , Canales de Potasio de la Superfamilia Shaker/metabolismo , Factores de Tiempo , Enfermedades Vestibulares/metabolismo , Enfermedades Vestibulares/fisiopatología , Potenciales Vestibulares Miogénicos Evocados , Vestíbulo del Laberinto/fisiopatologíaRESUMEN
Nitric oxide (NO) is a signaling molecule which can generally be formed by three nitric oxide synthases (NOS). Two of them, the endothelial nitric oxide synthase (eNOS) and the neural nitric oxide synthase (nNOS), are calcium/calmodulin-dependent and constitutively expressed in many cell types. Both isoforms are found in the vertebrate cochlea. The inducible nitric oxide synthase (iNOS) is independent of calcium and normally not detectable in the un-stimulated cochlea. In the inner ear, as in other tissues, NO was identified as a multitask molecule involved in various processes such as neurotransmission and neuromodulation. In addition, increasing evidence demonstrates that the NO-dependent processes of cell protection or, alternatively, cell destruction seem to depend, among other things, on changes in the local cochlear NO-concentration. These alterations can occur at the cellular level or within a distinct cell population both leading to an NO-imbalance within the hearing organ. This dysfunction can result in hearing loss or even in deafness. In cases of cochlear malfunction, regulatory systems such as the gap junction system, the blood vessels or the synaptic region might be affected temporarily or permanently by an altered NO-level. This review discusses potential cellular mechanisms how NO might contribute to different forms of hearing disorders. Approaches of NO-reduction are evaluated and the transfer of results obtained from experimental animal models to human medication is discussed.
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Cóclea/metabolismo , Trastornos de la Audición/metabolismo , Óxido Nítrico/metabolismo , Animales , Antioxidantes/metabolismo , Ácido Ascórbico/farmacología , Cóclea/efectos de los fármacos , Uniones Comunicantes/metabolismo , Gentamicinas/efectos adversos , Humanos , RatonesRESUMEN
Aminoglycoside antibiotics, due to their strong antibacterial effects and broad antimicrobial spectra, have been very commonly used in clinical practice in the past half century. However, aminoglycoside antibiotics manifest severe ototoxicity and nephrotoxicity, and are one of top factors in hearing loss. In this study, three members of the aminoglycoside antibiotics family, gentamycin, neomycin and streptomycin, were chosen as the representatives to be investigated for their toxicity to the embryonic development and the larva hair cells in zebrafish, and also to their target genes associated with hearing-related genes. The results showed that: (1) the lethal effect of all three drugs demonstrated a significant dependence on concentration, and the severity order of the lethal effect was streptomycin > neomycin > gentamycin; (2) all the three drugs caused the larva trunk bending in resting state at 5 dpf (day past fertilization), probably due to their ototoxicity in the physical imbalance and postural abnormalities; (3) impairment and reducing of the hair cells were observed in all three cases of drug treatment; (4) four genes, eya1, val, otx2 and dlx6a, which play an important role in the development of hearing organs, showed differential and significant decrease of gene expression in a drug concentration-dependent manner. This study for the first time reports the relevance between the expression of hearing genes and the three ototoxic antibiotics and also proved the feasibility of establishing a simple, accurate, intuitive and fast model with zebrafish for the detection of drug ototoxicity.
Asunto(s)
Aminoglicósidos/toxicidad , Antibacterianos/toxicidad , Desarrollo Embrionario/efectos de los fármacos , Células Ciliadas Auditivas/efectos de los fármacos , Trastornos de la Audición/inducido químicamente , Animales , Regulación de la Expresión Génica , Gentamicinas/toxicidad , Células Ciliadas Auditivas/citología , Trastornos de la Audición/genética , Trastornos de la Audición/metabolismo , Proteínas de Homeodominio/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Larva/efectos de los fármacos , Sistema de la Línea Lateral/efectos de los fármacos , Factor de Transcripción MafB/metabolismo , Modelos Animales , Neomicina/toxicidad , Proteínas del Tejido Nervioso/metabolismo , Proteínas Nucleares/metabolismo , Factores de Transcripción Otx/metabolismo , Inhibidores de la Síntesis de la Proteína/toxicidad , Proteínas Tirosina Fosfatasas/metabolismo , Estreptomicina/toxicidad , Pez Cebra/embriología , Proteínas de Pez Cebra/metabolismoRESUMEN
Normal blood supply to the cochlea is critically important for establishing the endocochlear potential and sustaining production of endolymph. Abnormal cochlear microcirculation has long been considered an etiologic factor in noise-induced hearing loss, age-related hearing loss (presbycusis), sudden hearing loss or vestibular function, and Meniere's disease. Knowledge of the mechanisms underlying the pathophysiology of cochlear microcirculation is of fundamental clinical importance. A better understanding of cochlear blood flow (CoBF) will enable more effective management of hearing disorders resulting from aberrant blood flow. This review focuses on recent discoveries and findings related to the physiopathology of the cochlear microvasculature.
Asunto(s)
Cóclea/irrigación sanguínea , Trastornos de la Audición/fisiopatología , Microcirculación , Microvasos/fisiopatología , Animales , Trastornos de la Audición/metabolismo , Trastornos de la Audición/patología , Humanos , Microvasos/metabolismo , Microvasos/patología , Flujo Sanguíneo RegionalRESUMEN
The transient receptor potential mucolipins (TRPMLs) are the most recently discovered subfamily of TRP ion channel proteins. Positional cloning approach has identified two mutations in the TRPML3 (Mcoln3) gene that cause the varitint-waddler mouse phenotypes. Short for variable tint (diluted coat color), the varitint-waddler consists two phenotypes Va and Va ( J ). The mutation associated with the Va phenotype is an alanine to proline substitution at position 419 (A419P) within the predicted fifth transmembrane (TM5) domain of TRPML3. The second Va ( J ) mouse phenotype arose spontaneously from an isoleucine to threonine substitution at position 362 (I362T) that is proximal to the predicted TM3 domain in addition to the existing A419P mutation on TM5. Mice with the Va and Va ( J ) mutations exhibit a spectrum of disease phenotypes from diluted coat color to auditory and vestibular problems, depending on which alleles are present. It has been over 5 years since the discovery of these TRPML3 mutations, and it was just recently that the nature of these mutations has been characterized. In this review, we discuss the molecular and cell physiological effects of the two distinct TRPML3 mutations. We reveal the effects of proline substitution on transmembrane domain structure and channel function and discuss how the Va mutation confers its cytotoxicity, while the Va ( J ) mutation results in an apparent rescue phenotype. Finally, we briefly tackle molecular strategies that have been employed to neutralize the cytotoxic effect and constitutive channel activity of the Va mutation.
Asunto(s)
Calcio/metabolismo , Mutación , Canales Catiónicos TRPM/genética , Canales Catiónicos TRPM/metabolismo , Alanina , Animales , Predisposición Genética a la Enfermedad , Genotipo , Color del Cabello/genética , Audición/genética , Trastornos de la Audición/genética , Trastornos de la Audición/metabolismo , Isoleucina , Potenciales de la Membrana , Ratones , Ratones Mutantes , Modelos Moleculares , Fenotipo , Prolina , Conformación Proteica , Estructura Terciaria de Proteína , Pigmentación de la Piel/genética , Canales Catiónicos TRPM/química , Treonina , Canales de Potencial de Receptor TransitorioRESUMEN
The Eph receptor tyrosine kinases and their membrane-anchored ligands, ephrins, are signaling proteins that act as axon guidance molecules during chick auditory brainstem development. We recently showed that Eph proteins also affect patterns of neural activation in the mammalian brainstem. However, functional deficits in the brainstems of mutant mice have not been assessed physiologically. The present study characterizes neural activation in Eph protein deficient mice in the auditory brainstem response (ABR). We recorded the ABR of EphA4 and ephrin-B2 mutant mice, aged postnatal day 18-20, and compared them to wild type controls. The peripheral hearing threshold of EphA4(-/-) mice was 75% higher than that of controls. Waveform amplitudes of peak 1 (P1) were 54% lower in EphA4(-/-) mice than in controls. The peripheral hearing thresholds in ephrin-B2(lacZ/)(+) mice were also elevated, with a mean value 20% higher than that of controls. These ephrin-B2(lacZ/)(+) mice showed a 38% smaller P1 amplitude. Significant differences in latency to waveform peaks were also observed. These elevated thresholds and reduced peak amplitudes provide evidence for hearing deficits in both of these mutant mouse lines, and further emphasize an important role for Eph family proteins in the formation of functional auditory circuitry.
Asunto(s)
Vías Auditivas/metabolismo , Umbral Auditivo , Efrina-A4/metabolismo , Efrina-B2/metabolismo , Potenciales Evocados Auditivos del Tronco Encefálico , Trastornos de la Audición/metabolismo , Estimulación Acústica , Animales , Vías Auditivas/fisiopatología , Efrina-A4/deficiencia , Efrina-A4/genética , Efrina-B2/deficiencia , Efrina-B2/genética , Genotipo , Trastornos de la Audición/genética , Trastornos de la Audición/fisiopatología , Ratones , Ratones Noqueados , Fenotipo , Tiempo de Reacción , Factores de TiempoRESUMEN
Aqueous humor is actively produced in the ciliary epithelium of the anterior chamber and has important functions for the eye. Under normal physiological conditions, the inflow and outflow of the aqueous humor are tightly regulated, but in the pathologic state this balance is lost. Aqueous outflow involves structures of the anterior chamber and experiences most resistance at the level of the trabecular meshwork (TM) that acts as a filter. The modulation of the TM structure regulates the filter and its mechanism remains poorly understood. Proteomic analyses have identified cochlin, a protein of poorly understood function, in the glaucomatous TM but not in healthy control TM from human cadaver eyes. The presence of cochlin has subsequently been confirmed by Western and immunohistochemical analyses. Functionally, cochlin undergoes multimerization induced by shear stress and other changes in the microenvironment. Cochlin along with mucopolysaccharide deposits has been found in the TM of glaucoma patients and in the inner ear of subjects affected by the hearing disorder DNFA9, a late-onset, progressive disease that also involves alterations in fluid shear regimes. In vitro, cochlin induces aggregation of primary TM cells suggesting a role in cell adhesion, possibly in mechanosensation, and in modulation of the TM filter.
Asunto(s)
Glaucoma/metabolismo , Fenómenos Fisiológicos Oculares , Proteínas/fisiología , Animales , Humor Acuoso/metabolismo , Matriz Extracelular/metabolismo , Proteínas de la Matriz Extracelular , Trastornos de la Audición/metabolismo , Humanos , Mutación , Estructura Terciaria de Proteína , Proteínas/genética , Proteínas/metabolismo , Malla Trabecular/metabolismoRESUMEN
OBJECTIVE: To examine the effects of estrogen suppression on age-related changes in distortion product otoacoustic emissions (DPOAEs) and contralateral suppression (CS) of DPOAEs in CBA mice. STUDY DESIGN AND SETTING: Young CBA mice received a slow-release shoulder implantation of either tamoxifen or placebo. Serial DPOAEs and CS of DPOAEs were obtained at 3-week intervals over a period of 9 weeks. RESULTS: Although DPOAEs were maintained over the study interval, CS of DPOAEs decreased significantly with age in the experimental group. No such declines were observed in either the control animals or the untreated male mice. CONCLUSIONS: Estrogen suppression negatively affects the MOC efferent feedback system. SIGNIFICANCE: Our results support the hypothesis that estrogen plays an important role in the maintenance of auditory integrity. Additionally, our findings raise intriguing questions about auditory effects of hormonal shifts in humans resulting from menopause, hormone supplements such as oral contraceptives, and hormone replacement therapy as well as antiestrogens.