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1.
Biochem Pharmacol ; 220: 115962, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38043717

RESUMO

Puerarin (PUE), a flavonoid derivative with vasodilatory effects found in the traditional Chinese medicine kudzu, has anti-sensorineural hearing loss properties. However, the mechanism of its protective effect against ototoxicity is not well understood. In this study, we used in vitro and in vivo methods to investigate the protective mechanism of puerarin against cisplatin (CDDP)-induced ototoxicity. We established an ototoxicity model of CDDP in BALB/c mice and assessed the degree of hearing loss and cochlear cell damage. We used bioinformatics analysis, molecular docking, histological analysis, and biochemical and molecular biology to detect the expression of relevant factors. Our results show that puerarin improved CDDP-induced hearing loss and reduced hair cell loss. It also blocked CDDP-induced activation of TRPV1 and inhibited activation of IP3R1 to prevent intracellular calcium overload. Additionally, puerarin blocked CDDP-stimulated p65 activation, reduced excessive ROS production, and alleviated cochlear cell apoptosis. Our study provides new evidence and potential targets for the protective effect of puerarin against drug-induced hearing loss. Puerarin ameliorates cisplatin-induced ototoxicity and blocks cellular apoptosis by inhibiting CDDP activated TRPV1/IP3R1/p65 pathway, blocking induction of calcium overload and excessive ROS expression.


Assuntos
Antineoplásicos , Perda Auditiva , Isoflavonas , Ototoxicidade , Animais , Camundongos , Antineoplásicos/efeitos adversos , Apoptose , Cálcio/metabolismo , Linhagem Celular , Cisplatino/efeitos adversos , Perda Auditiva/induzido quimicamente , Perda Auditiva/prevenção & controle , Perda Auditiva/metabolismo , Simulação de Acoplamento Molecular , Espécies Reativas de Oxigênio/metabolismo , Canais de Cátion TRPV/genética
2.
J Biomol Struct Dyn ; 40(21): 10940-10951, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34423747

RESUMO

Hereditary hearing impairment (HI) is a common disease with the highest incidence among sensory defects. Several genes have been identified to affect stereocilia structure causing HI, including the unconventional myosin3A. Interestingly, we noticed that variants in MYO3A gene have been previously found to cause variable HI onset and severity. Using clinical exome sequencing, we identified a novel pathogenic variant p.(Lys50Arg) in the MYO3A kinase domain (MYO3A-KD). Previous in vitro studies supported its damaging effect as a 'kinase-dead' mutant. We further analyzed this variation through molecular dynamics which predicts that changes in flexibility of MYO3A structure would influence the protein-ATP binding properties. This Lys50Arg mutation segregated with congenital profound non-syndromic HI. To better investigate this variability, we collected previously identified MYO3A-KDs variants, p.(Tyr129Cys), p.(His142Gln) and p.(Pro189Thr), and built both wild type and mutant 3 D MYO3A-KD models to assess their impact on the protein structure and function. Our results suggest that KD mutations could either cause a congenital profound form of HI, when particularly affecting the kinase activity and preventing the auto-phosphorylation of the motor, or a late onset and progressive form, when partially or completely inactivating the MYO3A protein. In conclusion, we report a novel pathogenic variant affecting the ATP-binding site within the MYO3A-KD causing congenital profound HI. Through computational approaches we provide a deeper understanding on the correlation between the effects of MYO3A-KD mutations and the variable hearing phenotypes. To the best of our knowledge this is the first study to correlate mutations' genotypes with the variable phenotypes of DFNB30.Communicated by Ramaswamy H. Sarma.


Assuntos
Perda Auditiva Neurossensorial , Perda Auditiva , Miosina Tipo III , Humanos , Perda Auditiva Neurossensorial/genética , Perda Auditiva/genética , Perda Auditiva/metabolismo , Mutação , Trifosfato de Adenosina , Cadeias Pesadas de Miosina/genética , Miosina Tipo III/genética
3.
Int J Mol Sci ; 22(13)2021 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-34206364

RESUMO

Umbilical cord-derived mesenchymal stromal cells (UCMSCs) have potential applications in regenerative medicine. UCMSCs have been demonstrated to repair tissue damage in many inflammatory and degenerative diseases. We have previously shown that UCMSC exosomes reduce nerve injury-induced pain in rats. In this study, we characterized UCMSC exosomes using RNA sequencing and proteomic analyses and investigated their protective effects on cisplatin-induced hearing loss in mice. Two independent experiments were designed to investigate the protective effects on cisplatin-induced hearing loss in mice: (i) chronic intraperitoneal cisplatin administration (4 mg/kg) once per day for 5 consecutive days and intraperitoneal UCMSC exosome (1.2 µg/µL) injection at the same time point; and (ii) UCMSC exosome (1.2 µg/µL) injection through a round window niche 3 days after chronic cisplatin administration. Our data suggest that UCMSC exosomes exert protective effects in vivo. The post-traumatic administration of UCMSC exosomes significantly improved hearing loss and rescued the loss of cochlear hair cells in mice receiving chronic cisplatin injection. Neuropathological gene panel analyses further revealed the UCMSC exosomes treatment led to beneficial changes in the expression levels of many genes in the cochlear tissues of cisplatin-injected mice. In conclusion, UCMSC exosomes exerted protective effects in treating ototoxicity-induced hearing loss by promoting tissue remodeling and repair.


Assuntos
Doenças Cocleares/etiologia , Doenças Cocleares/terapia , Exossomos/metabolismo , Células Ciliadas Auditivas Externas/efeitos dos fármacos , Células Ciliadas Auditivas Externas/metabolismo , Células-Tronco Mesenquimais/metabolismo , Cordão Umbilical/citologia , Animais , Antineoplásicos/efeitos adversos , Terapia Biológica , Biomarcadores , Cisplatino/efeitos adversos , Doenças Cocleares/patologia , Modelos Animais de Doenças , Exossomos/transplante , Células Ciliadas Auditivas Externas/patologia , Perda Auditiva/etiologia , Perda Auditiva/metabolismo , Perda Auditiva/terapia , Imunofenotipagem , Camundongos , MicroRNAs/genética , Proteômica/métodos , Resultado do Tratamento
4.
Sci Rep ; 9(1): 19248, 2019 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-31848399

RESUMO

Photobiomodulation (PBM) has been suggested to have a therapeutic effect on irreversible hearing loss induced by aminoglycosides, including gentamicin (GM). However, its intracellular mechanism(s) in GM-induced ototoxicity remain poorly understood. In the present study, we investigated the effect of PBM in GM-induced ototoxicity in auditory cells. We tried to characterize the downstream process by PBM, and the process that triggered the increased cell viability of auditory cells. As a result, the effects of PBM against GM-induced ototoxicity by increasing ATP levels and mitochondrial membrane potential was confirmed. These results suggest a theory to explain the therapeutic effects and support the use of PBM for aminoglycoside-induced hearing loss.


Assuntos
Trifosfato de Adenosina/biossíntese , Gentamicinas/efeitos adversos , Células Ciliadas Auditivas , Perda Auditiva , Terapia com Luz de Baixa Intensidade , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Animais , Linhagem Celular , Gentamicinas/farmacologia , Células Ciliadas Auditivas/metabolismo , Células Ciliadas Auditivas/patologia , Perda Auditiva/induzido quimicamente , Perda Auditiva/metabolismo , Perda Auditiva/patologia , Perda Auditiva/terapia , Camundongos
5.
Int J Mol Sci ; 20(19)2019 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-31547176

RESUMO

Noise-induced hearing loss (NIHL) relates closely to auditory cortex (AC) injury, so countermeasures aiming at the AC recovery would be of benefit. In this work, the effect of hyperbaric oxygen treatment on NIHL was elucidated, which was imposed on mice before (HBOP), during (HBOD) or after (HBOA) noise exposure. Morphology of neurons was assayed by hematoxylin-eosin or Nissl staining. Ceramide (Cer) level was measured through immunohistochemistry analysis. Apoptotic neurons were counted using transferase-mediated dUTP nick end labeling (TUNEL) staining. We demonstrated that the intense, broad band noise raised the threshold of auditory brainstem response, evoked neuronal degeneration or apoptosis and triggered the Cer accumulation in AC, all of which were restored significantly by HBOP, but not HBOD or HBOA. Cer over-generation reversed the advantages of HBOP significantly, while its curtailment recapitulated the effect. Next, noise exposure raised the superoxide or malondialdehyde (MDA) production which was blocked by HBOP or Cer repression. Oxidative control not only attenuated the hearing loss or neurodegeneration but, in turn, reduced the Cer formation significantly. In summary, mutual regulation between Cer and oxidative stress underlies the HBOP's curative effect on hearing loss and neuronal damage in noise-exposed mice.


Assuntos
Córtex Auditivo , Ceramidas/metabolismo , Perda Auditiva , Oxigenoterapia Hiperbárica , Ruído/efeitos adversos , Animais , Córtex Auditivo/patologia , Córtex Auditivo/fisiopatologia , Perda Auditiva/metabolismo , Perda Auditiva/patologia , Perda Auditiva/fisiopatologia , Perda Auditiva/terapia , Masculino , Camundongos
6.
Development ; 146(17)2019 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-31477580

RESUMO

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.


Assuntos
Diferenciação Celular/fisiologia , Células Ciliadas Auditivas Internas/metabolismo , Organoides/citologia , Adulto , Animais , Animais Recém-Nascidos , Avaliação Pré-Clínica de Medicamentos/métodos , Perda Auditiva/tratamento farmacológico , Perda Auditiva/genética , Perda Auditiva/metabolismo , Humanos , Recém-Nascido , Mamíferos/embriologia , Mamíferos/crescimento & desenvolvimento , Camundongos , Células-Tronco Neurais/metabolismo , Células-Tronco Pluripotentes/metabolismo , Regeneração
7.
J Physiol ; 597(13): 3389-3406, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31069810

RESUMO

KEY POINTS: The physiological maturation of auditory hair cells and their innervation requires precise temporal and spatial control of cell differentiation. The transcription factor gata3 is essential for the earliest stages of auditory system development and for survival and synaptogenesis in auditory sensory afferent neurons. We show that during postnatal development in the mouse inner ear gata3 is required for the biophysical maturation, growth and innervation of inner hair cells; in contrast, it is required only for the survival of outer hair cells. Loss of gata3 in inner hair cells causes progressive hearing loss and accounts for at least some of the deafness associated with the human hypoparathyroidism, deafness and renal anomaly (HDR) syndrome. The results show that gata3 is critical for later stages of mammalian auditory system development where it plays distinct, complementary roles in the coordinated maturation of sensory hair cells and their innervation. ABSTRACT: The zinc finger transcription factor gata3 regulates inner ear development from the formation of the embryonic otic placode. Throughout development, gata3 is expressed dynamically in all the major cochlear cell types. Its role in afferent formation is well established but its possible involvement in hair cell maturation remains unknown. Here, we find that in heterozygous gata3 null mice (gata3+/- ) outer hair cells (OHCs) differentiate normally but their numbers are significantly lower. In contrast, inner hair cells (IHCs) survive normally but they fail to acquire adult basolateral membrane currents, retain pre-hearing current and efferent innervation profiles and have fewer ribbon synapses. Targeted deletion of gata3 driven by otoferlin-cre recombinase (gata3fl/fl otof-cre+/- ) in IHCs does not affect OHCs or the number of IHC afferent synapses but it leads to a failure in IHC maturation comparable to that observed in gata3+/- mice. Auditory brainstem responses in gata3fl/fl otof-cre+/- mice reveal progressive hearing loss that becomes profound by 6-7 months, whilst distortion product otoacoustic emissions are no different to control animals up to this age. Our results, alongside existing data, indicate that gata3 has specific, complementary functions in different cell types during inner ear development and that its continued expression in the sensory epithelium orchestrates critical aspects of physiological development and neural connectivity. Furthermore, our work indicates that hearing loss in human hypoparathyroidism, deafness and renal anomaly (HDR) syndrome arises from functional deficits in IHCs as well as loss of function from OHCs and both afferent and efferent neurons.


Assuntos
Cóclea/metabolismo , Cóclea/fisiologia , Fator de Transcrição GATA3/metabolismo , Células Ciliadas Auditivas Internas/metabolismo , Células Ciliadas Auditivas Internas/fisiologia , Animais , Diferenciação Celular/fisiologia , Células Ciliadas Auditivas Externas/metabolismo , Células Ciliadas Auditivas Externas/fisiologia , Células Ciliadas Vestibulares/metabolismo , Células Ciliadas Vestibulares/fisiologia , Audição/fisiologia , Perda Auditiva/metabolismo , Perda Auditiva/fisiopatologia , Proteínas de Membrana/metabolismo , Camundongos Knockout , Camundongos Transgênicos , Células Receptoras Sensoriais/metabolismo , Células Receptoras Sensoriais/fisiologia , Sinapses/metabolismo
8.
Hear Res ; 377: 208-223, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30981948

RESUMO

Ototoxic-drug-induced hearing disturbances in the auditory periphery are associated with tonotopic map reorganization and neural activity modulation, as well as changes in neural correlates in the central auditory pathway, including the auditory cortex (AC). Previous studies have reported that peripheral auditory impairment induces AC plasticity that involves changes in the balance of excitatory vs. inhibitory synapses, within existing and newly forming patterns of connectivity. Although we know that such plastic changes modulate sound-evoked neural responses and the organization of tonotopic maps in the primary AC (A1), little is known about the effects of peripheral impairment on other frequency-organized AC subfields, such as the anterior auditory field (AAF) and the secondary auditory cortex (A2). Therefore, to examine ototoxic-drug-induced spatiotemporal effects on AC subfields, we measured sound-evoked neural activity in mice before and after the administration of kanamycin sulfate (1 mg/g body weight) and bumetanide (0.05 mg/g body weight), using in vivo transcranial flavoprotein autofluorescence imaging over a 4-week period. At first, ototoxic treatment gradually reduced responses driven by tone bursts with lower- (≤8 kHz) and middle- (e.g., 16 kHz) range frequencies in all AC subfields. Subsequently, response intensities in the A1 recovered to more than 78% of the pre-drug condition; however, in the AAF and A2, they remained significantly lower and were unchanged over 3 weeks. Furthermore, after drug administration, the best frequency (BF) areas of the lower (4 and 8 kHz) and higher (25 and 32 kHz) ranges in all subfields were reduced and shifted to those of a middle range (centered around 16 kHz) during the 3 weeks following drug administration. Our results also indicated that, compared with A1, BF distributions in the AAF and A2 were sharper around 16 kHz 3 weeks after drug administration. These results indicate that the ototoxic-damage-induced tonotopic map reorganizations that occurred in each of the three AC subfields were similar, but that there were subfield-dependent differences in the extent of response intensities and in the activated areas that were responsive to tone bursts with specific frequencies. Thus, by examining cortical reorganization induced by ototoxic drugs, we may contribute to the understanding of how this reorganization can be caused by peripheral damage.


Assuntos
Estimulação Acústica , Córtex Auditivo/diagnóstico por imagem , Mapeamento Encefálico , Flavoproteínas/metabolismo , Perda Auditiva/diagnóstico por imagem , Audição , Microscopia de Fluorescência , Imagem Óptica , Animais , Córtex Auditivo/metabolismo , Córtex Auditivo/fisiopatologia , Limiar Auditivo , Bumetanida , Modelos Animais de Doenças , Potenciais Evocados Auditivos , Feminino , Perda Auditiva/induzido quimicamente , Perda Auditiva/metabolismo , Perda Auditiva/fisiopatologia , Canamicina , Camundongos Endogâmicos C57BL , Plasticidade Neuronal , Tempo de Reação , Fatores de Tempo
9.
Auris Nasus Larynx ; 46(5): 703-708, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30799140

RESUMO

OBJECTIVE: Tsumura Suzuki Obese Diabetes (TSOD) mice exhibit early age-associated hearing loss. Histopathological analysis of these mice shows narrowing of capillaries in the stria vascularis and chronic reduction of blood flow in the cochlea. In this study, we investigated the effect of oral administration of a herbal medicine or calorie restriction on hearing in TSOD mice. METHODS: TSOD mice were divided into 4 groups: CR (calorie restriction), BF and DS (treated with the herbal medicines, Bofutsushosan and Daisaikoto, respectively), and the control group. Body weight, blood glucose levels, and auditory brainstem responses (ABRs) were measured. The cochleae were excised and evaluated histopathologically. RESULTS: Blood glucose levels were suppressed in the CR, BF, and DS groups. In addition, the elevation of ABR thresholds was inhibited in the CR, BF, and DS groups. Cochlear blood vessels remained wide in the three treatment groups compared with the control group. These results suggested that the administration of these herbal medicines improved glucose tolerance and yielded results similar to those on calorie restriction. CONCLUSION: Oral administration of 2 herbal medicines can prevent hearing function disorder in a model mouse of diabetes. The results may clarify the possibility of clinical application.


Assuntos
Restrição Calórica , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Medicamentos de Ervas Chinesas/farmacologia , Potenciais Evocados Auditivos do Tronco Encefálico/efeitos dos fármacos , Perda Auditiva/metabolismo , Preparações de Plantas/farmacologia , Administração Oral , Animais , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Capilares/efeitos dos fármacos , Capilares/patologia , Cóclea/irrigação sanguínea , Cóclea/efeitos dos fármacos , Cóclea/patologia , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Tipo 2/complicações , Modelos Animais de Doenças , Progressão da Doença , Perda Auditiva/etiologia , Camundongos , Estria Vascular/efeitos dos fármacos , Estria Vascular/patologia
10.
Mol Med Rep ; 19(1): 51-58, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30431080

RESUMO

Salicylate is widely used to produce animal models of tinnitus in mice and/or rats. The side effects on auditory function, including hearing loss and tinnitus, are considered the results of the auditory nerve dysfunction. A recent study indicated that chronic treatment with salicylate for several weeks reduces compressed action potential amplitude, which is contradictory to the studies reporting excessive activation of N­methyl­D­aspartate receptors (NMDAR) in tinnitus­induced animals. The specific aims of the experiment were to detect the effect of salicylate on the inner hair cells (IHCs), ribbon synapse, as well as the association between the hearing threshold and the number of mismatched ribbon synapses. In the present study, mice were injected intraperitoneally with a low dose of salicylate (200 mg/kg) for 14 days. The auditory brainstem response and otoacoustic emission were measured to assess auditory function of the mice. The postsynaptic regions of IHC were identified with two types of immunostaining targets: Postsynaptic density protein 95 and Glu2/3. The number of spheres was counted and the synapses were reconstructed in 3­dimensional images. Increases in distortion product otoacoustic emissions amplitudes of the salicylate group were detected, however, an elevation in the hearing threshold was also observed. A mismatch between pre­and post­ribbon synapses was observed. In addition, the cochlear components, including the numbers of outer hair cells and IHCs, were unlikely to be affected by salicylate. IHC ribbon synapses were more susceptible to salicylate stimuli. Furthermore, mismatch of pre­ and post­ribbon synapses may indicate a competitive inhibition between NMDAR and α-amino­3­hydroxy-5-methyl-4-isoxa-zole-propionate receptors and dysfunction of ribbon synapses.


Assuntos
Células Ciliadas Auditivas Internas/efeitos dos fármacos , Receptores de AMPA/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Ácido Salicílico/farmacologia , Sinapses/metabolismo , Estimulação Acústica/métodos , Animais , Cóclea/efeitos dos fármacos , Cóclea/metabolismo , Potenciais Evocados Auditivos do Tronco Encefálico/efeitos dos fármacos , Células Ciliadas Auditivas Internas/metabolismo , Audição/efeitos dos fármacos , Perda Auditiva/tratamento farmacológico , Perda Auditiva/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Emissões Otoacústicas Espontâneas/efeitos dos fármacos
11.
Sci Rep ; 8(1): 14165, 2018 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-30242206

RESUMO

Cochlear implantation, a surgical method to bypass cochlear hair cells and directly stimulate the spiral ganglion, is the standard treatment for severe-to-profound hearing loss. Changes in cochlear implant electrode array design and surgical approach now allow for preservation of acoustic hearing in the implanted ear. Electrocochleography (ECochG) was performed in eight hearing preservation subjects to assess hair cell and neural function and elucidate underlying genetic hearing loss. Three subjects had pathogenic variants in TMPRSS3 and five had pathogenic variants in genes known to affect the cochlear sensory partition. The mechanism by which variants in TMPRSS3 cause genetic hearing loss is unknown. We used a 500-Hz tone burst to record ECochG responses from an intracochlear electrode. Responses consist of a cochlear microphonic (hair cell) and an auditory nerve neurophonic. Cochlear microphonics did not differ between groups. Auditory nerve neurophonics were smaller, on average, in subjects with TMPRSS3 deafness. Results of this proof-of-concept study provide evidence that pathogenic variants in TMPRSS3 may impact function of the spiral ganglion. While ECochG as a clinical and research tool has been around for decades, this study illustrates a new application of ECochG in the study of genetic hearing and deafness in vivo.


Assuntos
Cóclea/metabolismo , Cóclea/fisiopatologia , Surdez/metabolismo , Surdez/fisiopatologia , Proteínas de Membrana/metabolismo , Proteínas de Neoplasias/metabolismo , Serina Endopeptidases/metabolismo , Gânglio Espiral da Cóclea/metabolismo , Gânglio Espiral da Cóclea/fisiopatologia , Estimulação Acústica/métodos , Adolescente , Adulto , Audiometria de Resposta Evocada/métodos , Criança , Implante Coclear/métodos , Implantes Cocleares , Nervo Coclear/metabolismo , Nervo Coclear/fisiologia , Feminino , Células Ciliadas Auditivas/metabolismo , Células Ciliadas Auditivas/fisiologia , Audição/fisiologia , Perda Auditiva/metabolismo , Perda Auditiva/fisiopatologia , Humanos , Masculino , Proteínas de Membrana/fisiologia , Pessoa de Meia-Idade , Adulto Jovem
12.
Acta Otolaryngol ; 138(8): 676-684, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29513056

RESUMO

OBJECTIVE: The present study is aimed at determining the efficacy and exploring the mechanisms by which l-N-acetylcysteine (l-NAC) provides protection against tumor necrosis factor-alpha (TNFα)-induced oxidative stress damage and hair cell loss in 3-day-old rat organ of Corti (OC) explants. Previous work has demonstrated a high level of oxidative stress in TNFα-challenged OC explants. TNFα can potentially play a significant role in hair cell loss following an insult to the inner ear. l-NAC has shown to provide effective protection against noise-induced hearing loss in laboratory animals but mechanisms of this otoprotective effect are not well-defined. DESIGN: Rat OC explants were exposed to either: (1) saline control (N = 12); (2) TNFα (2 µg/ml, N = 12); (3) TNFα+l-NAC (5 mM, N = 12); (4) TNFα+l-NAC (10 mM, N = 12); or (5) l-NAC (10 mM, N = 12). Outer hair cell (OHC) density, levels of reactive oxygen species (ROS), lipid peroxidation of cell membranes, gluthathione activity, and mitochondrial viability were assayed. RESULTS: l-NAC (5 and 10 mM) provided protection for OHCs from ototoxic level of TNFα in OC explants. Groups treated with TNFα+l-NAC (5 mM) showed a highly significant reduction of both ROS (p < 0.01) and 4-hydroxy-2-nonenal immunostaining (p < 0.001) compared to TNFα-challenged explants. Total glutathione levels were low in TNFα-challenged explants compared to control and TNFα+l-NAC (5 mM) treated explants (p < 0.001). CONCLUSIONS: l-NAC is a promising treatment for protecting auditory HCs from TNFα-induced oxidative stress and subsequent loss via programmed cell death.


Assuntos
Acetilcisteína/uso terapêutico , Sequestradores de Radicais Livres/uso terapêutico , Células Ciliadas Auditivas Externas/efeitos dos fármacos , Perda Auditiva/prevenção & controle , Estresse Oxidativo/efeitos dos fármacos , Acetilcisteína/farmacologia , Aldeídos , Animais , Avaliação Pré-Clínica de Medicamentos , Sequestradores de Radicais Livres/farmacologia , Glutationa/metabolismo , Glutationa Sintase/metabolismo , Perda Auditiva/metabolismo , Técnicas In Vitro , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Fator de Necrose Tumoral alfa
13.
Neurochem Res ; 41(6): 1343-53, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26886762

RESUMO

Lesion-induced cochlear damage can result in synaptic outgrowth in the ventral cochlear nucleus (VCN). Tinnitus may be associated with the synaptic outgrowth and hyperactivity in the VCN. However, it remains unclear how hearing loss triggers structural synaptic modifications in the VCN of rats subjected to salicylate-induced tinnitus. To address this issue, we evaluated tinnitus-like behavior in rats after salicylate treatment and compared the amplitude of the distortion product evoked otoacoustic emission (DPOAE) and auditory brainstem response (ABR) between control and treated rats. Moreover, we observed the changes in the synaptic ultrastructure and in the expression levels of growth-associated protein (GAP-43), brain-derived neurotrophic factor (BDNF), the microglial marker Iba-1 and glial fibrillary acidic protein (GFAP) in the VCN. After salicylate treatment (300 mg/kg/day for 4 and 8 days), analysis of the gap prepulse inhibition of the acoustic startle showed that the rats were experiencing tinnitus. The changes in the DPOAE and ABR amplitude indicated an improvement in cochlear sensitivity and a reduction in auditory input following salicylate treatment. The treated rats displayed more synaptic vesicles and longer postsynaptic density in the VCN than the control rats. We observed that the GAP-43 expression, predominantly from medial olivocochlear (MOC) neurons, was significantly up-regulated, and that BDNF- and Iba-1-immunoreactive cells were persistently decreased after salicylate administration. Furthermore, GFAP-immunoreactive astrocytes, which is associated with synaptic regrowth, was significantly increased in the treated groups. Our study revealed that reduced auditory nerve activity triggers synaptic outgrowth and hyperactivity in the VCN via a MOC neural feedback circuit. Structural synaptic modifications may be a reflexive process that compensates for the reduced auditory input after salicylate administration. However, massive increases in excitatory synapses in the VCN may represent a detrimental process that causes central hyperactivity, leading to tinnitus.


Assuntos
Núcleo Coclear/ultraestrutura , Retroalimentação Fisiológica , Perda Auditiva/induzido quimicamente , Rede Nervosa/ultraestrutura , Salicilatos/toxicidade , Sinapses/ultraestrutura , Estimulação Acústica/métodos , Animais , Anti-Inflamatórios não Esteroides/toxicidade , Núcleo Coclear/efeitos dos fármacos , Núcleo Coclear/metabolismo , Retroalimentação Fisiológica/efeitos dos fármacos , Retroalimentação Fisiológica/fisiologia , Perda Auditiva/metabolismo , Perda Auditiva/patologia , Masculino , Rede Nervosa/efeitos dos fármacos , Rede Nervosa/metabolismo , Distribuição Aleatória , Ratos , Ratos Wistar , Sinapses/efeitos dos fármacos , Sinapses/metabolismo
14.
J Nutr Biochem ; 26(12): 1424-33, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26321228

RESUMO

Omega-3 polyunsaturated fatty acids (PUFAs) are essential nutrients well known for their beneficial effects, among others on cognitive development and maintenance, inflammation and oxidative stress. Previous studies have shown an inverse association between high plasma levels of PUFAs and age-related hearing loss, and the relationship between low serum folate and elevated plasma homocysteine levels and hearing loss. Therefore, we used C57BL/6J mice and long-term omega-3 supplementation to evaluate the impact on hearing by analyzing their auditory brainstem response (ABR) and distortion product otoacoustic emissions (DPOAE) thresholds. The omega-3 group showed significantly lower ABR hearing thresholds (~25 dB sound pressure level) and higher DPOAE amplitudes in mid-high frequencies when compared to the control group. These changes did not correlate with alterations between groups in plasma homocysteine or serum folate levels as measured by high-performance liquid chromatography and a microbiological method, respectively. Aging in the control group was associated with imbalanced cytokine expression toward increased proinflammatory cytokines as determined by quantitative reverse transcriptase polymerase chain reaction; these changes were prevented by omega-3 supplementation. Genes involved in homocysteine metabolism showed decreased expression during aging of control animals, and only alterations in Bhmt and Cbs were significantly prevented by omega-3 feeding. Western blotting showed that omega-3 supplementation precluded the CBS protein increase detected in 10-month-old controls but also produced an increase in BHMT protein levels. Altogether, the results obtained suggest a long-term protective role of omega-3 supplementation on cochlear metabolism and progression of hearing loss.


Assuntos
Cóclea/metabolismo , Suplementos Nutricionais , Ácidos Graxos Ômega-3/administração & dosagem , Perda Auditiva/metabolismo , Homocisteína/metabolismo , Animais , Biomarcadores/metabolismo , Peso Corporal , Cromatografia Líquida de Alta Pressão , Potenciais Evocados Auditivos do Tronco Encefálico , Feminino , Ácido Fólico/sangue , Homocisteína/sangue , Inflamação , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo , Pressão , Reação em Cadeia da Polimerase Via Transcriptase Reversa
15.
Hear Res ; 330(Pt B): 200-12, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26188103

RESUMO

Mutations in the OTOF gene encoding otoferlin result in a disrupted function of the ribbon synapses with impairment of the multivesicular glutamate release. Most affected subjects present with congenital hearing loss and abnormal auditory brainstem potentials associated with preserved cochlear hair cell activities (otoacoustic emissions, cochlear microphonics [CMs]). Transtympanic electrocochleography (ECochG) has recently been proposed for defining the details of potentials arising in both the cochlea and auditory nerve in this disorder, and with a view to shedding light on the pathophysiological mechanisms underlying auditory dysfunction. We review the audiological and electrophysiological findings in children with congenital profound deafness carrying two mutant alleles of the OTOF gene. We show that cochlear microphonic (CM) amplitude and summating potential (SP) amplitude and latency are normal, consistently with a preserved outer and inner hair cell function. In the majority of OTOF children, the SP component is followed by a markedly prolonged low-amplitude negative potential replacing the compound action potential (CAP) recorded in normally-hearing children. This potential is identified at intensities as low as 90 dB below the behavioral threshold. In some ears, a synchronized CAP is superimposed on the prolonged responses at high intensity. Stimulation at high rates reduces the amplitude and duration of the prolonged potentials, consistently with their neural generation. In some children, however, the ECochG response only consists of the SP, with no prolonged potential. Cochlear implants restore hearing sensitivity, speech perception and neural CAP by electrically stimulating the auditory nerve fibers. These findings indicate that an impaired multivesicular glutamate release in OTOF-related disorders leads to abnormal auditory nerve fiber activation and a consequent impairment of spike generation. The magnitude of these effects seems to vary, ranging from no auditory nerve fiber activation to an abnormal generation of EPSPs that occasionally trigger a synchronized electrical activity, resulting in high-threshold CAPs.


Assuntos
Cóclea/inervação , Nervo Coclear/fisiopatologia , Sinais (Psicologia) , Perda Auditiva/genética , Audição , Proteínas de Membrana/genética , Mutação , Percepção da Fala , Transmissão Sináptica , Estimulação Acústica , Animais , Audiometria de Resposta Evocada , Vias Auditivas/metabolismo , Vias Auditivas/fisiopatologia , Limiar Auditivo , Implante Coclear , Potenciais Microfônicos da Cóclea , Nervo Coclear/metabolismo , Predisposição Genética para Doença , Ácido Glutâmico/metabolismo , Perda Auditiva/diagnóstico , Perda Auditiva/metabolismo , Perda Auditiva/fisiopatologia , Perda Auditiva/psicologia , Perda Auditiva/reabilitação , Humanos , Percepção Sonora , Proteínas de Membrana/metabolismo , Pessoas com Deficiência Auditiva/psicologia , Fenótipo , Tempo de Reação , Inteligibilidade da Fala , Fatores de Tempo
16.
Hear Res ; 327: 89-101, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25987502

RESUMO

AIM: This study evaluated the impact of a dexamethasone-releasing silicone implant on hearing function preservation, cochlear morphology and perilymph pharmacokinetics after cochlear implantation. METHODS: Guinea pigs were implanted unilaterally with silicone rods containing either 2% dexamethasone (DEXA group, n = 18) or no dexamethasone (control group, n = 17). Auditory brainstem response (ABR) and distortion product otoacoustic emissions (DPOAEs) were measured preoperatively and over 6 months postoperatively. Cochlear histology using standard hematoxylin and eosin (H&E) staining and tumor necrosis factor (TNF)-alpha staining was performed 1 month postoperatively. Twenty-two guinea pigs were involved in the pharmacokinetic study, and real-time drug concentrations in perilymph were investigated using high-performance liquid chromatography (HPLC). The Mann-Whitney U test (1-tailed) was used for statistical analyses. RESULTS: ABR and DPOAE testing demonstrated decreased hearing function immediately postoperatively followed by a progressive hearing loss within the first day postoperatively. There was almost no observable hearing improvement in the control group from 1 week to 6 months postoperatively, but hearing levels in the DEXA group improved gradually from 1 week to 12 weeks. Hearing loss in the DEXA and control group was 5.0 ± 3.4 dB and 21.7 ± 5.3 dB, respectively at a 16-kHz stimulus frequency 6 months postoperatively. The difference in threshold shifts was present throughout all measured frequencies, and it was significant at 4-24 kHz. The morphological study revealed new fibrosis formation in the scala tympani, which encapsulated the implanted electrode. TNF-alpha positive staining in the cochleae of the DEXA group was less evident than the control group. The pharmacokinetic study revealed a peak perilymph concentration 30 min postoperatively and sustained dexamethasone release at least 1 week postoperatively. CONCLUSION: Cochlear implants that incorporate dexamethasone can release drug chronically in the inner ear and induce significant long-term recovery and preservation of auditory function after implantation.


Assuntos
Cóclea/efeitos dos fármacos , Implantes Cocleares , Dexametasona/administração & dosagem , Dexametasona/farmacocinética , Glucocorticoides/administração & dosagem , Glucocorticoides/farmacocinética , Perda Auditiva/prevenção & controle , Audição/efeitos dos fármacos , Estimulação Acústica , Animais , Limiar Auditivo/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Cóclea/metabolismo , Cóclea/patologia , Cóclea/fisiopatologia , Modelos Animais de Doenças , Implantes de Medicamento , Potenciais Evocados Auditivos do Tronco Encefálico/efeitos dos fármacos , Fibrose , Cobaias , Perda Auditiva/diagnóstico , Perda Auditiva/etiologia , Perda Auditiva/metabolismo , Perda Auditiva/fisiopatologia , Emissões Otoacústicas Espontâneas/efeitos dos fármacos , Perilinfa/metabolismo , Silicones/química , Fator de Necrose Tumoral alfa/metabolismo
17.
Exp Gerontol ; 57: 224-32, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24952098

RESUMO

Since Korean red ginseng (KRG) has been proven to protect against gentamicin-induced vestibular and hearing dysfunction, the effects of KRG on age-related inner ear disorder in C57BL/6 mice were investigated. While age-related hearing loss was detected at the age of 6months (32kHz) and 9months (16kHz) in the control group, it was significantly delayed (p<0.05) in the 150mg/kg KRG-treated group. Vestibular dysfunction was observed in the tail-hanging and swimming tests, with significantly different severity scores and swimming times detected between the control and 150mg/kg KRG-treated group at the age of 12months (p<0.05). Mice treated with 500mg/kg KRG exhibited irritability and aggravated inner ear dysfunction. Histological observation supported the findings of hearing and vestibular function defects. In conclusion, C57BL/6 mice showed early-onset hearing loss and progressive vestibular dysfunction with aging, which were delayed by treatment with 150mg/kg KRG. However, 500mg/kg KRG treatment may induce aggressive behavior.


Assuntos
Perda Auditiva/prevenção & controle , Panax , Fitoterapia , Extratos Vegetais/uso terapêutico , Doenças Vestibulares/prevenção & controle , Envelhecimento/efeitos dos fármacos , Animais , Citocromos c/metabolismo , Avaliação Pré-Clínica de Medicamentos , Células Ciliadas Auditivas/efeitos dos fármacos , Células Ciliadas Auditivas/ultraestrutura , Perda Auditiva/metabolismo , Masculino , Medicina Tradicional Coreana , Camundongos Endogâmicos C57BL , Extratos Vegetais/farmacologia , Distribuição Aleatória , Doenças Vestibulares/metabolismo , Proteína bcl-X/metabolismo
18.
Otol Neurotol ; 35(3): 533-9, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24518411

RESUMO

HYPOTHESIS: Oral supplementation with mitoquinone (MitoQ) prevents gentamicin-induced ototoxicity in guinea pigs. BACKGROUND: Antioxidants have been shown to protect against aminoglycoside (AG)-induced ototoxicity. MitoQ, a mitochondria-targeted derivative of the antioxidant ubiquinone, is attached to a lipophilic triphenylphosphonium (TPP) cation, which enables its accumulation inside the mitochondria several hundred-fold over the untargeted antioxidant. MitoQ has improved bioavailability and can reach most tissues and has been used in Parkinson's disease and hepatitis C human trials, which demonstrated that MitoQ can be safely used in humans. Thus, MitoQ is a promising novel therapeutic approach for protecting against AG-induced ototoxicity. METHODS: Gentamicin-treated guinea pigs were supplied with water alone (control), decyl-TPP (positive control), or MitoQ-supplemented drinking water. Auditory function was assessed by auditory brainstem response. Cochlear damage was assessed using scanning electron microscopy. Western blotting was performed to evaluate changes in proteins related to apoptosis and oxidative damage in the cochlea. RESULTS: Threshold shifts at 4 and 8 kHz at 4 and 7 weeks after gentamicin treatment were smaller in animals treated with MitoQ compared with those in the control- and decyl-TPP-treated animals (p < 0.05). Protein carbonyls and levels of the proapoptotic protein Bak were lower (p < 0.05 and p = 0.008, respectively), whereas the level of the antioxidant enzyme manganese superoxide dismutase was higher (p = 0.01) in the cochlea of MitoQ-treated animals. The expression of 3-nitrotyrosine and Hrk were not different between groups (p > 0.05). CONCLUSION: Oral supplementation with MitoQ attenuated gentamicin-induced cochlear damage and hearing loss in guinea pigs. MitoQ holds promise as a means for protecting against AG ototoxicity.


Assuntos
Antioxidantes/uso terapêutico , Cóclea/efeitos dos fármacos , Doenças Cocleares/tratamento farmacológico , Potenciais Evocados Auditivos do Tronco Encefálico/efeitos dos fármacos , Perda Auditiva/tratamento farmacológico , Compostos Organofosforados/uso terapêutico , Ubiquinona/análogos & derivados , Animais , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Cóclea/metabolismo , Doenças Cocleares/induzido quimicamente , Doenças Cocleares/metabolismo , Potenciais Evocados Auditivos do Tronco Encefálico/fisiologia , Gentamicinas , Cobaias , Perda Auditiva/induzido quimicamente , Perda Auditiva/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Compostos Organofosforados/farmacologia , Oxirredução , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Superóxido Dismutase/metabolismo , Ubiquinona/farmacologia , Ubiquinona/uso terapêutico
20.
Int J Audiol ; 52(12): 816-23, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24160854

RESUMO

OBJECTIVE: The metabolic disorder Pompe disease mainly affects the skeletal muscle in adults. The hearing impairment due to stapedius muscle involvement in adult patients is not known. DESIGN: The frequency, severity, and type of hearing impairment was characterized prospectively using pure-tone audiometry, tympanometry, stapedial reflexes, otoacoustic emissions, and brainstem-evoked response audiometry in adult patients on enzyme replacement therapy for genetically confirmed Pompe disease. STUDY SAMPLE: 11 adult patients (median age: 47 years, range: 22-71). RESULTS: Four patients complained about subjective hearing disturbances. Using World Health Organization definition of hearing impairment, abnormal hearing thresholds resulting in mild hearing loss were found in 36% of patients. Compared to normative data (ISO 7029), the hearing threshold was below the median in all but three ears. Stapedial reflexes could not be elicited ipsilateral in 18% and contralateral in 36%. Auditory brainstem responses showed no retrocochlear pathology. CONCLUSIONS: The prevalence of hearing loss slightly exceeded the normative data of the general population. Consistent with previous studies the hearing impairment was usually mild. The percentage of pathological stapedial reflexes exceeded that of matched control subjects and suggests a selective involvement of the stapedius muscle, potentially as a sequela of Pompe disease.


Assuntos
Doença de Depósito de Glicogênio Tipo II/epidemiologia , Perda Auditiva/epidemiologia , Testes de Impedância Acústica , Estimulação Acústica , Adulto , Idade de Início , Idoso , Audiometria de Tons Puros , Limiar Auditivo , Terapia de Reposição de Enzimas , Potenciais Evocados Auditivos do Tronco Encefálico , Alemanha/epidemiologia , Doença de Depósito de Glicogênio Tipo II/diagnóstico , Doença de Depósito de Glicogênio Tipo II/tratamento farmacológico , Doença de Depósito de Glicogênio Tipo II/metabolismo , Perda Auditiva/diagnóstico , Perda Auditiva/metabolismo , Perda Auditiva/fisiopatologia , Humanos , Pessoa de Meia-Idade , Prevalência , Estudos Prospectivos , Reflexo Acústico , Índice de Gravidade de Doença , Estapédio/metabolismo , Estapédio/patologia , Adulto Jovem
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