RESUMO
Noise is the most common occupational and environmental hazard, and noise-induced hearing loss (NIHL) is the second most common form of sensorineural hearing deficit. Although therapeutics that target the free-radical pathway have shown promise, none of these compounds is currently approved against NIHL by the United States Food and Drug Administration. The present study has demonstrated that tetrandrine (TET), a traditional Chinese medicinal alkaloid and the main chemical isolate of the Stephania tetrandra S. Moore herb, significantly attenuated NIHL in CBA/CaJ mice. TET is known to exert antihypertensive and antiarrhythmic effects through the blocking of calcium channels. Whole-cell patch-clamp recording from adult spiral ganglion neurons showed that TET blocked the transient Ca2+ current in a dose-dependent manner and the half-blocking concentration was 0.6 + 0.1 µM. Consistent with previous findings that modulations of calcium-based signaling pathways have both prophylactic and therapeutic effects against neural trauma, NIHL was significantly diminished by TET administration. Importantly, TET has a long-lasting protective effect after noise exposure (48 weeks) in comparison to 2 weeks after noise exposure. The otoprotective effects of TET were achieved mainly by preventing outer hair cell damage and synapse loss between inner hair cells and spiral ganglion neurons. Thus, our data indicate that TET has great potential in the prevention and treatment of NIHL.
Assuntos
Benzilisoquinolinas/uso terapêutico , Bloqueadores dos Canais de Cálcio/uso terapêutico , Perda Auditiva Provocada por Ruído/prevenção & controle , Fitoterapia , Stephania tetrandra , Animais , Benzilisoquinolinas/análise , Benzilisoquinolinas/farmacologia , Bloqueadores dos Canais de Cálcio/farmacologia , Avaliação Pré-Clínica de Medicamentos , Potenciais Evocados Auditivos do Tronco Encefálico/efeitos dos fármacos , Feminino , Masculino , Camundongos , Gânglio Espiral da Cóclea/efeitos dos fármacosRESUMO
BACKGROUND: Subjective tinnitus is a hearing disorder in which a person perceives sound when no external sound is present. It can be acute or chronic. Because our current understanding of its pathology is incomplete, no effective cures have yet been established. Mouse models are useful for studying the pathophysiology of tinnitus as well as for developing therapeutic treatments. NEW METHOD: We have developed a new method for determining acute and chronic tinnitus in mice, called sound-based avoidance detection (SBAD). The SBAD method utilizes one paradigm to detect tinnitus and another paradigm to monitor possible confounding factors, such as motor impairment, loss of motivation, and deficits in learning and memory. RESULTS: The SBAD method has succeeded in monitoring both acute and chronic tinnitus in mice. Its detection ability is further validated by functional studies demonstrating an abnormal increase in neuronal activity in the inferior colliculus of mice that had previously been identified as having tinnitus by the SBAD method. COMPARISON WITH EXISTING METHODS: The SBAD method provides a new means by which investigators can detect tinnitus in a single mouse accurately and with more control over potential confounding factors than existing methods. CONCLUSION: This work establishes a new behavioral method for detecting tinnitus in mice. The detection outcome is consistent with functional validation. One key advantage of mouse models is they provide researchers the opportunity to utilize an extensive array of genetic tools. This new method could lead to a deeper understanding of the molecular pathways underlying tinnitus pathology.
Assuntos
Condicionamento Operante , Modelos Animais de Doenças , Zumbido/diagnóstico , Estimulação Acústica , Análise de Variância , Animais , Aprendizagem da Esquiva , Eletrochoque , Desenho de Equipamento , Potenciais Evocados Auditivos do Tronco Encefálico/fisiologia , Feminino , Colículos Inferiores/fisiopatologia , Masculino , Camundongos Endogâmicos C57BL , Atividade Motora , Neurônios/fisiologia , Emissões Otoacústicas Espontâneas/fisiologia , Salicilato de Sódio , Zumbido/fisiopatologia , Técnicas de Cultura de Tecidos , Imagens com Corantes Sensíveis à VoltagemRESUMO
Age-related synaptic change is associated with the functional decline of the nervous system. It is unknown whether this synaptic change is the cause or the consequence of neuronal cell loss. We have addressed this question by examining mice genetically engineered to over- or underexpress neuregulin-1 (NRG1), a direct modulator of synaptic transmission. Transgenic mice overexpressing NRG1 in spiral ganglion neurons (SGNs) showed improvements in hearing thresholds, whereas NRG1 -/+ mice show a complementary worsening of thresholds. However, no significant change in age-related loss of SGNs in either NRG1 -/+ mice or mice overexpressing NRG1 was observed, while a negative association between NRG1 expression level and survival of inner hair cells during aging was observed. Subsequent studies provided evidence that modulating NRG1 levels changes synaptic transmission between SGNs and hair cells. One of the most dramatic examples of this was the reversal of lower hearing thresholds by "turning-off" NRG1 overexpression. These data demonstrate for the first time that synaptic modulation is unable to prevent age-related neuronal loss in the cochlea.
Assuntos
Envelhecimento/metabolismo , Cóclea/metabolismo , Sinapses/fisiologia , Estimulação Acústica/métodos , Envelhecimento/patologia , Animais , Contagem de Células/métodos , Sobrevivência Celular/fisiologia , Cóclea/inervação , Cóclea/patologia , Perda Auditiva/metabolismo , Perda Auditiva/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neuregulina-1/genética , Neuregulina-1/fisiologia , Gânglio Espiral da Cóclea/patologia , Sinapses/patologia , Transmissão Sináptica/fisiologiaRESUMO
Neuregulin-1 (Nrg-1) contains an intracellular domain (Nrg-ICD) that translocates into the nucleus, where it may regulate gene expression upon neuronal depolarization. However, the identity of its target promoters and the mechanisms by which it regulates transcription have been elusive. Here we report that, in the mouse cochlea, synaptic activity increases the level of nuclear Nrg-ICD and upregulates postsynaptic density protein-95 (PSD-95), a scaffolding protein that is enriched in post-synaptic structures. Nrg-ICD enhances the transcriptional activity of the PSD-95 promoter by binding to a zinc-finger transcription factor, Eos. The Nrg-ICD-Eos complex induces endogenous PSD-95 expression in vivo through a signaling pathway that is mostly independent of gamma-secretase regulation. This upregulation of PSD-95 expression by the Nrg-ICD-Eos complex provides a molecular basis for activity-dependent synaptic plasticity.