RESUMO
Auditory neuropathy is caused by the loss of afferent input to the brainstem via the components of the neural pathway comprising inner hair cells and the first order neurons of the spiral ganglion. Recent work has identified the synapse between cochlear primary afferent neurons and sensory hair cells as a particularly vulnerable component of this pathway. Loss of these synapses due to noise exposure or aging results in the pathology identified as hidden hearing loss, an initial stage of cochlear dysfunction that goes undetected in standard hearing tests. We show here that repulsive axonal guidance molecule a (RGMa) acts to prevent regrowth and synaptogenesis of peripheral auditory nerve fibers with inner hair cells. Treatment of noise-exposed animals with an anti-RGMa blocking antibody regenerated inner hair cell synapses and resulted in recovery of wave-I amplitude of the auditory brainstem response, indicating effective reversal of synaptopathy.
Assuntos
Proteínas Ligadas por GPI/antagonistas & inibidores , Perda Auditiva Provocada por Ruído/tratamento farmacológico , Proteínas do Tecido Nervoso/antagonistas & inibidores , Regeneração/efeitos dos fármacos , Estimulação Acústica/métodos , Animais , Limiar Auditivo , Cóclea/citologia , Cóclea/efeitos dos fármacos , Cóclea/patologia , Modelos Animais de Doenças , Feminino , Proteínas Ligadas por GPI/metabolismo , Células Ciliadas Auditivas Internas/efeitos dos fármacos , Perda Auditiva Provocada por Ruído/patologia , Humanos , Masculino , Camundongos , Proteínas do Tecido Nervoso/metabolismo , Sinapses/efeitos dos fármacos , Sinapses/patologiaRESUMO
TrkB agonist drugs are shown here to have a significant effect on the regeneration of afferent cochlear synapses after noise-induced synaptopathy. The effects were consistent with regeneration of cochlear synapses that we observed in vitro after synaptic loss due to kainic acid-induced glutamate toxicity and were elicited by administration of TrkB agonists, amitriptyline, and 7,8-dihydroxyflavone, directly into the cochlea via the posterior semicircular canal 48 hours after exposure to noise. Synaptic counts at the inner hair cell and wave 1 amplitudes in the auditory brainstem response (ABR) were partially restored 2 weeks after drug treatment. Effects of amitriptyline on wave 1 amplitude and afferent auditory synapse numbers in noise-exposed ears after systemic (as opposed to local) delivery were profound and long-lasting; synapses in the treated animals remained intact 1 year after the treatment. However, the effect of systemically delivered amitriptyline on synaptic rescue was dependent on dose and the time window of administration: it was only effective when given before noise exposure at the highest injected dose. The long-lasting effect and the efficacy of postexposure treatment indicate a potential broad application for the treatment of synaptopathy, which often goes undetected until well after the original damaging exposures.
Assuntos
Perda Auditiva Provocada por Ruído/tratamento farmacológico , Glicoproteínas de Membrana/agonistas , Amitriptilina/administração & dosagem , Amitriptilina/farmacologia , Animais , Limiar Auditivo/efeitos dos fármacos , Limiar Auditivo/fisiologia , Cóclea/efeitos dos fármacos , Cóclea/fisiopatologia , Nervo Coclear/efeitos dos fármacos , Nervo Coclear/fisiopatologia , Técnicas de Cocultura , Modelos Animais de Doenças , Potenciais Evocados Auditivos do Tronco Encefálico/efeitos dos fármacos , Potenciais Evocados Auditivos do Tronco Encefálico/fisiologia , Flavonas/administração & dosagem , Flavonas/farmacologia , Células Ciliadas Auditivas Internas/efeitos dos fármacos , Células Ciliadas Auditivas Internas/fisiologia , Perda Auditiva Provocada por Ruído/fisiopatologia , Glicoproteínas de Membrana/fisiologia , Camundongos , Camundongos Endogâmicos CBA , Proteínas Tirosina Quinases/fisiologia , Regeneração/efeitos dos fármacos , Regeneração/fisiologia , Sinapses/efeitos dos fármacos , Sinapses/fisiologiaRESUMO
Sphingolipid metabolites including ceramide, sphingosine (Sph), and sphingosine-1-phosphate (S1P) play important roles in the regulation of cell survival and death. Sphingosine kinase (Sk) phosphorylates Sph to S1P. Sk is reportedly overexpressed in various cancer cells, and Sk inhibitors are therefore a target of anti-tumor therapy. However, the effects of Sph and Sk inhibitors on cochlear hair cells were unknown. In the present study, expression of Sk isotypes in the cochlea was examined. In addition, the changes in Sk activity induced by cisplatin (CDDP) and the effects of an Sk inhibitor, Sph, and S1P on CDDP ototoxicity were investigated using tissue culture techniques. Cochleae were dissected from SpragueDawley rats on postnatal days 35. Organ of Corti explants were exposed to 5 lM CDDP for 48 h with or without the Sk inhibitor, Sph, or S1P. Both Sk1 and Sk2 were expressed in the normal cochlea. CDDP activated Sk. The Sk inhibitor itself caused hair cell loss at a high concentration, and at lower concentrations, it increased CDDP-induced hair cell loss. Sph itself also induced hair cell death and increased hair cell loss induced by CDDP. However, S1P decreased hair cell loss induced by CDDP. Sk inhibitor has the function by increasing ototoxic Sph and decreasing otoprotective S1P and therefore potentially causes ototoxicity. Consideration of the possibility of ototoxicity is required in the usage of Sk inhibitors.