RESUMEN
Spread of antimicrobial resistance and shortage of novel antibiotics have led to an urgent need for new antibacterials. Although aminoglycoside antibiotics (AGs) are very potent anti-infectives, their use is largely restricted due to serious side-effects, mainly nephrotoxicity and ototoxicity. We evaluated the ototoxicity of various AGs selected from a larger set of AGs on the basis of their strong antibacterial activities against multidrug-resistant clinical isolates of the ESKAPE panel: gentamicin, gentamicin C1a, apramycin, paromomycin and neomycin. Following local round window application, dose-dependent effects of AGs on outer hair cell survival and compound action potentials showed gentamicin C1a and apramycin as the least toxic. Strikingly, although no changes were observed in compound action potential thresholds and outer hair cell survival following treatment with low concentrations of neomycin, gentamicin and paromomycin, the number of inner hair cell synaptic ribbons and the compound action potential amplitudes were reduced. This indication of hidden hearing loss was not observed with gentamicin C1a or apramycin at such concentrations. These findings identify the inner hair cells as the most vulnerable element to AG treatment, indicating that gentamicin C1a and apramycin are promising bases for the development of clinically useful antibiotics.
Asunto(s)
Antibacterianos/efectos adversos , Gentamicinas/farmacología , Pérdida Auditiva/genética , Nebramicina/análogos & derivados , Ototoxicidad/metabolismo , Aminoglicósidos/efectos adversos , Aminoglicósidos/farmacología , Animales , Antiinfecciosos/efectos adversos , Antiinfecciosos/farmacología , Línea Celular , Farmacorresistencia Bacteriana/efectos de los fármacos , Farmacorresistencia Bacteriana/genética , Gentamicinas/efectos adversos , Gentamicinas/uso terapéutico , Cobayas , Células Ciliadas Auditivas Internas/efectos de los fármacos , Células Ciliadas Auditivas Internas/patología , Pérdida Auditiva/inducido químicamente , Pérdida Auditiva/patología , Humanos , Nebramicina/efectos adversos , Nebramicina/farmacología , Neomicina/efectos adversos , Neomicina/farmacología , Ototoxicidad/patología , Inhibidores de la Síntesis de la Proteína/efectos adversos , Inhibidores de la Síntesis de la Proteína/farmacología , Ventana Redonda/efectos de los fármacos , Ventana Redonda/patologíaRESUMEN
AIM: Hearing loss is the most common sensory disorder in humans, its main cause being the loss of cochlear hair cells. We studied the potential of human mesenchymal stem cells (hMSCs) to differentiate towards hair cells and auditory neurons. MATERIALS & METHODS: hMSCs were first differentiated to neural progenitors and subsequently to hair cell- or auditory neuron-like cells using in vitro culture methods. RESULTS: Differentiation of hMSCs to an intermediate neural progenitor stage was critical for obtaining inner ear sensory lineages. hMSCs generated hair cell-like cells only when neural progenitors derived from nonadherent hMSC cultures grown in serum-free medium were exposed to EGF and retinoic acid. Auditory neuron-like cells were obtained when treated with retinoic acid, and in the presence of defined growth factor combinations containing Sonic Hedgehog. CONCLUSION: The results show the potential of hMSCs to give rise to inner ear sensory cells.
