RESUMEN
Biomarkers in easy-to-access body fluid compartments, such as blood, are commonly used to assess health of various organ systems in clinical medicine. At present, no such biomarkers are available to inform on the health of the inner ear. Previously, we proposed the outer-hair-cell-specific protein prestin, as a possible biomarker and provided proof of concept in noise- and cisplatin-induced hearing loss. Our ototoxicity data suggest that circulatory prestin changes after inner ear injury are not static and that there is a temporal pattern of change that needs to be further characterized before practical information can be extracted. To achieve this goal, we set out to 1) describe the time course of change in prestin after intense noise exposure, and 2) determine if the temporal patterns and prestin levels are sensitive to severity of injury. After assessing auditory brainstem thresholds and distortion product otoacoustic emission levels, rats were exposed to intense octave band noise for 2â¯h at either 110 or 120â¯dB SPL. Auditory function was re-assessed 1 and 14 days later. Blood samples were collected at baseline, 4, 24, 48, 72â¯h and 7 and 14 days post exposure and prestin concentrations were measured using enzyme-linked immunosorbent assay (ELISA). Functional measures showed temporary hearing loss 1 day after exposure in the 110â¯dB SPL group, but permanent loss through Day 14 in the 120â¯dB SPL group. Prestin levels temporarily increased 5% at 4â¯h after 120â¯dB SPL exposure, but not in the 110â¯dB SPL group. There was a gradual decline in prestin levels in both groups thereafter, with prestin being below baseline on Day 14 by 5% in the 110â¯dB group (NS) and more than 10% in the 120â¯dB SPL group (pâ¯=â¯0.043). These results suggest that there is a temporal pattern of change in serum prestin level after noise-induced hearing loss that is related to severity of hearing loss. Circulatory levels of prestin may be able to act as surrogate biomarker for hearing loss involving OHC loss.
Asunto(s)
Pérdida Auditiva Provocada por Ruido/sangre , Transportadores de Sulfato/sangre , Animales , Umbral Auditivo/fisiología , Biomarcadores/sangre , Modelos Animales de Enfermedad , Potenciales Evocados Auditivos del Tronco Encefálico/fisiología , Células Ciliadas Auditivas Externas/patología , Células Ciliadas Auditivas Externas/fisiología , Pérdida Auditiva Provocada por Ruido/patología , Pérdida Auditiva Provocada por Ruido/fisiopatología , Humanos , Masculino , Emisiones Otoacústicas Espontáneas/fisiología , Ratas Wistar , Factores de TiempoRESUMEN
HYPOTHESIS: SENS-401 (R-azasetron besylate) is effective against severe acoustic trauma-induced hearing loss. BACKGROUND: SENS-401 has calcineurin inhibiting properties and attenuates cisplatin-induced hearing loss in a rat model. Cisplatin-induced and acoustic trauma-induced hearing loss share common apoptotic pathways. METHODS: The dose-response relationship of SENS-401 (6.6âmg/kg BID, 13.2âmg/kg BID, 26.4âmg/kg QD) and treatment time-window (13.2âmg/kg BID starting 24, 72, and 96âh posttrauma) versus placebo for 28 days were evaluated in a male rat model of severe acoustic trauma-induced hearing loss (120âdB SPL, 2âh) using auditory brainstem response (ABR) and distortion product otoacoustic emissions (DPOAE) measures followed by cochlear outer hair cell (OHC) counting with myosin-VIIa immunolabeling. RESULTS: All SENS-401 doses improved ABR threshold shift and recovery, reaching statistical significance (pâ<â0.05) for ABR threshold recoveries after 28-days treatment. DPOAE amplitude loss and recovery improved markedly for 13.2âmg/kg BID SENS-401, reaching significance after 14 days (pâ<â0.05). Significant improvements in ABR threshold shifts/recovery and DPOAE amplitude loss occurred with up to 96-hours delay in initiating SENS-401 (pâ<â0.05), and in DPOAE amplitude recovery with up to 72-hours delay (pâ<â0.05). Significantly more surviving OHCs were present after SENS-401 treatment compared with placebo after 24 to 96-hours delay posttrauma, with up to 5.3-fold more cells in the basal cochlea turn. CONCLUSIONS: In vivo data support the otoprotective potential of twice daily oral SENS-401. Improvements in hearing loss recovery make SENS-401 a promising clinical candidate for acoustic trauma-induced hearing loss, including when treatment is not initiated immediately.
Asunto(s)
Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Potenciales Evocados Auditivos del Tronco Encefálico/efectos de los fármacos , Pérdida Auditiva Provocada por Ruido/tratamiento farmacológico , Pérdida Auditiva Sensorineural/tratamiento farmacológico , Oxazinas/farmacología , Estimulación Acústica/efectos adversos , Animales , Compuestos Bicíclicos Heterocíclicos con Puentes/administración & dosificación , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Cisplatino/toxicidad , Células Ciliadas Auditivas Externas/efectos de los fármacos , Pérdida Auditiva Sensorineural/inducido químicamente , Masculino , Emisiones Otoacústicas Espontáneas/efectos de los fármacos , Oxazinas/administración & dosificación , Oxazinas/uso terapéutico , Ratas , Ratas WistarRESUMEN
HYPOTHESIS: SENS-401, an oral clinical-stage drug, may reduce cisplatin-induced hearing loss and cochlear damage in an in vivo model. BACKGROUND: Cisplatin is commonly associated with hearing loss, causing significant learning and behavioral difficulties in the pediatric cancer population, and for which there are currently no clinical solutions. SENS-401 has previously been shown to improve acoustic trauma-induced hearing loss in vivo. METHODS: The effect of SENS-401 (R-azasetron besylate) on cisplatin IC50 values was evaluated in a panel of cisplatin-sensitive cell lines (NIH:OVCAR-3, SK-N-AS, NCI-H460, FaDu). Auditory brainstem response and distortion product otoacoustic emission tests were performed in a rat model of cisplatin-induced hearing-loss (8âmg/kg, day 1) at baseline, and after 14 days of SENS-401 (6.6, 13.2, 26.4âmg/kg/d). Cochlear outer hair cells were counted after immunolabeling for myosin-VIIa. RESULTS: Cisplatin cytotoxicity was not impacted by the addition of SENS-401 (up to 10âµM) in any of the cell types evaluated. In vivo, all SENS-401 doses significantly improved auditory brainstem response threshold shift (up to 30âdB) and distortion product otoacoustic emission amplitude loss (up to 19âdB) over placebo. Body weight and survival were not significantly different between rats receiving placebo and those receiving 26.4âmg/kg SENS-401. Significantly more surviving outer hair cells were present after SENS-401 treatment compared with placebo (pâ<â0.001), with up to 11-fold more in the basal turn of the cochlea. CONCLUSION: In vivo and in vitro data support the otoprotective potential and tolerability of SENS-401 without impacting chemotherapeutic potential. Oral SENS-401 is a promising candidate for treating cisplatin-induced ototoxicity.
Asunto(s)
Cóclea/efectos de los fármacos , Potenciales Evocados Auditivos del Tronco Encefálico/efectos de los fármacos , Células Ciliadas Auditivas Externas/efectos de los fármacos , Pérdida Auditiva/tratamiento farmacológico , Administración Oral , Animales , Antineoplásicos/farmacología , Audiometría , Cisplatino , Cóclea/metabolismo , Modelos Animales de Enfermedad , Células Ciliadas Auditivas Externas/metabolismo , Pérdida Auditiva/inducido químicamente , Miosina VIIa , Miosinas/metabolismo , Emisiones Otoacústicas Espontáneas/efectos de los fármacos , Ratas , Ratas WistarRESUMEN
Damage to inner ear afferent terminals is believed to result in many auditory and vestibular dysfunctions. The sequence of afferent injuries and repair, as well as their correlation with vertigo symptoms, remains poorly documented. In particular, information on the changes that take place at the primary vestibular endings during the first hours following a selective insult is lacking. In the present study, we combined histological analysis with behavioral assessments of vestibular function in a rat model of unilateral vestibular excitotoxic insult. Excitotoxicity resulted in an immediate but transient alteration of the balance function that was resolved within a week. Concomitantly, vestibular primary afferents underwent a sequence of structural changes followed by spontaneous repair. Within the first two hours after the insult, a first phase of pronounced vestibular dysfunction coincided with extensive swelling of afferent terminals. In the next 24â h, a second phase of significant but incomplete reduction of the vestibular dysfunction was accompanied by a resorption of swollen terminals and fiber retraction. Eventually, within 1 week, a third phase of complete balance restoration occurred. The slow and progressive withdrawal of the balance dysfunction correlated with full reconstitution of nerve terminals. Competitive re-innervation by afferent and efferent terminals that mimicked developmental synaptogenesis resulted in full re-afferentation of the sensory epithelia. By deciphering the sequence of structural alterations that occur in the vestibule during selective excitotoxic impairment, this study offers new understanding of how a vestibular insult develops in the vestibule and how it governs the heterogeneity of vertigo symptoms.
Asunto(s)
Conducta Animal , Neuronas Aferentes/patología , Neurotoxinas/toxicidad , Vértigo/patología , Vestíbulo del Laberinto/inervación , Vestíbulo del Laberinto/patología , Animales , Recuento de Células , Modelos Animales de Enfermedad , Oído Medio/efectos de los fármacos , Oído Medio/patología , Epitelio/efectos de los fármacos , Epitelio/patología , Femenino , Células Ciliadas Vestibulares/patología , Células Ciliadas Vestibulares/ultraestructura , Inyecciones , Ácido Kaínico/administración & dosificación , Modelos Biológicos , Neuronas Aferentes/efectos de los fármacos , Ratas Wistar , Vesículas Sinápticas/efectos de los fármacos , Vesículas Sinápticas/metabolismo , Vesículas Sinápticas/ultraestructura , Sinaptofisina/metabolismo , Factores de Tiempo , Vestíbulo del Laberinto/ultraestructuraRESUMEN
Vestibular neuritis is a neuroinflammatory, peripheral vestibular pathology leading to chronic deficits and long-term disability. While current corticosteroid-based therapy does not appear to positively influence the long term outcome for the patient, a recent clinical pilot study suggested a functional vestibuloprotective effect of the anti-emetic ondansetron in the treatment of vestibular neuritis. We here demonstrate that systemic post-insult administration of ondansetron in a novel rat model of severe excitotoxic vestibular insult reproduces the clinically demonstrated functional benefits. This ondansetron-conferred reduction of functional deficits stems from the protection of synapses between sensory hair cells and primary neurons from excitotoxically induced lesion.