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1.
Otol Neurotol ; 38(2): 180-186, 2017 02.
Artículo en Inglés | MEDLINE | ID: mdl-27898607

RESUMEN

BACKGROUND: Stereotactic radiosurgery for lateral skull base tumors can cause hearing loss when the cochleae are exposed to high doses of single-fraction radiation. Currently, there are no known nondosimetric preventative treatments for radiation-induced ototoxicity. HYPOTHESIS: Intratympanic (IT) dexamethasone (DXM), a synthetic steroid, protects against radiation-induced auditory hair cell (HC) and hearing losses in rats in vivo. METHODS: Seven rats received radiation (12 Gy) to both cochleae. In irradiated rats and six nonirradiated rats, IT DXM was randomized to one ear, while tympanic puncture without DXM was performed on the contralateral ear. Baseline and 4-week postradiation auditory-evoked potential tests were performed. The cochleae were processed for HC viability. RESULTS: Cochleae exposed to radiation demonstrated more outer HC (OHC) loss in all turns than nonirradiated ears (p <0.05). OHCs were more susceptible to radiation injury than inner HCs in the middle and basal turns (p <0.05). In irradiated cochleae, there was a nonsignificant trend for less OHC loss with IT DXM in the basal turn when compared with placebo. IT DXM did not improve radiation-induced hearing threshold shifts; however, a high rate of tympanic membrane perforations occurred with irradiated ears which may contribute to this finding. CONCLUSION: Radiation induced loss of OHCs in all turns of the cochlea. IT DXM reduced OHC loss in the basal turn of irradiated ears; however, this finding did not achieve statistical significance. Although IT DXM did not affect radiation-induced hearing threshold shifts in adult rats in vivo, this may be due to a high rate of tympanic membrane perforations.


Asunto(s)
Cóclea/efectos de los fármacos , Dexametasona/uso terapéutico , Potenciales Evocados Auditivos/efectos de los fármacos , Células Ciliadas Auditivas Externas/efectos de los fármacos , Pérdida Auditiva/prevención & control , Membrana Timpánica/efectos de los fármacos , Animales , Cóclea/efectos de la radiación , Dexametasona/administración & dosificación , Potenciales Evocados Auditivos/efectos de la radiación , Células Ciliadas Auditivas Externas/efectos de la radiación , Pérdida Auditiva/etiología , Masculino , Radiación , Ratas , Membrana Timpánica/efectos de la radiación
2.
Otol Neurotol ; 36(10): 1741-7, 2015 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-26485588

RESUMEN

HYPOTHESIS: Dexamethasone (DXM) protects against radiation-induced loss of auditory hair cells (HCs) in rat organ of Corti (OC) explants by reducing levels of oxidative stress and apoptosis. BACKGROUND: Radiation-induced sensorineural hearing loss (HL) is progressive, dose-dependent, and irreversible. Currently, there are no preventative therapeutic modalities for radiation-induced HL. DXM is a synthetic steroid that can potentially target many of the pathways involved in radiation-induced ototoxicity. METHODS: Whole OC explants were dissected from 3-day-old rat cochleae exposed to specific dosages of single-fraction radiation (0, 2, 5, 10, or 20 Gy), were either untreated or treated with DXM (75, 150, 300 µg/mL), and then cultured for 48 or 96 hours. Confocal microscopy for oxidative stress (CellRox, 48 h) and apoptosis (TUNEL assay, 96 h) and fluorescent microscopy for viable HC counts (fluorescein isothiocyanate-phalloidin, 96 h) were performed. Analysis of variance and Tukey post hoc testing were used for statistical analysis. RESULTS: Radiation exposure initiated dose-dependent losses of inner and outer HCs, predominantly in the basal turns of the OC explants. DXM protected against radiation-induced HC losses in a dose-dependent manner. DXM significantly reduced levels of oxidative stress and apoptosis in radiation-injured OC explants (p < 0.001). CONCLUSIONS: Radiation-initiated HC losses were dose-dependent in OC explants. DXM treatment protected explant HCs against radiation-initiated losses by decreasing the levels of oxidative stress and apoptosis. DXM may potentially be a therapeutic modality for preventing radiation-induced HL; further in vivo studies are necessary.


Asunto(s)
Antiinflamatorios/farmacología , Dexametasona/farmacología , Células Ciliadas Auditivas/efectos de los fármacos , Traumatismos Experimentales por Radiación/tratamiento farmacológico , Animales , Apoptosis/efectos de los fármacos , Modelos Animales de Enfermedad , Células Ciliadas Auditivas/efectos de la radiación , Pérdida Auditiva Sensorineural/etiología , Pérdida Auditiva Sensorineural/prevención & control , Etiquetado Corte-Fin in Situ , Microscopía Confocal , Técnicas de Cultivo de Órganos , Órgano Espiral/efectos de los fármacos , Órgano Espiral/efectos de la radiación , Estrés Oxidativo/efectos de los fármacos , Ratas
3.
Otol Neurotol ; 36(9): 1566-71, 2015 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-26375980

RESUMEN

HYPOTHESIS: Dexamethasone (DXM) protects against cisplatin-induced auditory hair cell (HC) loss in rat organ of Corti (OC) explants in vitro by reducing levels of oxidative stress and NADPH-Oxidase-3 (NOX-3). BACKGROUND: Intratympanic DXM has demonstrated protective effects against cisplatin-induced hearing loss in a few animal studies and one clinical trial. However, levels of protection with intratympanic DXM vary significantly between studies, which may not be a result of the intrinsic properties of DXM but rather reflect the diffusion of DXM into the cochlea. The molecular mechanisms and degree of DXM protection against cisplatin ototoxicity are currently unknown. METHODS: OC explants from 3-day-old rats were cultured with no treatment or various concentrations of cisplatin (2, 5, or 10 µM) and DXM (75, 150, or 300 µg/mL) in vitro. HC viability and TUNEL assay were performed after 72 hours in vitro and levels of oxidative stress and NOX-3 were evaluated with confocal microscopy after 48 hours in vitro. Analysis of variance with Tukey's post hoc testing was performed. RESULTS: Cisplatin initiated dose-dependent losses of outer HCs (OHCs) in the basal turns of exposed explants (p < 0.001). DXM protected against cisplatin (2 µM)-induced OHC loss in a dose-dependent manner with complete protection at 300 µg/mL of DXM (p < 0.001). DXM (150 µg/mL) significantly reduced levels of oxidative stress, NOX-3, and apoptosis in the basal turn of explants exposed to cisplatin (2 µM). CONCLUSIONS: DXM protects against cisplatin-induced loss of OHCs in the basal turn of rat OC explants as demonstrated by reductions in oxidative stress and NOX-3 production and decreased levels of apoptotic cell death.


Asunto(s)
Antineoplásicos/toxicidad , Apoptosis/efectos de los fármacos , Cisplatino/toxicidad , Dexametasona/farmacología , Glucocorticoides/farmacología , Células Ciliadas Auditivas/efectos de los fármacos , NADPH Oxidasas/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Animales , Supervivencia Celular/efectos de los fármacos , Células Ciliadas Auditivas/metabolismo , Células Ciliadas Auditivas/patología , Etiquetado Corte-Fin in Situ , Técnicas In Vitro , Microscopía Confocal , NADPH Oxidasas/metabolismo , Órgano Espiral/efectos de los fármacos , Órgano Espiral/metabolismo , Órgano Espiral/patología , Ratas , Ratas Sprague-Dawley
4.
Otolaryngol Head Neck Surg ; 148(5): 834-40, 2013 May.
Artículo en Inglés | MEDLINE | ID: mdl-23401256

RESUMEN

OBJECTIVE: Evaluate the effectiveness of short interfering RNA against Bax (Bax siRNA) as a treatment for tumor necrosis factor α (TNFα)-induced auditory hair cell (HC) loss in rat organ of Corti (OC) explants. STUDY DESIGN: Basic science. SETTING: Basic science laboratory, University of Miami Ear Institute. METHODS: Organ of Corti explants dissected from 3-day-old rats were cultured in control media, TNFα, and TNFα + Bax siRNA at 0, 48, and 72 hours in vitro. Real-time polymerase chain reaction, enzyme-linked immunosorbent assay, HC viability studies, immunofluorescence, and confocal microscopy were performed. Analysis of variance with post hoc testing was used with P < .05 considered significant. RESULTS: The TNFα-damaged explants demonstrated significant decreases in viable HCs in the basal turn with corresponding increased levels of Bax gene and protein expression, compared with control explant levels. The levels of viable HCs and Bax gene and protein expression in TNFα + Bax siRNA-treated explants approached levels measured in control explants. Immunolocalization studies showed increased Bax protein expression in basal turn HCs in TNFα-treated explants, whereas control explants and TNFα + Bax siRNA-treated explants had low levels of Bax expression. CONCLUSION: TNFα initiates the programmed cell death of auditory HCs in OC explants through upregulation of proapoptotic Bax gene and protein expression. Bax siRNA blocks TNFα-induced apoptosis of HCs by decreasing the TNFα-induced levels of Bax mRNA and protein expression in treated explants. Bax siRNA is an effective treatment for TNFα-induced ototoxicity in OC explants in vitro and has great potential to be a therapeutic agent against trauma/inflammation-induced hearing loss.


Asunto(s)
Pérdida Auditiva/terapia , Órgano Espiral/efectos de los fármacos , ARN Interferente Pequeño/uso terapéutico , Factor de Necrosis Tumoral alfa/metabolismo , Proteína X Asociada a bcl-2/biosíntesis , Animales , Apoptosis , Supervivencia Celular , Modelos Animales de Enfermedad , Expresión Génica , Células Ciliadas Auditivas/efectos de los fármacos , Pérdida Auditiva/etiología , Ratas , Ratas Sprague-Dawley , Factor de Necrosis Tumoral alfa/efectos adversos , Factor de Necrosis Tumoral alfa/farmacología
5.
Otol Neurotol ; 33(9): 1656-63, 2012 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-22996158

RESUMEN

HYPOTHESIS: Mannitol has otoprotective effects against tumor necrosis factor (TNF) α-induced auditory hair cell (HC) loss. BACKGROUND: Mannitol has been demonstrated to possess cytoprotective effects in several organ systems. Its protective effect on postischemic hearing loss has also been shown. Mannitol's otoprotective mechanism and site of action are at present unknown. MATERIALS AND METHODS: Organ of Corti (OC) explants were dissected from 3 day-old rat pups. The safety (nonototoxicity) of mannitol was assessed at 4 different concentrations (1-100 mM). Three experimental arms were designed including: a control group, TNFα group, and TNFα + mannitol group. Cell viability was determined by counts of fluorescein isothiocyanate (FITC) phalloidin stained HC. Immunofluorescence assay of phospho-c-Jun and the proapoptotic mediators, cleaved caspase-3, apoptosis inducing factor (AIF), and endonuclease G (Endo G) were performed. RESULTS: Analysis of HC density confirmed the safety of mannitol at concentration ranges of 1 to 100 mM. The ototoxic effect of TNFα was demonstrated (p < 0.05). The otoprotective effect of 100 mM mannitol in TNFα-challenged OC explants was also demonstrated (p < 0.001). Mannitol treatment reduced the high levels of phospho-c-Jun observed in the TNFα-challenged group. AIF cluster formation and EndoG translocation into the nuclei of HCs were also reduced by mannitol treatment. CONCLUSION: Mannitol significantly reduces the ototoxic effects of TNFα against auditory HC's potentially by inhibiting c-Jun N terminal kinase (JNK) activation pathway and AIF, EndoG nuclear translocation. This local otoprotective effect may have therapeutic implications in inner ear surgery, for example, cochlear implants, protection of residual hearing, as well as implications for postischemic inner ear insults.


Asunto(s)
Células Ciliadas Auditivas/efectos de los fármacos , Manitol/farmacología , Fármacos Neuroprotectores , Factor de Necrosis Tumoral alfa/toxicidad , Animales , Apoptosis/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Colorantes , Técnica del Anticuerpo Fluorescente , Células Ciliadas Auditivas/ultraestructura , Manitol/efectos adversos , Microscopía Confocal , Órgano Espiral/citología , Órgano Espiral/efectos de los fármacos , Ratas , Fijación del Tejido
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