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1.
J Assoc Res Otolaryngol ; 19(6): 653-668, 2018 12.
Artículo en Inglés | MEDLINE | ID: mdl-30187298

RESUMEN

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.


Asunto(s)
Bencilisoquinolinas/uso terapéutico , Bloqueadores de los Canales de Calcio/uso terapéutico , Pérdida Auditiva Provocada por Ruido/prevención & control , Fitoterapia , Stephania tetrandra , Animales , Bencilisoquinolinas/análisis , Bencilisoquinolinas/farmacología , Bloqueadores de los Canales de Calcio/farmacología , Evaluación Preclínica de Medicamentos , Potenciales Evocados Auditivos del Tronco Encefálico/efectos de los fármacos , Femenino , Masculino , Ratones , Ganglio Espiral de la Cóclea/efectos de los fármacos
2.
J Int Adv Otol ; 14(1): 22-26, 2018 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-28639555

RESUMEN

OBJECTIVE: The purpose of this study was to examine the anti-ototoxic impact of Ginkgo biloba extract and lycopene on the model of cisplatin-induced ototoxicity in rats. MATERIALS AND METHODS: Thirty-two Wistar albino rats were examined with the distortion product otoacoustic emission (DPOAE) test (MADSEN Capella2 ; GN Otometrics, ICS Medical, Chicago USA), and they were randomly divided into four groups. Group 1 (n=8) was defined as the healthy control group. Cisplatin was given intraperitoneally as single dose of 12 mg/kg to group 2 (n=8), group 3 (n=8), and group 4 (n=8). Group 2 was determined as ototoxic control group. G. biloba extract (100 mg/kg) was given to group 3, and 20 mg/kg lycopene was given to group 4 with orogastric feeding tube daily for 10 days. DPOAE test was repeated on day 10 on all the groups. Finally, histopathological examination was performed. The study has been lead in agreement with the principles by the Institutional Animal Care and Use Committee Review Board at Kocaeli University Medical Center (KOÜ HADYEK- 1/9-14). The animals were treated in accordance with protocols approved by this committee. RESULTS: When DPOAE tests were compared, there was no significant difference in the four groups before the application (p > 0.05). At the end of day 10, in groups 2 to 4, statistically significant changes were observed (p < 0.05). According to the cisplatin group, a significant increase in the DP-grams on G. biloba and lycopene groups was observed (p < 00.5). Corti organ and spiral ganglion neurons of groups 1, 3, and 4 were observed to have weak expression. Strong reactions were determined in organum spirale and some spiral ganglions of the cisplatin group. The striae vascularis damage on group 2 was found to be more significant more compared with groups 3 and 4. CONCLUSION: There is a protective effect of G. biloba and lycopene on cisplatin-dependent ototoxic rat model.


Asunto(s)
Cisplatino/toxicidad , Enfermedades del Oído/inducido químicamente , Licopeno/efectos adversos , Extractos Vegetales/efectos adversos , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/toxicidad , Antioxidantes/efectos adversos , Antioxidantes/uso terapéutico , Cisplatino/administración & dosificación , Cóclea/efectos de los fármacos , Cóclea/patología , Enfermedades del Oído/patología , Enfermedades del Oído/fisiopatología , Enfermedades del Oído/prevención & control , Ginkgo biloba , Inyecciones Intraperitoneales , Licopeno/administración & dosificación , Licopeno/uso terapéutico , Masculino , Órgano Espiral/efectos de los fármacos , Emisiones Otoacústicas Espontáneas/efectos de los fármacos , Extractos Vegetales/uso terapéutico , Ratas , Ratas Wistar , Ganglio Espiral de la Cóclea/efectos de los fármacos
3.
Neurotoxicology ; 62: 151-161, 2017 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-28655499

RESUMEN

Carbon disulfide (CS2) is used in industry; it has been shown to have neurotoxic effects, causing central and distal axonopathies.However, it is not considered cochleotoxic as it does not affect hair cells in the organ of Corti, and the only auditory effects reported in the literature were confined to the low-frequency region. No reports on the effects of combined exposure to low-frequency noise and CS2 have been published to date. This article focuses on the effects on rat hearing of combined exposure to noise with increasing concentrations of CS2 (0, 63,250, and 500ppm, 6h per day, 5 days per week, for 4 weeks). The noise used was a low-frequency noise ranging from 0.5 to 2kHz at an intensity of 106dB SPL. Auditory function was tested using distortion product oto-acoustic emissions, which mainly reflects the cochlear performances. Exposure to noise alone caused an auditory deficit in a frequency area ranging from 3.6 to 6 kHz. The damaged area was approximately one octave (6kHz) above the highest frequency of the exposure noise (2.8kHz); it was a little wider than expected based on the noise spectrum.Consequently, since maximum hearing sensitivity is located around 8kHz in rats, low-frequency noise exposure can affect the cochlear regions detecting mid-range frequencies. Co-exposure to CS2 (250-ppm and over) and noise increased the extent of the damaged frequency window since a significant auditory deficit was measured at 9.6kHz in these conditions.Moreover, the significance at 9.6kHz increased with the solvent concentrations. Histological data showed that neither hair cells nor ganglion cells were damaged by CS2. This discrepancy between functional and histological data is discussed. Like most aromatic solvents, carbon disulfide should be considered as a key parameter in hearing conservation régulations.


Asunto(s)
Disulfuro de Carbono/toxicidad , Audición/efectos de los fármacos , Audición/efectos de la radiación , Ruido/efectos adversos , Estimulación Acústica , Análisis de Varianza , Animales , Disulfuro de Carbono/sangre , Relación Dosis-Respuesta en la Radiación , Femenino , Pruebas Auditivas , Microscopía de Fuerza Atómica , Miosinas/metabolismo , Órgano Espiral/efectos de los fármacos , Órgano Espiral/metabolismo , Órgano Espiral/efectos de la radiación , Órgano Espiral/ultraestructura , Ratas , Ratas Wistar , Ganglio Espiral de la Cóclea/efectos de los fármacos , Ganglio Espiral de la Cóclea/metabolismo , Ganglio Espiral de la Cóclea/efectos de la radiación , Ganglio Espiral de la Cóclea/ultraestructura , Tiazolidinas/orina , Factores de Tiempo
4.
J Neurosci Res ; 95(3): 869-875, 2017 03.
Artículo en Inglés | MEDLINE | ID: mdl-27400677

RESUMEN

Today a cochlear implant (CI) may significantly restore auditory function, even for people with a profound hearing loss. Because the efficacy of a CI is believed to depend mainly on the remaining population of spiral ganglion neurons (SGNs), it is important to understand the timeline of the degenerative process of the auditory neurons following deafness. Guinea pigs were transtympanically deafened with neomycin, verified by recording auditory brainstem responses (ABRs), and then sacrificed at different time points. Loss of SGNs as well as changes in cell body and nuclear volume were estimated. To study the effect of delayed treatment, a group of animals that had been deaf for 12 weeks was implanted with a stimulus electrode mimicking a CI, after which they received a 4-week treatment with glial cell-derived neurotrophic factor (GDNF). The electrical responsiveness of the SGNs was measured by recording electrically evoked ABRs. There was a rapid degeneration during the first 7 weeks, shown as a significant reduction of the SGN population. The degenerative process then slowed, and there was no difference in the amount of remaining neurons between weeks 7 and 18. © 2016 The Authors Journal of Neuroscience Research Published by Wiley Periodicals, Inc.


Asunto(s)
Sordera/patología , Oído Interno/patología , Estimulación Acústica , Animales , Núcleo Celular/efectos de los fármacos , Núcleo Celular/patología , Sordera/inducido químicamente , Sordera/tratamiento farmacológico , Sordera/fisiopatología , Modelos Animales de Enfermedad , Potenciales Evocados Auditivos del Tronco Encefálico/efectos de los fármacos , Femenino , Factor Neurotrófico Derivado de la Línea Celular Glial/uso terapéutico , Cobayas , Masculino , Neomicina/toxicidad , Inhibidores de la Síntesis de la Proteína/toxicidad , Células Receptoras Sensoriales/efectos de los fármacos , Células Receptoras Sensoriales/patología , Ganglio Espiral de la Cóclea/efectos de los fármacos , Ganglio Espiral de la Cóclea/patología , Factores de Tiempo
5.
Pharm Biol ; 54(11): 2777-2781, 2016 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-27158843

RESUMEN

CONTEXT: Pycnogenol®, which is French maritime pine bark extract, is a potent antioxidant. It is used in medical conditions caused by oxidative stress. Cisplatin (cis-diamminedichloroplatinum II) is an antineoplastic agent. However, its serious side effects such as ototoxicity limit its usage. OBJECTIVE: Antioxidants can be used to prevent ototoxicity. We investigated the effect of Pycnogenol® on cisplatin-induced ototoxicity. MATERIALS AND METHODS: Rats were randomly assigned to four groups of five. Distortion product-evoked otoacoustic emissions (DPOAE) test was performed for each rat. The experimental groups were as follows: Control Group, Pycnogenol® Group: 10 mg/kg Pycnogenol® intraperitoneally for 7 days, Cisplatin Group: intraperitoneally 15 mg/kg single injection of cisplatin on the fifth day, Cisplatin + Pycnogenol® Group: intraperitoneally 10 mg/kg Pycnogenol® treatment for 7 days, additionally on the fifth day, 15 mg/kg single injection of cisplatin was given. On the eighth day, DPOAE was re-performed and rats were sacrificed. Apoptosis was evaluated histopathologically. RESULTS: Mean percentage of apoptotic cells was 1.5, 3, 30 and 11% in organ of Corti and 2, 2, 40, 15% in spiral ganglion neurons in Control Group, Pycnogenol® Group, Cisplatin Group and Cisplatin + Pycnogenol® Group, respectively. Cisplatin Group and Cisplatin + Pycnogenol® Group were significantly different when compared to Control Group histopathologically both in organ of Corti and spiral ganglion neuron (p <0.001, p = 0.019, p = 0.001, p = 0.015). DPOAE results showed that Cisplatin + Pycnogenol® Group was significantly different when compared to Cisplatin Group at 3, 6 and 8 kHz (p < 0.05). CONCLUSION: Pycnogenol protected against cisplatin ototoxicity. Also, pycnogenol is not ototoxic.


Asunto(s)
Antineoplásicos/toxicidad , Cisplatino/toxicidad , Cóclea/efectos de los fármacos , Flavonoides/farmacología , Animales , Cóclea/fisiología , Masculino , Órgano Espiral/efectos de los fármacos , Emisiones Otoacústicas Espontáneas/efectos de los fármacos , Extractos Vegetales , Ratas , Ganglio Espiral de la Cóclea/efectos de los fármacos
6.
J Assoc Res Otolaryngol ; 14(2): 187-211, 2013 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-23392612

RESUMEN

Both neurotrophic support and neural activity are required for normal postnatal development and survival of cochlear spiral ganglion (SG) neurons. Previous studies in neonatally deafened cats demonstrated that electrical stimulation (ES) from a cochlear implant can promote improved SG survival but does not completely prevent progressive neural degeneration. Neurotrophic agents combined with an implant may further improve neural survival. Short-term studies in rodents have shown that brain-derived neurotrophic factor (BDNF) promotes SG survival after deafness and may be additive to trophic effects of stimulation. Our recent study in neonatally deafened cats provided the first evidence of BDNF neurotrophic effects in the developing auditory system over a prolonged duration Leake et al. (J Comp Neurol 519:1526-1545, 2011). Ten weeks of intracochlear BDNF infusion starting at 4 weeks of age elicited significant improvement in SG survival and larger soma size compared to contralateral. In the present study, the same deafening and BDNF infusion procedures were combined with several months of ES from an implant. After combined BDNF + ES, a highly significant increase in SG numerical density (>50 % improvement re: contralateral) was observed, which was significantly greater than the neurotrophic effect seen with ES-only over comparable durations. Combined BDNF + ES also resulted in a higher density of myelinated radial nerve fibers within the osseous spiral lamina. However, substantial ectopic and disorganized sprouting of these fibers into the scala tympani also occurred, which may be deleterious to implant function. EABR thresholds improved (re: initial thresholds at time of implantation) on the chronically stimulated channels of the implant. Terminal electrophysiological studies recording in the inferior colliculus (IC) revealed that the basic cochleotopic organization was intact in the midbrain in all studied groups. In deafened controls or after ES-only, lower IC thresholds were correlated with more selective activation widths as expected, but no such correlation was seen after BDNF + ES due to much greater variability in both measures.


Asunto(s)
Factor Neurotrófico Derivado del Encéfalo/farmacología , Cóclea/inervación , Sordera/fisiopatología , Sordera/terapia , Terapia por Estimulación Eléctrica , Neuronas/fisiología , Ganglio Espiral de la Cóclea/fisiología , Animales , Umbral Auditivo/efectos de los fármacos , Umbral Auditivo/fisiología , Gatos , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Cóclea/crecimiento & desarrollo , Cóclea/fisiopatología , Implantes Cocleares , Modelos Animales de Enfermedad , Fenómenos Electrofisiológicos/efectos de los fármacos , Fenómenos Electrofisiológicos/fisiología , Neovascularización Fisiológica/efectos de los fármacos , Neovascularización Fisiológica/fisiología , Neuronas/citología , Neuronas/efectos de los fármacos , Ganglio Espiral de la Cóclea/citología , Ganglio Espiral de la Cóclea/efectos de los fármacos
7.
Neurotoxicology ; 34: 42-50, 2013 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-23164932

RESUMEN

3-Nitropropionic acid (3-NP), a mitochondrial toxin, has been reported to induce an acute cochlear damage. Korean red ginseng (KRG) is known to have protective effects from some types of hearing loss. This study aimed to observe the protective effect of KRG in an ototoxic animal model using 3-NP intratympanic injection. BALB/c mice were classified into 5 groups (n=15) and dose-dependent toxic effects after intratympanic injection with 3-NP (300-5000 mM) on the left ear were investigated to determine the appropriate toxicity level of 3-NP. For observation of the protective effects of KRG, 23 mice were grouped into 3-NP (500 mM, n=12) and KRG+3-NP groups (300 mg/kg KRG for 7 days before 500 mM 3-NP administration, n=11). Auditory brain response (ABR) and cochlear morphological evaluations were performed before and after drug administration. The ABR thresholds in the 800-5000 mM groups exceeded the maximum recording limit at 16 and 32 kHz 1 day after 3-NP administration. The ABR threshold in the 500 mM 3-NP+KRG group was significantly lower than that in the 500 mM 3-NP group from post 1 week to 1 month. The mean type II fibrocyte counts significantly differed between the control and 3-NP groups and between the 3-NP and 3-NP+KRG groups. Spiral ganglion cell degeneration in the 3-NP group was more severe than that in the 3-NP+KRG group. This animal model exhibited a dose-dependent hearing loss with histological changes. KRG administration ameliorated the deterioration of hearing by 3-NP.


Asunto(s)
Cóclea/efectos de los fármacos , Enfermedades Cocleares/prevención & control , Pérdida Auditiva/prevención & control , Nitrocompuestos , Panax , Extractos Vegetales/farmacología , Propionatos , Animales , Umbral Auditivo/efectos de los fármacos , Cóclea/patología , Cóclea/fisiopatología , Enfermedades Cocleares/inducido químicamente , Enfermedades Cocleares/patología , Enfermedades Cocleares/fisiopatología , Citoprotección , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Potenciales Evocados Auditivos del Tronco Encefálico/efectos de los fármacos , Células Ciliadas Auditivas Externas/efectos de los fármacos , Células Ciliadas Auditivas Externas/patología , Audición/efectos de los fármacos , Pérdida Auditiva/inducido químicamente , Pérdida Auditiva/patología , Pérdida Auditiva/fisiopatología , Masculino , Ratones , Ratones Endogámicos BALB C , Panax/química , Extractos Vegetales/aislamiento & purificación , Raíces de Plantas , Plantas Medicinales , Ganglio Espiral de la Cóclea/efectos de los fármacos , Ganglio Espiral de la Cóclea/patología , Factores de Tiempo
8.
Hear Res ; 291(1-2): 1-14, 2012 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-22796476

RESUMEN

Neurotrophins provide an effective tool for the rescue and regeneration of spiral ganglion neurons (SGNs) following sensorineural hearing loss. However, these nerve growth factors are also potent modulators of ion channel activity and expression, and in the peripheral auditory system brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT3) have previously been shown to alter the firing properties of auditory neurons and differentially regulate the expression of some potassium channels in vitro. In this study we examined the activity of the hyperpolarization-mediated mixed-cation current (I(h)) in early post-natal cultured rat SGNs following exposure to combined BDNF and NT3. Whole-cell patch-clamp recordings made after 1 or 2 days in vitro revealed no change in the firing adaptation of neurons in the presence of BDNF and NT3. Resting membrane potentials were also maintained, but spike latency and firing threshold was subject to regulation by both neurotrophins and time in vitro. Current clamp recordings revealed an activity profile consistent with activation of the hyperpolarization-activated current. Rapid membrane hyperpolarization was followed by a voltage- and time-dependent depolarizing voltage sag. In voltage clamp, membrane hyperpolarization evoked a slowly-activating inward current that was reversibly blocked with cesium and inhibited by ZD7288. The amplitude and current density of I(h) was significantly larger in BDNF and NT3 supplemented cultures, but this did not translate to a significant alteration in voltage sag magnitude. Neurotrophins provided at 50 ng/ml produced a hyperpolarizing shift in the voltage-dependence and slower time course of I(h) activation compared to SGNs in control groups or cultured with 10 ng/ml BDNF and NT3. Our results indicate that combined BDNF and NT3 increase the activity of hyperpolarization-activated currents and that the voltage-dependence and activation kinetics of I(h) in SGNs are sensitive to changes in neurotrophin concentration. In addition, BDNF and NT3 applied together induce a decrease in firing threshold, but does not generate a shift in firing adaptation.


Asunto(s)
Factor Neurotrófico Derivado del Encéfalo/administración & dosificación , Neurotrofina 3/administración & dosificación , Ganglio Espiral de la Cóclea/efectos de los fármacos , Ganglio Espiral de la Cóclea/fisiología , Potenciales de Acción/efectos de los fármacos , Animales , Células Cultivadas , Interacciones Farmacológicas , Fenómenos Electrofisiológicos , Pérdida Auditiva Sensorineural/tratamiento farmacológico , Pérdida Auditiva Sensorineural/fisiopatología , Potenciales de la Membrana/efectos de los fármacos , Modelos Neurológicos , Neuronas Aferentes/efectos de los fármacos , Neuronas Aferentes/fisiología , Técnicas de Placa-Clamp , Ratas
9.
Eur Arch Otorhinolaryngol ; 269(1): 45-52, 2012 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-21442422

RESUMEN

The aim of this study was to investigate the effectiveness of the oral administration of pomegranate extract (PE) as a protective agent against cisplatin-induced ototoxicity. The study included a prospective, controlled animal study Group 1 (n = 6), received no cisplatin or PE, and group 2 (n = 6) received cisplatin at 8 mg/kg/day for 3 consecutive days. Group 3 (n = 6) received not only cisplatin at 8 mg/kg/day for 3 consecutive days, but also received PE (100 µL/day) via gavage for 5 days prior to the cisplatin injection and for 3 days concomitantly with the cisplatin injections. To measure cisplatin ototoxic effects, "distortion product otoacoustic emissions" (DPOAE) were analyzed 3 days before and after the cisplatin injections. Histological changes in the cochleas were observed by light microscopy. Compared with group 3, the DPOAE amplitudes of group 2 decreased significantly. Among the groups, there was a statistically significant difference in basal and mid turn external ciliated cells (ECC) number, but there was no statistically significant difference in apical turn. Differences in stria vascularis (SV) changes were statistically significant between the groups, and the median score for SV injury was significantly greater in group 2 than in group 3. Differences in the median scores for SGC changes being significantly greater in group 2 than in group 3. In conclusion, these results indicated that oral administration of PE afforded statistically significant protection to the cochlea in rats from cisplatin toxicity, and thus, oral experimental dose of PE administration may have a protective effect against cisplatin ototoxicity in rats.


Asunto(s)
Antioxidantes/farmacología , Cisplatino/toxicidad , Cóclea/efectos de los fármacos , Lythraceae , Emisiones Otoacústicas Espontáneas/efectos de los fármacos , Extractos Vegetales/farmacología , Polifenoles/farmacología , Administración Oral , Animales , Cóclea/patología , Masculino , Ratas , Ratas Wistar , Ganglio Espiral de la Cóclea/efectos de los fármacos , Ganglio Espiral de la Cóclea/patología , Estría Vascular/efectos de los fármacos , Estría Vascular/patología
10.
Am J Otolaryngol ; 32(3): 228-34, 2011.
Artículo en Inglés | MEDLINE | ID: mdl-20447728

RESUMEN

OBJECTIVE: The aim of the study was to investigate the protective effects of Salvia miltiorrhiza (SM) against cisplatin-induced ototoxicity in guinea pigs. METHODS: Thirty-nine guinea pigs were randomly divided into 3 groups. The first group (control group) received physiologic saline by intraperitoneal (i.p.) injection for 5 days. The second group (cisplatin group) was treated with cisplatin (2 mg/kg per day, i.p. injection) for 5 days. The third group (SM group) was given SM (8 g/kg per day, i.p. injection) for 2 days and then was given SM (8 g/kg per day, i.p. injection) and cisplatin (2 mg/kg per day, i.p. injection) for 5 days. Auditory brain stem response (ABR) and cochlea blood flow measurement were used to evaluate cochlea function. The structures of cochlea were observed by light microscope, scanning electron microscope, transmission electron microscope (TEM), and immunohistochemical examination. RESULTS: Cisplatin could cause severe acoustic damages including significant elevation of ABR threshold, substantial losses of outer hair cells and inner hair cells, and severe damage on the stria vascularis and spiral ganglion cells (SGCs). Although in SM group, the increased tendency of threshold was milder than that in cisplatin group. The damages in cochlea and stria vascularis were also less severe than those in cisplatin group. The expression of induced nitric oxide synthase in the cochlea and SGC in SM group was lower than that in cisplatin group. CONCLUSIONS: Salvia miltiorrhiza can significantly reduce the cisplatin-induced side effects.


Asunto(s)
Pérdida Auditiva Sensorineural/prevención & control , Fitoterapia/métodos , Salvia miltiorrhiza , Animales , Cisplatino , Cóclea/efectos de los fármacos , Cóclea/patología , Modelos Animales de Enfermedad , Femenino , Cobayas , Células Ciliadas Auditivas/efectos de los fármacos , Células Ciliadas Auditivas/patología , Pérdida Auditiva Sensorineural/inducido químicamente , Pérdida Auditiva Sensorineural/patología , Inmunohistoquímica , Inyecciones Intraperitoneales , Masculino , Prevención Primaria/métodos , Distribución Aleatoria , Valores de Referencia , Ganglio Espiral de la Cóclea/efectos de los fármacos , Ganglio Espiral de la Cóclea/patología
11.
Acta Otolaryngol ; 130(12): 1316-23, 2010 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-20632907

RESUMEN

CONCLUSION: Excess glutamate (Glu) exposure (20 mM) in the cochlear perilymph affects the physiological function of outer hair cells (OHCs) within a 2 h period and induces apoptosis in the modiolus spiral ganglion neurons (SGNs) in an apoptosis-inducing factor (AIF)-dependent manner. OBJECTIVES: To determine whether high-dose Glu affects the function of OHCs and whether it induces AIF- and caspase-3-dependent apoptosis in the cochlear SGNs. METHODS: Perilymphatic perfusions of Glu (20 mM) and artificial perilymph (AP) solutions were performed in adult guinea pig cochleae. Both cochlear microphonics (CM) and electrical auditory brainstem response (eABR) were measured before and 2 h after perfusions. The hair cell morphologies were examined using transmission electron microscopy. The expression of two apoptotic indicators, AIF and caspase-3, was examined 8 h after perfusions. RESULTS: In contrast to AP perfusions, the perfusion of 20 mM Glu caused significant reduction in the CM and eABR amplitudes. Inner hair cells (IHCs) after Glu perfusion were deformed and exhibited vacuolization in the postsynaptic region, whereas the OHC system appeared unaffected. AIF expression was detected in the nuclei of SGNs 8 h after Glu exposure, but the expression of caspase-3 was not shown in any cochlear tissues.


Asunto(s)
Ácido Glutámico/toxicidad , Células Ciliadas Auditivas Internas/efectos de los fármacos , Células Ciliadas Auditivas Externas/efectos de los fármacos , Ganglio Espiral de la Cóclea/efectos de los fármacos , Animales , Apoptosis/efectos de los fármacos , Factor Inductor de la Apoptosis/metabolismo , Caspasa 3/metabolismo , Potenciales Microfónicos de la Cóclea/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Potenciales Evocados Auditivos del Tronco Encefálico/efectos de los fármacos , Cobayas , Células Ciliadas Auditivas Internas/patología , Células Ciliadas Auditivas Externas/patología , Microscopía Electrónica de Transmisión , Neuronas/efectos de los fármacos , Neuronas/patología , Perfusión , Perilinfa , Ganglio Espiral de la Cóclea/patología
12.
Neurosci Lett ; 479(1): 34-9, 2010 Jul 19.
Artículo en Inglés | MEDLINE | ID: mdl-20478357

RESUMEN

In the current study, we explored whether chronic salicylate exposure could induce apoptosis in outer hair cells (OHCs) and spiral ganglion neurons (SGNs) of the cochlea. Guinea pig received sodium salicylate (400 mg/kg/d) or saline vehicle for 10 consecutive days. Programmed cell death (PCD) executioner was evaluated with immunohistochemistry detection of activated caspase-3. Apoptosis was examined with a terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling (TUNEL) method. Repeated salicylate administration activated caspase-3 and caused apoptosis in OHCs and SGNs (p<0.01 vs. saline control for both measures and in both cell types). Cell counting showed a significant loss in OHCs (p<0.01 vs. saline control), but not in inner hair cells (IHCs). Transmission electron microscopy (TEM) revealed chromatin condensation and nucleus margination in salicylate-treated cochlea. Scanning electron microscopy (SEM) demonstrated stereociliary bundles breakdown and fusion at the apical of OHCs, villous matter was discovered to attach on the surface of SGNs. These findings suggest that long-term administration of high-dose salicylate can activate caspase-3 pathway to induce OHC and SGN apoptosis.


Asunto(s)
Apoptosis/efectos de los fármacos , Caspasa 3/metabolismo , Fármacos del Sistema Nervioso Central/toxicidad , Cóclea/efectos de los fármacos , Salicilato de Sodio/toxicidad , Animales , Apoptosis/fisiología , Recuento de Células , Núcleo Celular/efectos de los fármacos , Núcleo Celular/metabolismo , Núcleo Celular/patología , Cromatina/efectos de los fármacos , Cromatina/metabolismo , Cromatina/patología , Cóclea/metabolismo , Cóclea/patología , Cobayas , Células Ciliadas Auditivas Externas/efectos de los fármacos , Células Ciliadas Auditivas Externas/metabolismo , Células Ciliadas Auditivas Externas/patología , Inmunohistoquímica , Etiquetado Corte-Fin in Situ , Masculino , Microscopía Electrónica de Rastreo , Microscopía Electrónica de Transmisión , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/patología , Distribución Aleatoria , Ganglio Espiral de la Cóclea/efectos de los fármacos , Ganglio Espiral de la Cóclea/metabolismo , Ganglio Espiral de la Cóclea/patología
13.
J Assoc Res Otolaryngol ; 10(4): 525-44, 2009 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-19644644

RESUMEN

Significant sensory hair cell loss leads to irreversible hearing and balance deficits in humans and other mammals. Future therapeutic strategies to repair damaged mammalian auditory epithelium may involve inserting stem cells into the damaged epithelium, inducing non-sensory cells remaining in the epithelium to transdifferentiate into replacement hair cells via gene therapy, or applying growth factors. Little is currently known regarding the status and characteristics of the non-sensory cells that remain in the deafened auditory epithelium, yet this information is integral to the development of therapeutic treatments. A single high-dose injection of the aminoglycoside kanamycin coupled with a single injection of the loop diuretic furosemide was used to kill hair cells in adult mice, and the mice were examined 1 year after the drug insult. Outer hair cells are lost throughout the entire length of the cochlea and less than a third of the inner hair cells remain in the apical turn. Over 20% and 55% of apical organ of Corti support cells and spiral ganglion cells are lost, respectively. We examined the expression of several known support cell markers to investigate for possible support cell dedifferentiation in the damaged ears. The support cell markers investigated included the microtubule protein acetylated tubulin, the transcription factor Sox2, and the Notch signaling ligand Jagged1. Non-sensory epithelial cells remaining in the organ of Corti retain acetylated tubulin, Sox2 and Jagged1 expression, even when the epithelium has a monolayer-like appearance. These results suggest a lack of marked SC dedifferentiation in these aged and badly damaged ears.


Asunto(s)
Sordera/patología , Células Laberínticas de Soporte/citología , Envejecimiento/patología , Animales , Biomarcadores/análisis , Biomarcadores/metabolismo , Proteínas de Unión al Calcio/análisis , Proteínas de Unión al Calcio/biosíntesis , Diferenciación Celular , Sordera/inducido químicamente , Sordera/metabolismo , Diuréticos/administración & dosificación , Diuréticos/efectos adversos , Furosemida/administración & dosificación , Furosemida/efectos adversos , Células Ciliadas Auditivas/efectos de los fármacos , Células Ciliadas Auditivas/metabolismo , Células Ciliadas Auditivas/patología , Humanos , Péptidos y Proteínas de Señalización Intercelular/análisis , Péptidos y Proteínas de Señalización Intercelular/biosíntesis , Proteína Jagged-1 , Kanamicina/administración & dosificación , Kanamicina/efectos adversos , Células Laberínticas de Soporte/efectos de los fármacos , Células Laberínticas de Soporte/metabolismo , Proteínas de la Membrana/análisis , Proteínas de la Membrana/biosíntesis , Ratones , Inhibidores de la Síntesis de la Proteína/administración & dosificación , Inhibidores de la Síntesis de la Proteína/efectos adversos , Factores de Transcripción SOXB1/análisis , Factores de Transcripción SOXB1/biosíntesis , Proteínas Serrate-Jagged , Ganglio Espiral de la Cóclea/efectos de los fármacos , Ganglio Espiral de la Cóclea/patología , Tubulina (Proteína)/análisis , Tubulina (Proteína)/biosíntesis
14.
J Neurosci Res ; 87(6): 1389-99, 2009 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-19084902

RESUMEN

Electrical stimulation (ES) of spiral ganglion cells (SGC) via a cochlear implant is the standard treatment for profound sensor neural hearing loss. However, loss of hair cells as the morphological correlate of sensor neural hearing loss leads to deafferentation and death of SGC. Although immediate treatment with ES or glial cell line-derived neurotrophic factor (GDNF) can prevent degeneration of SGC, only few studies address the effectiveness of delayed treatment. We hypothesize that both interventions have a synergistic effect and that even delayed treatment would protect SGC. Therefore, an electrode connected to a pump was implanted into the left cochlea of guinea pigs 3 weeks after deafening. The contralateral untreated cochleae served as deafened intraindividual controls. Four groups were set up. Control animals received intracochlear infusion of artificial perilymph (AP/-). The experimental groups consisted of animals treated with AP in addition to continuous ES (AP/ES) or treated with GDNF alone (GDNF/-) or GDNF combined with continuous ES (GDNF/ES). Acoustically and electrically evoked auditory brain stem responses were recorded. All animals were killed 48 days after deafening; their cochleae were histologically evaluated. Survival of SGC increased significantly in the GDNF/- and AP/ES group compared with the AP/- group. A highly significant increase in SGC density was observed in the GDNF/ES group compared with the control group. Additionally, animals in the GDNF/ES group showed reduced EABR thresholds. Thus, delayed treatment with GDNF and ES can protect SGC from degeneration and may improve the benefits of cochlear implants.


Asunto(s)
Implantación Coclear , Sordera/terapia , Terapia por Estimulación Eléctrica , Factor Neurotrófico Derivado de la Línea Celular Glial/uso terapéutico , Neuronas/fisiología , Ganglio Espiral de la Cóclea/patología , Estimulación Acústica , Animales , Umbral Auditivo , Supervivencia Celular , Terapia Combinada , Sordera/patología , Sordera/fisiopatología , Potenciales Evocados Auditivos del Tronco Encefálico , Cobayas , Masculino , Neuronas/efectos de los fármacos , Ganglio Espiral de la Cóclea/efectos de los fármacos
15.
Artículo en Chino | MEDLINE | ID: mdl-21189568

RESUMEN

AIM: To study the expression of iNOS and AChE on ginea pigs cochlea spiral ganglion induced by streptomycin (SM) and attenuation by salvia miltiorrhiza injection (Chinese Traditional medicine-dansen DS). METHODS: 32 guinea pigs were divided into 4 groups randomly (n=8): control group, SM group, DS + SM group, DS group. SABC immunohistochemical staining and image quantitative analysis technique were used to observe the expression of iNOS and AChE, as well as grey value analysis, and ABR measurements were used to observe ototoxicity. RESULTS: After 10 days with drugs, the ABR threshold value of SM increased more significantly than that of the control (P < 0.01), while the ABR threshold value of DS+ SM co-treatment increased than the control group, but lower than that of SM group (P < 0.01). The results of immunohistochemical staining implied the expression of iNOS and AChE in SG of SM group were higher than that of control group, and had positive correlate. CONCLUSION: The ABR threshold value increases and the expression of iNOS and AChE strengthen on SM ototoxicity, and has some correlation. DS can attenuate the ototoxicity induced by SM, and has protective function.


Asunto(s)
Acetilcolinesterasa/metabolismo , Medicamentos Herbarios Chinos/farmacología , Óxido Nítrico Sintasa de Tipo II/metabolismo , Salvia miltiorrhiza/química , Ganglio Espiral de la Cóclea/efectos de los fármacos , Estreptomicina/toxicidad , Animales , Cóclea/efectos de los fármacos , Cóclea/metabolismo , Femenino , Cobayas , Pérdida Auditiva Sensorineural/inducido químicamente , Pérdida Auditiva Sensorineural/patología , Pérdida Auditiva Sensorineural/prevención & control , Masculino , Sustancias Protectoras/farmacología , Distribución Aleatoria , Ganglio Espiral de la Cóclea/metabolismo
16.
IEEE Trans Biomed Eng ; 54(6 Pt 1): 1138-48, 2007 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-17551571

RESUMEN

Spiral ganglion neurons (SGNs) are the target cells of the cochlear implant, a neural prosthesis designed to provide important auditory cues to severely or profoundly deaf patients. The ongoing degeneration of SGNs that occurs following a sensorineural hearing loss is, therefore, considered a limiting factor in cochlear implant efficacy. We review neurobiological techniques aimed at preventing SGN degeneration using exogenous delivery of neurotrophic factors. Application of these proteins prevents SGN degeneration and can enhance neurite outgrowth. Furthermore, chronic electrical stimulation of SGNs increases neurotrophic factor-induced survival and is correlated with functional benefits. The application of neurotrophic factors has the potential to enhance the benefits that patients can derive from cochlear implants; moreover, these techniques may be relevant for use with neural prostheses in other neurological conditions.


Asunto(s)
Cóclea/efectos de los fármacos , Implantes Cocleares/tendencias , Terapia por Estimulación Eléctrica/métodos , Pérdida Auditiva Sensorineural/fisiopatología , Pérdida Auditiva Sensorineural/terapia , Degeneración Nerviosa/prevención & control , Factores de Crecimiento Nervioso/administración & dosificación , Animales , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Cóclea/fisiopatología , Terapia Combinada , Modelos Animales de Enfermedad , Terapia por Estimulación Eléctrica/instrumentación , Electrodos Implantados , Potenciales Evocados Auditivos del Tronco Encefálico/efectos de los fármacos , Potenciales Evocados Auditivos del Tronco Encefálico/fisiología , Pérdida Auditiva Sensorineural/patología , Potenciales de la Membrana/fisiología , Degeneración Nerviosa/tratamiento farmacológico , Degeneración Nerviosa/fisiopatología , Neuronas Aferentes/efectos de los fármacos , Neuronas Aferentes/fisiología , Recuperación de la Función/efectos de los fármacos , Recuperación de la Función/fisiología , Ganglio Espiral de la Cóclea/efectos de los fármacos , Ganglio Espiral de la Cóclea/fisiología , Resultado del Tratamiento
17.
Neurobiol Dis ; 25(1): 189-97, 2007 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-17056263

RESUMEN

Sound conditioning primes the auditory system to low levels of acoustic stimuli and reduces damage caused by a subsequent acoustic trauma. This priming activates the HPA axis resulting in the elevation of plasma corticosterone with a consequent upregulation of glucocorticoid receptors (GR) in the cochlea and the paraventricular nucleus (PVN) of the hypothalamus in the mouse. This protective effect is blocked by adrenalectomy or pharmacological treatment with RU486 + metyrapone. Sound conditioning prevents GR down-regulation induced by acoustic trauma and subsequently enhances GR activity in spiral ganglion neurons. Increased SRC-1 expression, triggered by sound conditioning, positively correlates with the upregulation of GR in the cochlea. These findings will help to define the cellular mechanisms responsible for protecting the auditory system from hearing loss by sound conditioning.


Asunto(s)
Estimulación Acústica , Condicionamiento Psicológico/fisiología , Pérdida Auditiva Provocada por Ruido/fisiopatología , Audición/fisiología , Sistema Hipotálamo-Hipofisario/fisiología , Sistema Hipófiso-Suprarrenal/fisiología , Adrenalectomía , Hormona Adrenocorticotrópica/sangre , Animales , Western Blotting , Cóclea/fisiopatología , Corticosterona/sangre , Inhibidores Enzimáticos/farmacología , Potenciales Evocados Auditivos del Tronco Encefálico/fisiología , Glucocorticoides/antagonistas & inhibidores , Glucocorticoides/fisiología , Histona Acetiltransferasas/biosíntesis , Histona Acetiltransferasas/genética , Antagonistas de Hormonas/farmacología , Inmunohistoquímica , Masculino , Metirapona/farmacología , Ratones , Ratones Endogámicos CBA , Neuronas/metabolismo , Coactivador 1 de Receptor Nuclear , Núcleo Hipotalámico Paraventricular/citología , Núcleo Hipotalámico Paraventricular/metabolismo , Receptores de Glucocorticoides/biosíntesis , Transducción de Señal/fisiología , Ganglio Espiral de la Cóclea/efectos de los fármacos , Ganglio Espiral de la Cóclea/patología , Factores de Transcripción/biosíntesis , Factores de Transcripción/genética
18.
J Comp Neurol ; 486(2): 145-58, 2005 May 30.
Artículo en Inglés | MEDLINE | ID: mdl-15844207

RESUMEN

The development and maintenance of spiral ganglion neurons (SGNs) appears to be supported by both neural activity and neurotrophins. Removal of this support leads to their gradual degeneration. Here, we examined whether the exogenous delivery of the neurotrophin brain-derived neurotrophic factor (BDNF) in concert with electrical stimulation (ES) provides a greater protective effect than delivery of BDNF alone in vivo. The left cochlea of profoundly deafened guinea pigs was implanted with an electrode array and drug-delivery system. BDNF or artificial perilymph (AP) was delivered continuously for 28 days. ES induced neural activity in two cohorts (BDNF/ES and AP/ES), and control animals received BDNF or AP without ES (BDNF/- and AP/-). The right cochleae of the animals served as deafened untreated controls. Electrically evoked auditory brainstem responses (EABRs) were recorded immediately following surgery and at completion of the drug-delivery period. AP/ES and AP/- cohorts showed an increase in EABR threshold over the implantation period, whereas both BDNF cohorts exhibited a reduction in threshold (P < 0.001, t-test). Changes in neural sensitivity were complemented by significant differences in both SGN survival and soma area. BDNF cohorts demonstrated a significant trophic or survival advantage and larger soma area compared with AP-treated and deafened control cochleae; this advantage was greatest in the base of the cochlea. ES significantly enhanced the survival effects of BDNF throughout the majority of the cochlea (P < 0.05, Bonferroni's t-test), although there was no evidence of trophic support provided by ES alone. Cotreatment of SGNs with BDNF and ES provides a substantial functional and trophic advantage; this treatment may have important implications for neural prostheses.


Asunto(s)
Factor Neurotrófico Derivado del Encéfalo/farmacología , Cóclea/efectos de los fármacos , Terapia por Estimulación Eléctrica/métodos , Pérdida Auditiva Sensorineural/terapia , Degeneración Nerviosa/prevención & control , Neuronas Aferentes/efectos de los fármacos , Animales , Factor Neurotrófico Derivado del Encéfalo/uso terapéutico , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Cóclea/fisiología , Implantes Cocleares/normas , Implantes Cocleares/tendencias , Modelos Animales de Enfermedad , Terapia por Estimulación Eléctrica/instrumentación , Electrodos Implantados , Potenciales Evocados Auditivos del Tronco Encefálico/efectos de los fármacos , Potenciales Evocados Auditivos del Tronco Encefálico/fisiología , Cobayas , Pérdida Auditiva Sensorineural/patología , Pérdida Auditiva Sensorineural/fisiopatología , Potenciales de la Membrana/fisiología , Degeneración Nerviosa/tratamiento farmacológico , Degeneración Nerviosa/fisiopatología , Neuronas Aferentes/fisiología , Órgano Espiral/lesiones , Órgano Espiral/fisiopatología , Recuperación de la Función/efectos de los fármacos , Recuperación de la Función/fisiología , Ganglio Espiral de la Cóclea/efectos de los fármacos , Ganglio Espiral de la Cóclea/fisiología , Resultado del Tratamiento
19.
Ann Neurol ; 54(4): 451-8, 2003 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-14520656

RESUMEN

Hearing loss is the most frequent long-term complication of pneumococcal meningitis, affecting up to 40% of survivors. Unfortunately, adjuvant therapy with dexamethasone has failed to satisfactorily reduce its incidence. Therefore, we evaluated the use of antioxidants for the adjunctive therapy of meningitis-associated deafness. Eighteen hours after intracisternal injection of 7.5 x 10(5) colony-forming units of Streptococcus pneumoniae, rats were treated systemically either with ceftriaxone and the antioxidants and peroxynitrite scavengers Mn(III)tetrakis(4-benzoic acid)-porphyrin (MnTBAP) or N-acetyl-L-cysteine (NAC) or placebo (1 ml phosphate-buffered saline) for 4 days. Hearing was assessed by auditory brainstem response audiometry. Adjunctive antioxidant therapy significantly reduced the long-term hearing loss (14 days after infection) for square wave impulses (mean hearing loss +/- SD: ceftriaxone and placebo, 45+/-26 dB; ceftriaxone and MnTBAP, 9+/-23 dB; ceftriaxone and NAC, 19+/-30 dB) as well as 1 kHz (ceftriaxone and placebo, 28+/-19 dB; ceftriaxone and MnTBAP, 10+/-16 dB; ceftriaxone and NAC, 10+/-17 dB), and 10 kHz tone bursts (ceftriaxone and placebo, 62+/-27 dB; ceftriaxone and MnTBAP, 16+/-13 dB; ceftriaxone and NAC, 25+/-26 dB). Furthermore, both antioxidants attenuated the morphological correlates of meningogenic hearing loss, namely, long-term blood-labyrinth barrier disruption, spiral ganglion neuronal loss, and fibrous obliteration of the perilymphatic spaces. Adjuvant antioxidant therapy is highly otoprotective in meningitis and therefore is a promising future treatment option.


Asunto(s)
Antioxidantes/uso terapéutico , Pérdida Auditiva/prevención & control , Meningitis Neumocócica/complicaciones , Ácido Peroxinitroso/uso terapéutico , Acetilcisteína/uso terapéutico , Animales , Antibacterianos/uso terapéutico , Audiometría , Ceftriaxona/uso terapéutico , Recuento de Células/métodos , Cóclea/efectos de los fármacos , Cóclea/patología , Modelos Animales de Enfermedad , Interacciones Farmacológicas , Azul de Evans/metabolismo , Potenciales Evocados Auditivos del Tronco Encefálico/fisiología , Pérdida Auditiva/etiología , Laberintitis/microbiología , Laberintitis/patología , Masculino , Meningitis Neumocócica/microbiología , Metaloporfirinas/uso terapéutico , Ratas , Ratas Wistar , Ganglio Espiral de la Cóclea/efectos de los fármacos , Ganglio Espiral de la Cóclea/patología , Factores de Tiempo
20.
Hear Res ; 100(1-2): 181-91, 1996 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-8922993

RESUMEN

This study investigates whether auditory brainstem responses (ABRs) can be used to assess the functioning of electrically stimulated cochleas. Electrically evoked auditory brainstem responses (EABRs) were recorded in guinea pigs with normal hearing and guinea pigs deafened by amikacin, a powerful ototoxic antibiotic, combined with diuretic aminooxyacetic acid (AOAA). Two different types of EABRs were observed in normal animals, depending on the electrical pulse intensity applied to the round window: long-latency brainstem responses were evoked by low stimulation intensities, short-latency brainstem responses by high intensities. The absence of effect of strychnine applied intracochlearly ruled out the possibility of medial efferents being involved in these responses. Conversely, an intracochlear application of tetrodotoxin (TTX), an Na(+)-channel blocker, resulted in the disappearance of both types of responses, attesting that the sites activated by the electrical stimulation were located within the cochlea. In AOAA/ amikacin poisoned cochleas, in which most of the hair cells were missing with apparently normal ganglion neurons, the long-latency brainstem responses evoked by low intensities were completely lacking. These findings suggest that low currents applied to the round window of the guinea pig cochlea primarily activate the hair cells, the neurons being directly excited at higher intensities.


Asunto(s)
Cóclea/efectos de los fármacos , Potenciales Evocados Auditivos del Tronco Encefálico/efectos de los fármacos , Células Ciliadas Auditivas Internas/efectos de los fármacos , Estimulación Acústica , Amicacina/administración & dosificación , Amicacina/toxicidad , Ácido Aminooxiacético/administración & dosificación , Ácido Aminooxiacético/toxicidad , Animales , Antibacterianos/administración & dosificación , Antibacterianos/toxicidad , Cóclea/patología , Cóclea/ultraestructura , Sinergismo Farmacológico , Estimulación Eléctrica , Electrofisiología , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/toxicidad , Potenciales Evocados Auditivos del Tronco Encefálico/fisiología , Femenino , Cobayas , Células Ciliadas Auditivas Internas/citología , Células Ciliadas Auditivas Internas/ultraestructura , Masculino , Microscopía Electrónica , Neuronas Eferentes/citología , Neuronas Eferentes/efectos de los fármacos , Ganglio Espiral de la Cóclea/citología , Ganglio Espiral de la Cóclea/efectos de los fármacos , Estricnina/administración & dosificación , Estricnina/toxicidad , Tetrodotoxina/administración & dosificación , Tetrodotoxina/toxicidad
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