[Show abstract][Hide abstract] ABSTRACT: Peripheral sensorineural hearing loss is a very common inner ear disorder affecting nearly 10% of the population. At present there is no cure for this disorder but gene therapy has been suggested as a potentially effective method for clinical treatment in the future. Thus we investigated the effectiveness of adenoviral (Ad) and adeno-associated viral (AAV) vectors to transduce the cochlea of guinea pigs. After direct injection into the basal turn of the cochlea, we found that both Ad and AAV vectors coding for the reporter genes lacZ or GFP readily transduced spiral ganglion cells. In addition, some transgene expression was detected in the stria vascularis after AAV-GFP injection. Gene expression persisted at least 8 weeks after viral vector injection. Present findings will help to develop future gene therapy protocols in the inner ear by using Ad and AAV coding for neurotrophins such as NT-3, BDNF, GDNF and VEGF.
[Show abstract][Hide abstract] ABSTRACT: During the last decade, there have been numerous interesting findings regarding the roles of neurotrophins, nitric oxide, reactive oxygen species, glutamate receptors, and shock protein in the auditory system. These findings have provided a scientific basis for the development of techniques to protect the auditory system against trauma as well as for the treatment of peripheral hearing disorders. This review focuses on recent advances in experimental prevention and treatment of hearing impairment which are expected to be of clinical value in the near future. Viral vector and non-viral vector gene therapy and transplantation of stem cells are discussed as potential treatments of irreversible sensorineural inner ear damage.
Hearing Research 08/2002; 169(1-2):169-78. DOI:10.1016/S0378-5955(02)00484-7 · 2.85 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The role of glutamate receptors was investigated by infusing N-methyl-D-aspartate (NMDA) or alpha-amino-3-hydroxy-5-methyl-isoxazol-propionate (AMPA) into the guinea pig cochlea. Auditory brainstem response thresholds and forward masking were used to determine auditory sensitivity. In the presence of 330 microM NMDA, the auditory brainstem response (ABR) thresholds were elevated by 20-30 dB at 2 kHz and 8 kHz, and the slopes of the forward masking curves were not significantly different from controls. When a high concentration of NMDA (15 mM) was used, ABR thresholds were elevated by 40-50 dB at 2 kHz and 8 kHz and the slopes of the forward masking curves were significantly decreased. In contrast, when AMPA (150 microM) was infused, ABR thresholds were elevated by 20-35 dB at 2 and 8 kHz and the slopes of the forward masking curves were significantly decreased from the control group. When the concentration of AMPA was decreased (100 microM). ABR thresholds were not significantly altered but the slopes of the forward masking curves were significantly decreased from control values. The present study suggests that AMPA receptors play a significantly more important role in short-term adaptation than NMDA receptors.
[Show abstract][Hide abstract] ABSTRACT: MRI with a T1 contrast agent was used to investigate the normal and noise-damaged cochlea. The time course and distribution of the in vivo uptake of the gadodiamide chelate bound paramagnetic Gd ion (GdDTPA-BMA) throughout the membranous labyrinth of normal and impulse noise-damaged guinea pig cochleae were measured by MRI at 4.7T. Simultaneous signal enhancement of the basal, medial and apical scala tympani (ST) and scala vestibuli (SV) was observed within 10 min following i.v. injection, reaching maximum levels at around 100 min. ANOVA and post hoc paired t-tests showed statistically significant differences in the levels and rates of Gd uptake-enhancement between the scalae. The ST revealed the most rapid and extensive enhancement throughout the period of active Gd uptake, while the SV showed comparatively slower and less enhancement, and the intact scala media (SM) indicated insignificant enhancement. The in vivo Gd penetration and enhancement of the membranous SM increased significantly in the noise-damaged cochlea, suggesting lesioning of the cochlear membranes.
[Show abstract][Hide abstract] ABSTRACT: Hearing loss is a very common disorder; nearly 10 per cent of the population is affected. Recently, a few findings such as the roles of neurotrophins, nitric oxide, reactive oxygen species and glutamate receptors in the peripheral hearing system have been highlighted. In this review, focus is set on possible mechanisms of peripheral hearing disorders, and on recent advances to prevent and treat hearing loss. Clinically useful treatment strategies, especially gene therapy and the use of embryonic stem cells, are particularly stressed.
[Show abstract][Hide abstract] ABSTRACT: Hearing is conveyed from the auditory receptors, the hair cells in the organ of Corti, to the brain via the spiral ganglion neurons. Damage or loss of either spiral ganglion neurons or hair cells causes hearing impairment. Such hearing disorders are often permanent and can be caused by therapeutic agents, such as aminoglycoside antibiotics and cisplatin, or by aging, loud sounds, infections and mechanical injury (1). Brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3), members of the neurotrohin family of neurotrophic factors that also include nerve growth factor (NGF) and neurotrophin-4/5 (NT-4), are important in development of the neuronal components of the inner ear. We report here that the loss of target innervation and the degeneration of approximately 90% of the adult spiral ganglion neurons caused by aminoglycoside toxicity can be prevented by infusion of the neurotrophic factor, neurotrophin-3 (NT-3) in the membranous labyrinth in guinea pigs. The potency of NT-3 in protecting spiral ganglion neurons from degenerating suggests that neurotrophins may be useful for the treatment of hearing disorders.
Nature Medicine 05/1996; 2(4):463-7. DOI:10.1038/nm0496-463 · 28.05 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The goal of this study was to test the hypothesis that the inner hair cell complex (inner hair cell and dendritic contacts) is solely responsible for generating the slope of the forward masking curve. To test this hypothesis two experiments were performed. The first was to measure forward masking from the Bronx waltzing mouse, a mutant possessing an inner hair cell defect. The Bronx waltzing mouse demonstrated an approximately 60-dB auditory brainstem response (ABR) threshold shift compared to CBA/CBA mice at 8 and 12 kHz. The slope of the forward masking curve was significantly reduced compared to the control group, particularly at the early delay times between 0 and 4 ms. The second model employed kainic acid to affect the dendrites beneath the inner hair cell. After the intracochlear infusion of kainic acid, there was an approximately 47-dB ABR threshold shift at 4 and 8 kHz compared to pre-infusion thresholds. The slope of the forward masking curve from the kainic-acid group was significantly reduced compared to the artificial-perilymph group. Primarily the early delay times were affected by kainic acid (0-4 ms). Morphological analysis showed that there was extensive swelling of the afferent nerve radial dendrites under the inner hair cells. The results from the present study, as well as the preceding article, suggest that the analysis of the slope of the forward masking curve may be used for the detection of inner hair cell or radial dendrite damage, independent of outer hair cell damage. The present finding could provide a useful means of employing a clinical test for determining the function of the inner hair cell complex using a non-invasive measure of auditory function.
Audiology and Neurotology 01/1996; 1(6):320-7. DOI:10.1159/000259216 · 1.85 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Forward masking of the auditory brainstem response (ABR) was achieved by increasing the time interval from 0 to 12 ms between the masker offset and the probe onset. The forward masking response demonstrated a near linear function with an approximate 3.0-dB increase in masking threshold for every millisecond interval increase in the control guinea pig. The slope of the masking curve at selected frequencies together with the quantification of hair cell loss through the analysis of cochlear surface morphology was studied before and after chemical insult. The intracochlear infusion of sodium salicylate caused an approximately 45-dB threshold shift of the ABR whereas the slope of the forward masking curve was not significantly different from the control values at the tested frequencies (1, 4, and 8 kHz). Systemic kanamycin administration (400 mg/kg body weight for 9 consecutive days) caused a permanent ABR threshold shift of 43-63 dB at 1, 4, and 8 kHz. The slope of the forward masking curve was not significantly different at 1 kHz despite significant outer hair cell loss. The slope of the forward masking curve at 4 and 8 kHz showed significant reductions at the time intervals between 0 and 4 ms. Analysis of the kanamycin-treated cochleae revealed not only significant outer hair cell loss throughout the cochlea but significant inner hair cell and inner pillar cell loss in the basal end of the cochlea. The results suggest that the outer hair cells are not needed for maintaining a normal forward masking curve, whereas the slope of the forward masking curve is sensitive to alterations induced to either the inner hair cells or the inner pillar cells.
Audiology and Neurotology 01/1996; 1(6):309-19. DOI:10.1159/000259215 · 1.85 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The forward masking curve of the auditory brainstem response (ABR) at selected frequencies together with the quantification of hair cell loss through the analysis of cochlear surface morphology was studied in guinea pigs before and after acoustic trauma resulting in either a temporary or a permanent threshold shift. In the presence of a noise-induced temporary threshold shift, the slope of the forward masking curve was not significantly different from the pre-exposure curve. In contrast, during the acute phase of the permanent threshold shift, the slope of the forward masking curve was significantly reduced compared to the pre-exposure value. After a recovery period of 2 weeks, the slope of the forward masking curve from the permanently damaged group returned to nearly normal values despite a persisting ABR threshold shift and significant loss of outer hair cells. The potential for analyzing the slope of the forward masking curve in order to distinguish between the acute phase of a permanent threshold shift and a temporary threshold shift is discussed.
Audiology and Neurotology 01/1996; 1(6):328-38. DOI:10.1159/000259217 · 1.85 Impact Factor