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PubMed2006

Effects of antioxidants on the aging inner ear.

Age-related cochlear structural changes include the degeneration of sensory, neural cells and the stria vascularis. The hypothesis that cellular degeneration results from exposure to oxidative products of respiration was tested by supplementing aged dogs with a diet high in antioxidants and mitochondrial metabolites and by genetically modifying the expression level of the antioxidant, manganese superoxide dismutase (SOD2) in mice. Aged dogs received either a high antioxidant diet or a normal, control diet for the last 3 years of their life. Cellular measures were compared among the two aged groups (10-15 years) and young dogs. Both aged groups had cellular degeneration relative to young dogs, but the animals fed the antioxidant diet showed less degeneration at the base and apex than the control-diet group. Transgenic mice, heterozygous null for SOD2, produce only half as much enzyme as a normal mouse. These mice showed no increase in the amount of hearing loss relative to the background strain. A diet containing antioxidants reduced the magnitude of cochlear degeneration. Genetic reduction of one antioxidant, however, did not increase the magnitude of hearing loss in aging mice. A reduction in one enzyme seems to be compensated while the addition of a complex of factors is effective.

Aging↗
PubMed2006

Transdifferentiation and its applicability for inner ear therapy.

During normal development, cells divide, then differentiate to adopt their individual form and function in an organism. Under most circumstances, mature cells cannot transdifferentiate, changing their fate to adopt a different form and function. Because differentiated cells cannot usually divide, the repair of injuries as well as regeneration largely depends on the activation of stem cell reserves. The mature cochlea is an exception among epithelial cell layers in that it lacks stem cells. Consequently, the sensory hair cells that receive sound information cannot be replaced, and their loss results in permanent hearing impairment. The lack of a spontaneous cell replacement mechanism in the organ of Corti, the mammalian auditory sensory epithelium, has led researchers to investigate circumstances in which transdifferentiation does occur. The hope is that this information can be used to design therapies to replace lost hair cells and restore impaired hearing in humans.

Animals↗
PubMed2004

GATA3 and NeuroD distinguish auditory and vestibular neurons during development of the mammalian inner ear.

The function of the zinc finger transcription factor GATA3 was studied in a newly established, conditionally immortal cell line derived to represent auditory sensory neuroblasts migrating from the mouse otic vesicle at embryonic day E10.5. The cell line, US/VOT-33, expressed GATA3, the bHLH transcription factor NeuroD and the POU-domain transcription factor Brn3a, as do auditory neuroblasts in vivo. When GATA3 was knocked down reversibly with antisense oligonucleotides, NeuroD was reversibly down-regulated. Auditory and vestibular neurons form from neuroblasts that express NeuroD and that migrate from the antero-ventral, otic epithelium at E9.5-10.5. On the medial side, neuroblasts and epithelial cells express GATA3 but on the lateral side they do not. At E13.5 most auditory neurons express GATA3 but no longer express NeuroD, whereas vestibular neurons express NeuroD but not GATA3. Neuroblasts expressing NeuroD and GATA3 were located in the ventral, otic epithelium, the adjacent mesenchyme and the developing auditory ganglion. The results suggest that auditory and vestibular neurons arise from different, otic epithelial domains and that they gain their identity prior to migration. In auditory neuroblasts, NeuroD appears to be dependent on the expression of GATA3.

Animals↗
PubMed2005

Dynamic expression of COUP-TFI and COUP-TFII during development and functional maturation of the mouse inner ear.

COUP-TFs (chicken ovalbumin upstream promoter-transcription factors) are orphan members of the nuclear receptor superfamily of ligand-activated receptors for which their ligands have not been identified. The two mammalian proteins, COUP-TFI and COUP-TFII, share 80% sequence identity and regulate many aspects of mammalian development and differentiation. In this report, we systemically examined the temporal and spatial expression of COUP-TFI and COUP-TFII transcripts and, for the first time, their protein during development and functional maturation of the cochlea. Both COUP-TFI and COUP-TFII were expressed early in the developing otic vesicle. COUP-TFI expression correlated with the differentiation of hair cells and support cells in the organ of Corti, whereas COUP-TFII expression was down-regulated with differentiation of the organ of Corti. Furthermore, we report for the first time, that the generally nuclear COUP-TFI receptor protein was localized in the cytoplasm of maturing hair cells and pillar cells. Collectively, although COUP-TFI and COUP-TFII are homologues, the expression of each orphan receptor has a restricted and dynamic expression during cochlea development particularly during patterning and differentiation of the cochlear structures.

Animals↗
PubMed2005

NGF stimulates extensive neurite outgrowth from implanted dorsal root ganglion neurons following transplantation into the adult rat inner ear.

Neuronal tissue transplantation is a potential way to replace degenerated spiral ganglion neurons (SGNs) since these cells cannot regenerate in adult mammals. To investigate whether nerve growth factor (NGF) can stimulate neurite outgrowth from implanted neurons, mouse embryonic dorsal root ganglion (DRG) cells expressing enhanced green fluorescent protein (EGFP) were transplanted into the scala tympani of adult rats with a supplement of NGF or artificial perilymph. DRG neurons were observed in the cochlea for up to 6 weeks postoperatively. A significant difference was identified in the number of DRG neurons between the NGF and non-NGF groups. In the NGF group, extensive neurite projections from DRGs were found penetrating the osseous modiolus towards the spiral ganglion. These results suggest the possibility that embryonic neuronal implants may become integrated within the adult auditory nervous system. In combination with a cochlear prosthesis, a neuronal implantation strategy may provide a possibility for further treatment of profoundly deaf patients.

Animals↗
PubMed2004

Expression and distribution of mu opioid receptors in the inner ear of the rat.

Opioid peptides have demonstrated modulatory effects on the vestibular afferent discharge and are putative vestibular efferent neuromodulators. The distribution of their receptors in the mammalian vestibular epithelia is not known. We used reverse transcriptase-polymerase chain reaction (RT-PCR), in situ hybridization, Western blots and immunohistochemistry to study the expression of mu opioid receptor (MOR) in the Scarpa's ganglia and cristae ampullares of rats. MOR transcript was only detected in the somata of the vestibular afferent neurons. MOR-like immunoreactivity was observed in the somata of vestibular afferents and in nerve terminals in the cristae ampullares epithelia both in the center and peripheral regions. Double labeling of cristae sections with the MOR1 antibody in combination with antibodies against calretinin (a marker for vestibular afferents terminating in calices) and peripherin (a marker for afferents terminating in boutons), respectively showed that MOR1 immunoreactivity was in calyx, dimorphic and bouton vestibular afferents. MOR immunoreactivity was not detected in vestibular efferent fibers identified with choline acetyltransferase immunohistochemistry. These results indicate that MOR may mediate effects of vestibular efferents on afferents.

Animals↗
PubMed2004

Vascular development in the retina and inner ear: control by Norrin and Frizzled-4, a high-affinity ligand-receptor pair.

Incomplete retinal vascularization occurs in both Norrie disease and familial exudative vitreoretinopathy (FEVR). Norrin, the protein product of the Norrie disease gene, is a secreted protein of unknown biochemical function. One form of FEVR is caused by defects in Frizzled-4 (Fz4), a presumptive Wnt receptor. We show here that Norrin and Fz4 function as a ligand-receptor pair based on (1) the similarity in vascular phenotypes caused by Norrin and Fz4 mutations in humans and mice, (2) the specificity and high affinity of Norrin-Fz4 binding, (3) the high efficiency with which Norrin induces Fz4- and Lrp-dependent activation of the classical Wnt pathway, and (4) the signaling defects displayed by disease-associated variants of Norrin and Fz4. These data define a Norrin-Fz4 signaling system that plays a central role in vascular development in the eye and ear, and they indicate that ligands unrelated to Wnts can act through Fz receptors.

Animals↗
PubMedDate not supplied

Four variations of the Mondini inner ear malformations as seen in microdissections.

Four variations and degrees of severity of the Mondini malformation were found in the temporal bones from two neonates, one with congenital heart disease and the other with trisomy D, and from one teenager with leukemia: 1) short cochlea and normal vestibular organs; 2) short cochlea and persistent horizontal canal anlage; 3) markedly shortened cochlea with no modiolus, wide internal auditory meatus, and persistent horizontal canal anlage; 4) same as variation 3, but with persistent anlagen in all semicircular canals. Variations 3 and 4 were from the case of trisomy D, in which the left cochlea had a normal hair cell population but few nerve fibers, and the intraganglionic spiral bundle was displaced from Rosenthal's canal to the osseous spiral lamina. The right ear had no cochlear nerve fibers; the organ of Corti was present, but hair cells were unusually small. In the case of trisomy D, both ears showed subtotal loss of vestibular nerve fibers. Although the rudimentary cristae of the right ear had numerous hair cells, the macular hair cells were fewer and malformed. No hydrops was present.

Adolescent↗
PubMedDate not supplied

Dissociated single cells from the inner ear: strial cells.

Using the enzyme dissociation technique, the authors successfully isolated strial marginal cells and intermediate cells from guinea pig and chinchilla cochleas. Dissociated cells were maintained for in vitro observation under the light microscope for up to 2 hours without gross evidence of cell damage. Such single cells were successfully prepared for scanning or transmission electron microscopic observation, which showed excellent cell shape and preservation of cell organelles. However, there was evidence of increased vesiculation in the dissociated marginal cells, which is interpreted to be evidence of increased pinocytotic activity.

Animals↗
PubMedDate not supplied

Hyaluronate production by the inner ear during otic capsule and perilymphatic space formation.

Otosclerosis has been hypothesized to result from a disorder of the extracellular matrix of the cartilaginous rests present in the adult temporal bone. Matrix relationship to bone formation and remodeling, as well as the fact that the pathogenesis of otosclerosis is expressed by the action of both of these processes, strongly suggests that more knowledge is needed about the process of otic capsule development. In pursuit of this goal, otic complexes were explanted from mouse embryos that ranged in age from 10.5 to 16 days old and were then exposed to 3H-glucosamine (50 microCi/ml) for 6 hours in vitro. Total labeled glycosaminoglycans (GAGs) and labeled hyaluronate content of each age group of otic explants were measured, and the results were compared to a developmental series of the otic regions of whole embryos stained with either toluidine blue or alcian blue. Increases in the synthesis of the total GAGs were observed on embryonic day 11 and for a prolonged period extending from gestation day 13.5 through day 16. The first increase of GAGs occurred at the initiation of metachromasia and positive staining by toluidine blue of the region of aggregated periotic mesenchyme cells that form the otic capsule. The second increase in GAGs was correlated with chondrification of the capsule. Hyaluronate production revealed a different pattern. Synthesis of hyaluronate exhibits peaks at 10.5, 12.5, and for an extended period of from 13.5 to 14.5 days of gestation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1998

The role of N-methyl-D-aspartate receptor in the guinea pig inner ear after unilateral labyrinthectomy.

To investigate the role of the N-methyl-D-aspartate (NMDA) receptor in the vestibular periphery, vestibular compensation in the guinea pig was studied following chemical unilateral labyrinthectomy by osmotic pump administration of streptomycin sulfate (SM) with or without D-2-amino-5-phosphonovalerate (D-APV), one of the NMDA receptor antagonists. All animals administrated SM (SM group) or SM and D-APV (SM + D-APV group) showed spontaneous nystagmus and head tilt. The maximum degree of yaw head tilt in the SM + D-APV group was statistically smaller than that in the SM group. Moreover the time constant for head tilt in the SM + D-APV group was statistically shorter than that in the SM group. These results indicate that the NMDA receptor in the vestibular periphery influences vestibular compensation after unilateral labyrinthectomy.

2-Amino-5-phosphonovalerate↗