scholarly journals Inhibition of mTOR by Rapamycin Results in Auditory Hair Cell Damage and Decreased Spiral Ganglion Neuron Outgrowth and Neurite FormationIn Vitro

2015 ◽  
Vol 2015 ◽  
pp. 1-10 ◽  
Author(s):  
Katharina Leitmeyer ◽  
Andrea Glutz ◽  
Vesna Radojevic ◽  
Cristian Setz ◽  
Nathan Huerzeler ◽  
...  
Keyword(s):  
Hair Cell ◽  
Hair Cells ◽  
Cell Damage ◽  
Spiral Ganglion ◽  
Ganglion Neuron ◽  
Spiral Ganglion Neuron ◽  
Dependent Manner ◽  
Auditory Hair Cells ◽  
Ganglion Neurons ◽  
Dose Dependent

Rapamycin is an antifungal agent with immunosuppressive properties. Rapamycin inhibits the mammalian target of rapamycin (mTOR) by blocking the mTOR complex 1 (mTORC1). mTOR is an atypical serine/threonine protein kinase, which controls cell growth, cell proliferation, and cell metabolism. However, less is known about the mTOR pathway in the inner ear. First, we evaluated whether or not the two mTOR complexes (mTORC1 and mTORC2, resp.) are present in the mammalian cochlea. Next, tissue explants of 5-day-old rats were treated with increasing concentrations of rapamycin to explore the effects of rapamycin on auditory hair cells and spiral ganglion neurons. Auditory hair cell survival, spiral ganglion neuron number, length of neurites, and neuronal survival were analyzedin vitro. Our data indicates that both mTOR complexes are expressed in the mammalian cochlea. We observed that inhibition of mTOR by rapamycin results in a dose dependent damage of auditory hair cells. Moreover, spiral ganglion neurite number and length of neurites were significantly decreased in all concentrations used compared to control in a dose dependent manner. Our data indicate that the mTOR may play a role in the survival of hair cells and modulates spiral ganglion neuronal outgrowth and neurite formation.

scholarly journals Anti-inflammatory compounds improve spiral ganglion neuron survival after aminoglycoside-induced hair cell loss in rats

2021 ◽  
Author(s):  
Muhammad T. Rahman ◽  
Erin M. Bailey ◽  
Benjamin M. Gansemer ◽  
Andrew Pieper ◽  
J. Robert Manak ◽  
...  
Keyword(s):  
Hair Cell ◽  
Hair Cells ◽  
Spiral Ganglion ◽  
Cell Loss ◽  
Spiral Ganglion Neuron ◽  
Auditory Information ◽  
Activated Macrophages ◽  
Hair Cell Loss ◽  
Cochlear Hair Cells ◽  
Ganglion Neurons

AbstractSpiral ganglion neurons (SGNs) relay auditory information from cochlear hair cells to the central nervous system. After hair cells are destroyed by aminoglycoside antibiotics, SGNs gradually die. However, the reasons for this cochlear neurodegeneration are unclear. We used microarray gene expression profiling to assess transcriptomic changes in the spiral ganglia of kanamycin-deafened and age-matched control rats and found that many of the genes upregulated after deafening are associated with immune/inflammatory responses. In support of this, we observed increased numbers of macrophages in the spiral ganglion of deafened rats. We also found, via CD68 immunoreactivity, an increase in activated macrophages after deafening. An increase in CD68-associated nuclei was observed by postnatal day 23, a time before significant SGN degeneration is observed. Finally, we show that the immunosuppressive drugs dexamethasone and ibuprofen, as well as the NAD salvage pathway activator P7C3, provide at least some neuroprotection post-deafening. Ibuprofen and dexamethasone also decreased the degree of macrophage activation. These results suggest that activated macrophages specifically, and perhaps a more general neuroinflammatory response, are actively contributing to SGN degeneration after hair cell loss.

scholarly journals Inner Hair Cell and Neuron Degeneration Contribute to Hearing Loss in a Dfna2-Like Mouse Model

2018 ◽  
Author(s):  
Camila Carignano ◽  
Esteban Pablo Barila ◽  
Ezequiel Ignacio Rías ◽  
Leonardo Dionisio ◽  
Eugenio Aztiria ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Hair Cell ◽  
Hair Cells ◽  
Spiral Ganglion ◽  
Outer Hair Cells ◽  
Ganglion Neuron ◽  
Spiral Ganglion Neuron ◽  
Inner Hair Cell ◽  
Neuron Degeneration ◽  
Knock Out

HIGHLIGHTSKCNQ4 knock-out mouse shows hair cells and spiral ganglion neuron degeneration.Inner hair cells and spiral ganglion neuron loss begin 30 weeks later than outer hair cells in Kcnq4-/- mice.Inner hair cell loss kinetic is faster than that of outer hair cells in cochlear basal turn in Kcnq4-/-.Outer hair cells from Kcnq4-/- mice degenerate slower in apical than in basal turn.Kcnq4 knock-out allele expressed in C3H/HeJ strain reproduces the two phases of DFNA2 hearing loss.GRAPHICAL ABSTRACT

scholarly journals Caffeine Induces Autophagy and Apoptosis in Auditory Hair Cells via the SGK1/HIF-1α Pathway

2021 ◽  
Vol 9 ◽  
Author(s):  
Xiaomin Tang ◽  
Yuxuan Sun ◽  
Chenyu Xu ◽  
Xiaotao Guo ◽  
Jiaqiang Sun ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Hair Cells ◽  
Stria Vascularis ◽  
Spiral Ganglion ◽  
Organ Of Corti ◽  
Spiral Ganglion Neurons ◽  
Auditory Hair Cells ◽  
Qrt Pcr ◽  
Ganglion Neurons

Caffeine is being increasingly used in daily life, such as in drinks, cosmetics, and medicine. Caffeine is known as a mild stimulant of the central nervous system, which is also closely related to neurologic disease. However, it is unknown whether caffeine causes hearing loss, and there is great interest in determining the effect of caffeine in cochlear hair cells. First, we explored the difference in auditory brainstem response (ABR), organ of Corti, stria vascularis, and spiral ganglion neurons between the control and caffeine-treated groups of C57BL/6 mice. RNA sequencing was conducted to profile mRNA expression differences in the cochlea of control and caffeine-treated mice. A CCK-8 assay was used to evaluate the approximate concentration of caffeine. Flow cytometry, TUNEL assay, immunocytochemistry, qRT-PCR, and Western blotting were performed to detect the effects of SGK1 in HEI-OC1 cells and basilar membranes. In vivo research showed that 120 mg/ kg caffeine injection caused hearing loss by damaging the organ of Corti, stria vascularis, and spiral ganglion neurons. RNA-seq results suggested that SGK1 might play a vital role in ototoxicity. To confirm our observations in vitro, we used the HEI-OC1 cell line, a cochlear hair cell-like cell line, to investigate the role of caffeine in hearing loss. The results of flow cytometry, TUNEL assay, immunocytochemistry, qRT-PCR, and Western blotting showed that caffeine caused autophagy and apoptosis via SGK1 pathway. We verified the interaction between SGK1 and HIF-1α by co-IP. To confirm the role of SGK1 and HIF-1α, GSK650394 was used as an inhibitor of SGK1 and CoCl2 was used as an inducer of HIF-1α. Western blot analysis suggested that GSK650394 and CoCl2 relieved the caffeine-induced apoptosis and autophagy. Together, these results indicated that caffeine induces autophagy and apoptosis in auditory hair cells via the SGK1/HIF-1α pathway, suggesting that caffeine may cause hearing loss. Additionally, our findings provided new insights into ototoxic drugs, demonstrating that SGK1 and its downstream pathways may be potential therapeutic targets for hearing research at the molecular level.

scholarly journals ROR1 is essential for proper innervation of auditory hair cells and hearing in humans and mice

2016 ◽  
Vol 113 (21) ◽  
pp. 5993-5998 ◽  
Author(s):  
Oscar Diaz-Horta ◽  
Clemer Abad ◽  
Levent Sennaroglu ◽  
Joseph Foster ◽  
Alexandra DeSmidt ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Inner Ear ◽  
Hair Cells ◽  
Spiral Ganglion ◽  
Auditory Neuropathy ◽  
Mutant Mice ◽  
Spiral Ganglion Neurons ◽  
Type I ◽  
Auditory Hair Cells ◽  
Ganglion Neurons

Hair cells of the inner ear, the mechanosensory receptors, convert sound waves into neural signals that are passed to the brain via the auditory nerve. Little is known about the molecular mechanisms that govern the development of hair cell–neuronal connections. We ascertained a family with autosomal recessive deafness associated with a common cavity inner ear malformation and auditory neuropathy. Via whole-exome sequencing, we identified a variant (c.2207G>C, p.R736T) in ROR1 (receptor tyrosine kinase-like orphan receptor 1), cosegregating with deafness in the family and absent in ethnicity-matched controls. ROR1 is a tyrosine kinase-like receptor localized at the plasma membrane. At the cellular level, the mutation prevents the protein from reaching the cellular membrane. In the presence of WNT5A, a known ROR1 ligand, the mutated ROR1 fails to activate NF-κB. Ror1 is expressed in the inner ear during development at embryonic and postnatal stages. We demonstrate that Ror1 mutant mice are severely deaf, with preserved otoacoustic emissions. Anatomically, mutant mice display malformed cochleae. Axons of spiral ganglion neurons show fasciculation defects. Type I neurons show impaired synapses with inner hair cells, and type II neurons display aberrant projections through the cochlear sensory epithelium. We conclude that Ror1 is crucial for spiral ganglion neurons to innervate auditory hair cells. Impairment of ROR1 function largely affects development of the inner ear and hearing in humans and mice.

scholarly journals Brimonidine Protects Auditory Hair Cells from in vitro-Induced Toxicity of Gentamicin

2017 ◽  
Vol 22 (3) ◽  
pp. 125-134 ◽  
Author(s):  
Maurizio Cortada ◽  
Soledad Levano ◽  
Daniel Bodmer
Keyword(s):  
Protein Expression ◽  
Protective Effect ◽  
Hair Cells ◽  
Spiral Ganglion ◽  
Organ Of Corti ◽  
Neuroprotective Effects ◽  
Auditory Hair Cells ◽  
Expression Levels ◽  
Ganglion Neurons

Brimonidine, an alpha-2 adrenergic receptor (α2-AR) agonist, has neuroprotective effects in the visual system and in spiral ganglion neurons. Auditory hair cells (HCs) express all 3 α2-AR subtypes, but their roles in HCs remain unknown. This study investigated the effects of brimonidine on auditory HCs that were also exposed to gentamicin, which is toxic to HCs. Organ of Corti explants were exposed to gentamicin in the presence or absence of brimonidine, and the α2-AR protein expression levels and Erk1/2 and Akt phosphorylation levels were determined. Brimonidine had a protective effect on auditory HCs against gentamicin-induced toxicity that was blocked by yohimbine. This suggested that the protective effect of brimonidine on HCs was mediated by the α2-AR. None of the treatments altered α2-AR protein expression levels, and brimonidine did not significantly change the activation levels of the Erk1/2 and Akt proteins. These observations indicated that brimonidine, acting directly via α2-AR, protects HCs from gentamicin-induced toxicity. Therefore, brimonidine shows potential for preventing or treating sensorineural hearing loss.

scholarly journals Ouabain-Induced Apoptosis in Cochlear Hair Cells and Spiral Ganglion NeuronsIn Vitro

2013 ◽  
Vol 2013 ◽  
pp. 1-16 ◽  
Author(s):  
Yong Fu ◽  
Dalian Ding ◽  
Lei Wei ◽  
Haiyan Jiang ◽  
Richard Salvi
Keyword(s):  
Hair Cells ◽  
Gene Array ◽  
Spiral Ganglion ◽  
Spiral Ganglion Neuron ◽  
Round Window Membrane ◽  
Spiral Ganglion Neurons ◽  
Cochlear Hair Cells ◽  
Ganglion Neurons

Ouabain is a common tool to explore the pathophysiological changes in adult mammalian cochleain vivo. In prior studies, locally administering ouabain via round window membrane demonstrated that the ototoxic effects of ouabainin vivovaried among mammalian species. Little is known about the ototoxic effectsin vitro. Thus, we prepared cochlear organotypic cultures from postnatal day-3 rats and treated these cultures with ouabain at 50, 500, and 1000 μM for different time to elucidate the ototoxic effects of ouabainin vitroand to provide insights that could explain the comparative ototoxic effects of ouabainin vivo. Degeneration of cochlear hair cells and spiral ganglion neurons was evaluated by hair-cell staining and neurofilament labeling, respectively. Annexin V staining was used to detect apoptotic cells. A quantitative RT-PCR apoptosis-focused gene array determined changes in apoptosis-related genes. The results showed that ouabain-induced damagein vitrowas dose and time dependent. 500 μM ouabain and 1000 μM ouabain were destructively traumatic to both spiral ganglion neurons and cochlear hair cells in an apoptotic signal-dependent pathway. The major apoptotic pathways in ouabain-induced spiral ganglion neuron apoptosis culminated in the stimulation of the p53 pathway and triggering of apoptosis by a network of proapoptotic signaling pathways.

Allicin protects auditory hair cells and spiral ganglion neurons from cisplatin - Induced apoptosis

2017 ◽  
Vol 116 ◽  
pp. 429-440 ◽  
Author(s):  
Xianmin Wu ◽  
Xiaofei Li ◽  
Yongdong Song ◽  
He Li ◽  
Xiaohui Bai ◽  
...  
Keyword(s):  
Hair Cells ◽  
Spiral Ganglion ◽  
Spiral Ganglion Neurons ◽  
Auditory Hair Cells ◽  
Induced Apoptosis ◽  
Ganglion Neurons
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