Cochlear Pathology of Sensorineural Deafness in Cats: Coadministration of Kanamycin and Aminooxyacetic Acid

The coadministration of kanamycin (400 mg/kg body weight, s.c.) and aminooxyacetic acid (25 mg/kg body weight, s.c.) results in rapid, total destruction of cochlear hair cells in cats. This drug combination is safer and the time course of hearing losses is less variable than with administration of aminoglycosides alone. Uniform survival of spiral ganglion neurons at 2 and 4 weeks after drug administration suggests a time course similar to that previously observed in neomycin-deafened cats, but more data with longer survival periods are needed to verify these preliminary observations.

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New insights into glutamate ototoxicity in cochlear hair cells and spiral ganglion neurons

Acta Oto-Laryngologica ◽

10.3109/00016489.2010.495133 ◽

2010 ◽

Vol 130 (12) ◽

pp. 1316-1323 ◽

Cited By ~ 5

Author(s):

Haitao Lu ◽

Xiang Wang ◽

Wenyan Sun ◽

Yao Hu ◽

Shusheng Gong

Keyword(s):

Hair Cells ◽

Spiral Ganglion ◽

Spiral Ganglion Neurons ◽

Cochlear Hair Cells ◽

Ganglion Neurons

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Syndromic deafness gene ATP6V1B2 controls degeneration of spiral ganglion neurons through modulating proton flux

10.21203/rs.3.rs-452428/v1 ◽

2021 ◽

Author(s):

Shiwei Qiu ◽

Weihao Zhao ◽

Xue Gao ◽

Dapeng Li ◽

Weiqian Wang ◽

...

Keyword(s):

Hearing Loss ◽

Hair Cells ◽

Intraperitoneal Administration ◽

Spiral Ganglion ◽

Sensorineural Deafness ◽

Autophagic Flux ◽

Spiral Ganglion Neurons ◽

Distortion Product ◽

Brainstem Response ◽

Ganglion Neurons

Abstract ATP6V1B2 encodes the V1B2 subunit in V-ATPase, a proton pump responsible for the acidification of lysosomes. Mutations in this gene cause DDOD syndrome, DOORS syndrome, and Zimmermann-Laband syndrome, which share overlapping feature of congenital sensorineural deafness, onychodystrophy, and different extents of intellectual disability without or with epilepsy. However, the underlying mechanism is unclear. To investigate the pathological role of mutant ATP6V1B2 in the auditory system, we evaluated auditory brainstem response, distortion product otoacoustic emissions, in a transgenic line of mice carrying c.1516 C > T (p.Arg506*) in Atp6v1b2, Atp6v1b2Arg506*/Arg506*. To explore the pathogenic mechanism of neurodegeneration in the auditory pathway, immunostaining, western blotting, and RNAscope analyses were performed in Atp6v1b2Arg506*/Arg506* mice. The Atp6v1b2Arg506*/Arg506* mice showed hidden hearing loss at early stages and developed late-onset hearing loss. We observed increased transcription of Atp6v1b1 in hair cells of Atp6v1b2Arg506*/Arg506* mice and inferred that Atp6v1b1 compensated for the Atp6v1b2 dysfunction by increasing its own transcription level. Genetic compensation in hair cells explains the milder hearing impairment in Atp6v1b2Arg506*/Arg506* mice. Apoptosis activated by lysosomal dysfunction and the subsequent blockade of autophagic flux induced the degeneration of spiral ganglion neurons and further impaired the hearing. Intraperitoneal administration of the apoptosis inhibitor, BIP-V5, improved both phenotypical and pathological outcomes in two live mutant mice. Based on the pathogenesis underlying hearing loss in ATP6V1B2-related syndromes, systemic drug administration to inhibit apoptosis might be an option for restoring the function of spiral ganglion neurons and promoting hearing, which provides a direction for future treatment.

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Effects of Kir2.1 gene transfection in cochlear hair cells and application of neurotrophic factors on survival and neurite growth of co-cultured cochlear spiral ganglion neurons

Molecular and Cellular Neuroscience ◽

10.1016/j.mcn.2009.12.006 ◽

2010 ◽

Vol 43 (3) ◽

pp. 326-339 ◽

Cited By ~ 4

Author(s):

Qingwei Ruan ◽

Dong Chen ◽

Zhengmin Wang ◽

Fanglu Chi ◽

Jinchun He ◽

...

Keyword(s):

Hair Cells ◽

Neurotrophic Factors ◽

Gene Transfection ◽

Spiral Ganglion ◽

Neurite Growth ◽

Spiral Ganglion Neurons ◽

Cochlear Hair Cells ◽

Cochlear Spiral Ganglion ◽

Ganglion Neurons

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

BioMed Research International ◽

10.1155/2013/628064 ◽

2013 ◽

Vol 2013 ◽

pp. 1-16 ◽

Cited By ~ 14

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.

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Syndromic Deafness Gene ATP6V1B2 Controls Degeneration of Spiral Ganglion Neurons Through Modulating Proton Flux

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.742714 ◽

2021 ◽

Vol 9 ◽

Author(s):

Shiwei Qiu ◽

Weihao Zhao ◽

Xue Gao ◽

Dapeng Li ◽

Weiqian Wang ◽

...

Keyword(s):

Hearing Loss ◽

Hair Cells ◽

Intraperitoneal Administration ◽

Spiral Ganglion ◽

Sensorineural Deafness ◽

Autophagic Flux ◽

Spiral Ganglion Neurons ◽

Distortion Product ◽

Brainstem Response ◽

Ganglion Neurons

ATP6V1B2 encodes the V1B2 subunit in V-ATPase, a proton pump responsible for the acidification of lysosomes. Mutations in this gene cause DDOD syndrome, DOORS syndrome, and Zimmermann–Laband syndrome, which share overlapping feature of congenital sensorineural deafness, onychodystrophy, and different extents of intellectual disability without or with epilepsy. However, the underlying mechanisms remain unclear. To investigate the pathological role of mutant ATP6V1B2 in the auditory system, we evaluated auditory brainstem response, distortion product otoacoustic emissions, in a transgenic line of mice carrying c.1516 C > T (p.Arg506∗) in Atp6v1b2, Atp6v1b2Arg506*/Arg506*. To explore the pathogenic mechanism of neurodegeneration in the auditory pathway, immunostaining, western blotting, and RNAscope analyses were performed in Atp6v1b2Arg506*/Arg506* mice. The Atp6v1b2Arg506*/Arg506* mice showed hidden hearing loss (HHL) at early stages and developed late-onset hearing loss. We observed increased transcription of Atp6v1b1 in hair cells of Atp6v1b2Arg506*/Arg506* mice and inferred that Atp6v1b1 compensated for the Atp6v1b2 dysfunction by increasing its own transcription level. Genetic compensation in hair cells explains the milder hearing impairment in Atp6v1b2Arg506*/Arg506* mice. Apoptosis activated by lysosomal dysfunction and the subsequent blockade of autophagic flux induced the degeneration of spiral ganglion neurons and further impaired the hearing. Intraperitoneal administration of the apoptosis inhibitor, BIP-V5, improved both phenotypical and pathological outcomes in two live mutant mice. Based on the pathogenesis underlying hearing loss in Atp6v1b2-related syndromes, systemic drug administration to inhibit apoptosis might be an option for restoring the function of spiral ganglion neurons and promoting hearing, which provides a direction for future treatment.

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