scholarly journals Pyroptosis Accelerates Spiral Ganglion Neuronal Degeneration Induced by Aminoglycosides in the Cochlea

2021 ◽  
Author(s):  
Yazhi Xing ◽  
Jia Fang ◽  
Zhuangzhuang Li ◽  
Mingxian Li ◽  
Chengqi Liu ◽  
...  
Keyword(s):  
Cell Death ◽  
Rna Sequencing ◽  
Hair Cells ◽  
Nlrp3 Inflammasome ◽  
Auditory Brainstem Response ◽  
Spiral Ganglion ◽  
Auditory Brainstem ◽  
Response Threshold ◽  
Brainstem Response ◽  
Ganglion Neurons

Abstract Background In aminoglycoside-induced hearing loss, damage to spiral ganglion neurons (SGNs) accelerates gradually after the acute outer hair cell death, accompanied by macrophage infiltration and cytokine release. Pyroptosis plays a critical role in neurodegenerative diseases. Here, we explored the potential role of pyroptosis in SGN degeneration. Methods C57BL/6J mice were randomly divided into a kanamycin plus furosemide group and saline control group. Auditory functions were evaluated by auditory brainstem response tests conducted before treatment and at 1, 5, 15, and 30 days after treatment. HCs and SGNs were assessed for morphological alterations. SGNs were subjected to RNA sequencing and mRNA and protein analyses of NLRP3 inflammasome-related molecules. Macrophage activation was evaluated based on morphological and mRNA alterations. The effect of NLRP3 inhibition on SGN survival after kanamycin treatment was evaluated in organ explant cultures treated with Mcc950, a specific inhibitor of the NLRP3 inflammasome. Results Kanamycin and furosemide administration led to irreversible deterioration of the auditory brainstem response threshold, accompanied by acute loss of outer hair cells and gradually progressive loss of inner hair cells. SGNs showed a progressive decrease in quantity, as well as swelling and membrane rupture, at 15 and 30 days. RNA sequencing of SGNs showed that inflammation and immune-related responses were significantly upregulated, as was the expression of the inflammasome-related gene NLRP3. During 30 days of kanamycin exposure, the canonical pyroptosis pathway was constantly activated in SGNs. Activation and infiltration of microglia-like cells/macrophages, and increased production of cytokines, hallmarks of neuroinflammation, were also observed. Mcc950 significantly ameliorated SGN degeneration by inhibiting NLRP3 expression and promoting release of interleukins 1β and 18. Conclusions Pyroptosis causes cell death during aminoglycoside-induced SGN degeneration. Activation of the NLRP3 inflammasome leads to a cascade of inflammatory events in SGNs. Inhibition of the NLRP3 inflammasome significantly alleviates SGN damage, suggesting that it could serve as a new molecular target for the treatment of aminoglycoside-induced SGN degeneration.

scholarly journals Cisplatin-Induced Ototoxicity in Rats Is Driven by RIP3-Dependent Necroptosis

Cells ◽  
2019 ◽  
Vol 8 (5) ◽  
pp. 409 ◽  
Author(s):  
Mi-Jin Choi ◽  
Hyunsook Kang ◽  
Yun Yeong Lee ◽  
Oak-Sung Choo ◽  
Jeong Hun Jang ◽  
...  
Keyword(s):  
Cell Death ◽  
Spiral Ganglion ◽  
Organ Of Corti ◽  
Auditory Brainstem ◽  
Sprague Dawley ◽  
Western Blots ◽  
Brainstem Response ◽  
Ganglion Neurons

Cisplatin-induced early-onset ototoxicity is linked to hearing loss. The mechanism by which cisplatin causes ototoxicity remains unclear. The purpose of this study was to identify the involvement of receptor-interacting protein kinase (RIP)3-dependent necroptosis in cisplatin-induced ototoxicity in vitro and in vivo. Sprague–Dawley rats (SD, 8 week) were treated via intraperitoneal (i.p.) injection with cisplatin (16 mg/kg for 1 day), and their hearing thresholds were measured by the auditory brainstem response (ABR) method. Hematoxylin and eosin (H & E) staining, immunohistochemistry, and western blots were performed to determine the effect of cisplatin-induced ototoxicity on cochlear morphology. Inhibitor experiments with necrostatin 1 (Nec-1) and Z-VAD were also performed in HEI-OC1 cell line. H&E stains revealed that the necroptotic changes were increased in the organ of Corti (OC) and spiral ganglion neurons (SGNs). Moreover, immunohistochemistry and western blot analysis showed that cisplatin treatment increased the protein levels of RIP3 in both OCs and SGNs. The treatment of Nec-1, a selective RIP1 inhibitor, resulted in markedly suppression of cisplatin-induced cell death in HEI-OC1 cells, whereas Z-VAD treatment did not change the cisplatin-induced cell death. Our results suggest that RIP3-dependent necroptosis was substantial in cisplatin-induced ototoxicity; inner cochlear regions, the OCs, and SGNs were especially sensitive to necroptosis.

Protective effects of brain-derived neurotrophic factor on the noise-damaged cochlear spiral ganglion

2010 ◽  
Vol 125 (5) ◽  
pp. 449-454 ◽  
Author(s):  
S-Q Zhai ◽  
W Guo ◽  
Y-Y Hu ◽  
N Yu ◽  
Q Chen ◽  
...  
Keyword(s):  
Neurotrophic Factor ◽  
Auditory Brainstem Response ◽  
Noise Exposure ◽  
Recombinant Adenovirus ◽  
Spiral Ganglion ◽  
Brain Derived Neurotrophic Factor ◽  
Auditory Brainstem ◽  
Response Threshold ◽  
Protective Effects ◽  
Brainstem Response

AbstractObjective:To explore the protective effects of brain-derived neurotrophic factor on the noise-damaged cochlear spiral ganglion.Methods:Recombinant adenovirus brain-derived neurotrophic factor vector, recombinant adenovirus LacZ and artificial perilymph were prepared. Guinea pigs with audiometric auditory brainstem response thresholds of more than 75 dB SPL, measured seven days after four hours of noise exposure at 135 dB SPL, were divided into three groups. Adenovirus brain-derived neurotrophic factor vector, adenovirus LacZ and perilymph were infused into the cochleae of the three groups, variously. Eight weeks later, the cochleae were stained immunohistochemically and the spiral ganglion cells counted.Results:The auditory brainstem response threshold recorded before and seven days after noise exposure did not differ significantly between the three groups. However, eight weeks after cochlear perfusion, the group receiving brain-derived neurotrophic factor had a significantly decreased auditory brainstem response threshold and increased spiral ganglion cell count, compared with the adenovirus LacZ and perilymph groups.Conclusion:When administered via cochlear infusion following noise damage, brain-derived neurotrophic factor appears to improve the auditory threshold, and to have a protective effect on the spiral ganglion cells.

Effect of early postnatal air-conduction auditory deprivation on the development and function of the rat spiral ganglion

2011 ◽  
Vol 125 (9) ◽  
pp. 917-923 ◽  
Author(s):  
F Wang ◽  
X Gao ◽  
J Chen ◽  
S-L Liu ◽  
F-Y Wang ◽  
...  
Keyword(s):  
Auditory Brainstem Response ◽  
Spiral Ganglion ◽  
Auditory Brainstem ◽  
Type I ◽  
Cochlear Function ◽  
Auditory Deprivation ◽  
Brainstem Response ◽  
Ganglion Neurons ◽  
And Function ◽  
Air Conduction

AbstractObjective:To evaluate the effect of early postnatal air-conduction auditory deprivation on the development and function of the rat spiral ganglion.Study design:Randomised animal study.Methods:Sixty neonatal Sprague–Dawley rats were randomly divided into two groups: controls (n = 30) given regular chow and water ad libitum; and study animals (n = 30) fed within a soundproof chamber. Auditory brainstem response testing was conducted in both groups on postnatal day 42.Results:Auditory deprivation between postnatal days 12 and 42 resulted in an increased hearing threshold and reduced auditory brainstem response amplitudes, together with degeneration of type I spiral ganglion neurons and the presence of apoptotic cells.Conclusion:Non-invasive auditory deprivation during a critical developmental period resulted in numerous changes in rat cochlear function and morphology.

Low-Frequency Auditory Brainstem Response Threshold

1988 ◽  
Vol 17 (3) ◽  
pp. 171-178 ◽  
Author(s):  
E. Laukli ◽  
O. Fjermedal ◽  
I. W. S. Mair
Keyword(s):  
Auditory Brainstem Response ◽  
Low Frequency ◽  
Auditory Brainstem ◽  
Response Threshold ◽  
Brainstem Response

scholarly journals Protection of cochlear synapses from noise-induced excitotoxic trauma by blockade of Ca2+-permeable AMPA receptors

2020 ◽  
Vol 117 (7) ◽  
pp. 3828-3838 ◽  
Author(s):  
Ning Hu ◽  
Mark A. Rutherford ◽  
Steven H. Green
Keyword(s):  
Ampa Receptors ◽  
Spiral Ganglion ◽  
Auditory Brainstem ◽  
Spiral Ganglion Neurons ◽  
Loud Sound ◽  
Selective Blockade ◽  
Hearing Thresholds ◽  
Brainstem Response ◽  
Low Threshold ◽  
Ganglion Neurons

Exposure to loud sound damages the postsynaptic terminals of spiral ganglion neurons (SGNs) on cochlear inner hair cells (IHCs), resulting in loss of synapses, a process termed synaptopathy. Glutamatergic neurotransmission via α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)-type receptors is required for synaptopathy, and here we identify a possible involvement of GluA2-lacking Ca2+-permeable AMPA receptors (CP-AMPARs) using IEM-1460, which has been shown to block GluA2-lacking AMPARs. In CBA/CaJ mice, a 2-h exposure to 100-dB sound pressure level octave band (8 to 16 kHz) noise results in no permanent threshold shift but does cause significant synaptopathy and a reduction in auditory brainstem response (ABR) wave-I amplitude. Chronic intracochlear perfusion of IEM-1460 in artificial perilymph (AP) into adult CBA/CaJ mice prevented the decrease in ABR wave-I amplitude and the synaptopathy relative to intracochlear perfusion of AP alone. Interestingly, IEM-1460 itself did not affect the ABR threshold, presumably because GluA2-containing AMPARs can sustain sufficient synaptic transmission to evoke low-threshold responses during blockade of GluA2-lacking AMPARs. On individual postsynaptic densities, we observed GluA2-lacking nanodomains alongside regions with robust GluA2 expression, consistent with the idea that individual synapses have both CP-AMPARs and Ca2+-impermeable AMPARs. SGNs innervating the same IHC differ in their relative vulnerability to noise. We found local heterogeneity among synapses in the relative abundance of GluA2 subunits that may underlie such differences in vulnerability. We propose a role for GluA2-lacking CP-AMPARs in noise-induced cochlear synaptopathy whereby differences among synapses account for differences in excitotoxic susceptibility. These data suggest a means of maintaining normal hearing thresholds while protecting against noise-induced synaptopathy, via selective blockade of CP-AMPARs.

Mitochondria-Targeted Antioxidant Mitoquinone Reduces Cisplatin-Induced Ototoxicity in Guinea Pigs

2016 ◽  
Vol 156 (3) ◽  
pp. 543-548 ◽  
Author(s):  
Alan D. Tate ◽  
Patrick J. Antonelli ◽  
Kyle R. Hannabass ◽  
Carolyn O. Dirain
Keyword(s):  
Hearing Loss ◽  
Auditory Brainstem Response ◽  
Guinea Pigs ◽  
Outer Hair Cell ◽  
Auditory Brainstem ◽  
Response Threshold ◽  
Saline Control ◽  
Control Group ◽  
Cochlear Hair Cells ◽  
Brainstem Response

Objective To determine if mitoquinone (MitoQ) attenuates cisplatin-induced hearing loss in guinea pigs. Study Design Prospective and controlled animal study. Setting Academic, tertiary medical center. Subjects and Methods Guinea pigs were injected subcutaneously with either 5 mg/kg MitoQ (n = 9) or normal saline (control, n = 9) for 7 days and 1 hour before receiving a single dose of 10 mg/kg cisplatin. Auditory brainstem response thresholds were measured before MitoQ or saline administration and 3 to 4 days after cisplatin administration. Results Auditory brainstem response threshold shifts after cisplatin treatment were smaller by 28 to 47 dB in guinea pigs injected with MitoQ compared with those in the control group at all tested frequencies (4, 8, 16, and 24 kHz, P = .0002 to .04). Scanning electron microscopy of cochlear hair cells showed less outer hair cell loss and damage in the MitoQ group. Conclusion MitoQ reduced cisplatin-induced hearing loss in guinea pigs. MitoQ appears worthy of further investigation as a means of preventing cisplatin ototoxicity in humans.

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