scholarly journals Anti-PD-1 Therapy Does Not Influence Hearing Ability in the Most Sensitive Frequency Range, but Mitigates Outer Hair Cell Loss in the Basal Cochlear Region

2020 ◽  
Vol 21 (18) ◽  
pp. 6701
Author(s):  
Judit Szepesy ◽  
Gabriella Miklós ◽  
János Farkas ◽  
Dániel Kucsera ◽  
Zoltán Giricz ◽  
...  
Keyword(s):  
Outer Hair Cell ◽  
Checkpoint Inhibitors ◽  
Spiral Ganglion ◽  
Auditory Brainstem ◽  
Outer Hair Cells ◽  
Antibody Treatment ◽  
High Frequency Region ◽  
Age Related ◽  
Brainstem Response ◽  
Ganglion Neurons

The administration of immune checkpoint inhibitors (ICIs) often leads to immune-related adverse events. However, their effect on auditory function is largely unexplored. Thorough preclinical studies have not been published yet, only sporadic cases and pharmacovigilance reports suggest their significance. Here we investigated the effect of anti-PD-1 antibody treatment (4 weeks, intraperitoneally, 200 μg/mouse, 3 times/week) on hearing function and cochlear morphology in C57BL/6J mice. ICI treatment did not influence the hearing thresholds in click or tone burst stimuli at 4–32 kHz frequencies measured by auditory brainstem response. The number and morphology of spiral ganglion neurons were unaltered in all cochlear turns. The apical-middle turns (<32 kHz) showed preservation of the inner and outer hair cells (OHCs), whilst ICI treatment mitigated the age-related loss of OHCs in the basal turn (>32 kHz). The number of Iba1-positive macrophages has also increased moderately in this high frequency region. We conclude that a 4-week long ICI treatment does not affect functional and morphological integrity of the inner ear in the most relevant hearing range (4–32 kHz; apical-middle turns), but a noticeable preservation of OHCs and an increase in macrophage activity appeared in the >32 kHz basal part of the cochlea.

scholarly journals Inner ear pathology and loss of hearing in estrogen receptor-β deficient mice

2009 ◽  
Vol 201 (3) ◽  
pp. 397-406 ◽  
Author(s):  
Rusana Simonoska ◽  
Annika E Stenberg ◽  
Maoli Duan ◽  
Konstantin Yakimchuk ◽  
Anders Fridberger ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Inner Ear ◽  
Spiral Ganglion ◽  
Organ Of Corti ◽  
Auditory Brainstem ◽  
Estrogen Receptor Β ◽  
Knock Out ◽  
Age Related ◽  
Brainstem Response ◽  
Knock Out Mice

There are well known differences between males and females in hearing. In the present study, the role of estrogen receptor-β (ER-β; listed as ESR2 in the MGI Database) in hearing was investigated by comparing hearing and morphology of the inner ear in ER-β knock-out mice (ER-β−/−) with that of wild-type (WT) littermates. Hearing was analyzed with auditory brainstem response audiometry at 3 and 12 months. The ER-β−/− mice were deaf at 1 year of age, and the morphological analysis showed absence of hair cells and loss of the whole organ of Corti initiated in the basal turn of the cochlea. Furthermore, in ER-β−/−, but not in WT mice, the spiral ganglion was lacking many of its neurons. Immunostaining showed the presence of both ER-α (listed as ESR1 in the MGI Database) and ER-β in the nuclei of some neurons in the inner ear in WT mice, but no ER-β was found in the ER-β−/− mice as expected. ER-α staining was predominant in the nuclei of large neurons and ER-β in nuclei of small neurons and fibroblasts. These results reveal that both ERs are present in the inner ear at specific localizations suggesting subtype-specific functions. It is concluded that ER-β is important for the prevention of age-related hearing loss. These findings strengthen the hypothesis that estrogen has a direct effect on hearing functions.

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 Deletion of Oncomodulin Gives Rise to Early Progressive Cochlear Dysfunction in C57 and CBA Mice

2021 ◽  
Vol 13 ◽  
Author(s):  
Leslie K. Climer ◽  
Aubrey J. Hornak ◽  
Kaitlin Murtha ◽  
Yang Yang ◽  
Andrew M. Cox ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Cell Function ◽  
Otoacoustic Emission ◽  
Cell Types ◽  
Auditory Brainstem ◽  
Outer Hair Cells ◽  
Distortion Product Otoacoustic Emission ◽  
Distortion Product ◽  
Age Related ◽  
Brainstem Response

Ca2+ signaling is a major contributor to sensory hair cell function in the cochlea. Oncomodulin (OCM) is a Ca2+ binding protein (CaBP) preferentially expressed in outer hair cells (OHCs) of the cochlea and few other specialized cell types. Here, we expand on our previous reports and show that OCM delays hearing loss in mice of two different genetic backgrounds: CBA/CaJ and C57Bl/6J. In both backgrounds, genetic disruption of Ocm leads to early progressive hearing loss as measured by auditory brainstem response (ABR) and distortion product otoacoustic emission (DPOAE). In both strains, loss of Ocm reduced hearing across lifetime (hearing span) by more than 50% relative to wild type (WT). Even though the two WT strains have very different hearing spans, OCM plays a considerable and similar role within their genetic environment to regulate hearing function. The accelerated age-related hearing loss (ARHL) of the Ocm KO illustrates the importance of Ca2+ signaling in maintaining hearing health. Manipulation of OCM and Ca2+ signaling may reveal important clues to the systems of function/dysfunction that lead to ARHL.

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.

Does Oral Monosodium Glutamate Have a Cochleotoxic Effect? An Experimental Study

2021 ◽  
pp. 1-13
Author(s):  
Selis Gulseven Guven ◽  
Onur Ersoy ◽  
Ruhan Deniz Topuz ◽  
Erdoğan Bulut ◽  
Gulnur Kizilay ◽  
...  
Keyword(s):  
Guinea Pigs ◽  
Outer Hair Cell ◽  
Monosodium Glutamate ◽  
Auditory Brainstem ◽  
Outer Hair Cells ◽  
Control Group ◽  
Distortion Product Otoacoustic Emission ◽  
Distortion Product ◽  
Significant Difference ◽  
Brainstem Response

<b><i>Introduction:</i></b> The effect of orally consumed monosodium glutamate (MSG), which is a common additive in the food industry, on the cochlea has not been investigated. The present study aimed to investigate the possible cochleotoxic effects of oral MSG in guinea pigs using electrophysiological, biochemical, and histopathological methods. <b><i>Methods:</i></b> Thirty guinea pigs were equally divided into control and intervention groups (MSG 100 mg/kg/day; MSG 300 mg/kg/day). At 1 month, 5 guinea pigs from each group were sacrificed; the rest were observed for another month. Electrophysiological measurements (distortion product otoacoustic emission [DPOAE] and auditory brainstem response [ABR]), glutamate levels in the perilymph and blood samples, and histopathological examinations were evaluated at 1 and 2 months. <b><i>Results:</i></b> Change in signal-to-noise ratio at 2 months was significantly different in the MSG 300 group at 0.75 kHz and 2 kHz (<i>p</i> = 0.013 and <i>p</i> = 0.044, respectively). There was no statistically significant difference in ABR wave latencies of the guinea pigs given MSG compared to the control group after 1 and 2 months; an increase was noted in ABR thresholds, although the difference was not statistically significant. In the MSG groups, moderate-to-severe degeneration and cell loss in outer hair cells, support cells, and spiral ganglia, lateral surface junction irregularities, adhesions in stereocilia, and partial loss of outer hair cell stereocilia were noted. <b><i>Conclusion:</i></b> MSG, administered in guinea pigs at a commonly utilized quantity and route of administration in humans, may be cochleotoxic.

scholarly journals Oncomodulin Delays Age-Related Hearing Loss in C57 and CBA Mice

2021 ◽  
Author(s):  
Leslie K Climer ◽  
Aubrey J Hornak ◽  
Kaitlin Murtha ◽  
Yang Yang ◽  
Andrew M Cox ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Cell Function ◽  
Otoacoustic Emission ◽  
Auditory Brainstem ◽  
Outer Hair Cells ◽  
Distortion Product Otoacoustic Emission ◽  
Progressive Hearing Loss ◽  
Distortion Product ◽  
Age Related ◽  
Brainstem Response

Ca2+ signaling is a major contributor to sensory hair cell function in the cochlea. Oncomodulin (OCM) is a Ca2+ binding protein preferentially expressed in outer hair cells of the cochlea and few other specialized cell types. Here, we expand on our previous reports and show that OCM prevents early progressive hearing loss in mice of two different genetic backgrounds: CBA/CaJ and C57Bl/6J. In both backgrounds, genetic disruption of Ocm leads to early progressive hearing loss as measured by auditory brainstem response (ABR) and distortion product otoacoustic emission (DPOAE). In both strains, loss of Ocm reduced hearing across lifetime (hearing span) by more than 50% relative to wild type (WT). Even though the two WT strains have very different hearing spans, OCM plays a considerable and similar role within their genetic environment to regulate hearing function. The accelerated ARHL of the Ocm KO illustrates the importance of Ca2+ signaling in maintaining hearing health.

scholarly journals Contralateral Suppression of DPOAEs in Mice after Ouabain Treatment

2018 ◽  
Vol 2018 ◽  
pp. 1-8 ◽  
Author(s):  
Jieying Li ◽  
Yan Chen ◽  
Shan Zeng ◽  
Chuijin Lai ◽  
Yanping Zhang ◽  
...  
Keyword(s):  
Otoacoustic Emissions ◽  
Round Window ◽  
Spiral Ganglion ◽  
Auditory Brainstem ◽  
Spiral Ganglion Neurons ◽  
Type I ◽  
Type Ii ◽  
Contralateral Suppression ◽  
Brainstem Response ◽  
Ganglion Neurons

Medial olivocochlear (MOC) efferent feedback is suggested to protect the ear from acoustic injury and to increase its ability to discriminate sounds against a noisy background. We investigated whether type II spiral ganglion neurons participate in the contralateral suppression of the MOC reflex. The application of ouabain to the round window of the mouse cochlea selectively induced the apoptosis of the type I spiral ganglion neurons, left the peripherin-immunopositive type II spiral ganglion neurons intact, and did not affect outer hairs, as evidenced by the maintenance of the distorted product otoacoustic emissions (DPOAEs). With the ouabain treatment, the threshold of the auditory brainstem response increased significantly and the amplitude of wave I decreased significantly in the ouabain-treated ears, consistent with the loss of type I neurons. Contralateral suppression was measured as reduction in the amplitude of the 2f1−f2 DPOAEs when noise was presented to the opposite ear. Despite the loss of all the type I spiral ganglion neurons, virtually, the amplitude of the contralateral suppression was not significantly different from the control when the suppressor noise was delivered to the treated cochlea. These results are consistent with the type II spiral ganglion neurons providing the sensory input driving contralateral suppression of the MOC reflex.

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.

scholarly journals Age-Related Hearing Loss in Mn-SOD Heterozygous Knockout Mice

2013 ◽  
Vol 2013 ◽  
pp. 1-12 ◽  
Author(s):  
Makoto Kinoshita ◽  
Takashi Sakamoto ◽  
Akinori Kashio ◽  
Takahiko Shimizu ◽  
Tatsuya Yamasoba
Keyword(s):  
Hearing Loss ◽  
Manganese Superoxide Dismutase ◽  
Stria Vascularis ◽  
Spiral Ganglion ◽  
Cell Loss ◽  
Auditory Brainstem ◽  
Spiral Ganglion Cell ◽  
Age Related ◽  
Brainstem Response ◽  
Age Related Hearing Loss

Age-related hearing loss (AHL) reduces the quality of life for many elderly individuals. Manganese superoxide dismutase (Mn-SOD), one of the antioxidant enzymes acting within the mitochondria, plays a crucial role in scavenging reactive oxygen species (ROS). To determine whether reduction in Mn-SOD accelerates AHL, we evaluated auditory function in Mn-SOD heterozygous knockout (HET) mice and their littermate wild-type (WT) C57BL/6 mice by means of auditory brainstem response (ABR). Mean ABR thresholds were significantly increased at 16 months when compared to those at 4 months in both WT and HET mice, but they did not significantly differ between them at either age. The extent of hair cell loss, spiral ganglion cell density, and thickness of the stria vascularis also did not differ between WT and HET mice at either age. At 16 months, immunoreactivity of 8-hydroxydeoxyguanosine was significantly greater in the SGC and SV in HET mice compared to WT mice, but that of 4-hydroxynonenal did not differ between them. These findings suggest that, although decrease of Mn-SOD by half may increase oxidative stress in the cochlea to some extent, it may not be sufficient to accelerate age-related cochlear damage under physiological aging process.

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