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The Journal of Biological Chemistry Jun 2024Hearing crucially depends on cochlear ion homeostasis as evident from deafness elicited by mutations in various genes encoding cation or anion channels and transporters....
Hearing crucially depends on cochlear ion homeostasis as evident from deafness elicited by mutations in various genes encoding cation or anion channels and transporters. Ablation of ClC‑K/barttin chloride channels causes deafness by interfering with the positive electrical potential of the endolymph, but roles of other anion channels in the inner ear have not been studied. Here we report the intracochlear distribution of all five LRRC8 subunits of VRAC, a volume-regulated anion channel that transports chloride, metabolites, and drugs such as the ototoxic anti-cancer drug cisplatin, and explore its physiological role by ablating its subunits. Sensory hair cells express all LRRC8 isoforms, whereas only LRRC8A, D and E were found in the potassium-secreting epithelium of the stria vascularis. Cochlear disruption of the essential LRRC8A subunit, or combined ablation of LRRC8D and E, resulted in cochlear degeneration and congenital deafness of Lrrc8a mice. It was associated with a progressive degeneration of the organ of Corti and its innervating spiral ganglion. Like disruption of ClC-K/barttin, loss of VRAC severely reduced the endocochlear potential. However, the mechanism underlying this reduction seems different. Disruption of VRAC, but not ClC-K/barttin, led to an almost complete loss of Kir4.1 (KCNJ10), a strial K channel crucial for the generation of the endocochlear potential. The strong downregulation of Kir4.1 might be secondary to a loss of VRAC-mediated transport of metabolites regulating inner ear redox potential such as glutathione. Our study extends the knowledge of the role of cochlear ion transport in hearing and ototoxicity.
PubMed: 38838775
DOI: 10.1016/j.jbc.2024.107436 -
International Journal of Cancer Jan 2024The impact of the temporal sequence by which cranial radiotherapy (CRT) and platin-based chemotherapy (PCth) are administered on sensorineural hearing loss (SNHL) in...
The impact of the temporal sequence of cranial radiotherapy and platin-based chemotherapy on hearing impairment in pediatric and adolescent CNS and head-and-neck cancer patients: A report from the PanCareLIFE consortium.
The impact of the temporal sequence by which cranial radiotherapy (CRT) and platin-based chemotherapy (PCth) are administered on sensorineural hearing loss (SNHL) in pediatric and adolescent central nervous system (CNS) and head-and-neck (HN) cancer patients has not yet been studied in detail. We examined the ototoxic effects of sequentially applied CRT and PCth. This study included children and adolescents with CNS and HN tumors who participated in the multicountry PanCareLIFE (PCL) consortium. Audiological outcomes were compared between patients who received CRT prior to PCth and those who received it afterwards. The incidence, degree and posttreatment progression of SNHL, defined as Muenster classification grade ≥MS2b, were evaluated in 141 patients. One hundred and nineteen patients were included in a time-to-onset analysis. Eighty-eight patients received CRT prior to PCth (Group 1) and 53 patients received PCth before CRT (Group 2). Over a median follow-up time of 1.6 years, 72.7% of patients in Group 1 experienced SNHL ≥ MS2b compared to 33.9% in Group 2 (P < .01). A time-to-onset analysis was performed for 74 patients from Group 1 and 45 patients from Group 2. Median time to hearing loss (HL) ≥ MS2b was 1.2 years in Group 1 and 4.4 years in Group 2 (P < .01). Thus, audiological outcomes were better for patients who received CRT after PCth than before. This finding should be further evaluated and considered within clinical practice in order to minimize hearing loss in children and adolescents with CNS and HN tumors.
Topics: Humans; Child; Adolescent; Hearing Loss; Central Nervous System; Hearing Loss, Sensorineural; Cranial Irradiation; Head and Neck Neoplasms
PubMed: 37715472
DOI: 10.1002/ijc.34732 -
BioRxiv : the Preprint Server For... Jan 2024Cisplatin is a commonly used chemotherapy that causes permanent hearing loss by injuring cochlear hair cells. The underlying mechanisms that drive hair cell loss remain...
Cisplatin is a commonly used chemotherapy that causes permanent hearing loss by injuring cochlear hair cells. The underlying mechanisms that drive hair cell loss remain unknown, but mitochondria have emerged as potential mediators of cisplatin ototoxicity. Direct observation of changes in hair cell mitochondrial function are challenging because the mammalian inner ear is optically inaccessible. Here, we perform live imaging of hair cells within the zebrafish lateral-line organ to evaluate the role of mitochondria in cisplatin ototoxicity. Using a genetically encoded biosensor that measures cumulative mitochondrial activity in hair cells, we demonstrate that greater redox history increases susceptibility to cisplatin. Next, we conduct time-lapse imaging of individual hair cells to understand dynamic changes in mitochondrial homeostasis. We observe spikes in mitochondrial calcium and cytosolic calcium immediately prior to hair cell death. Furthermore, we use a mitochondrially-localized probe that fluoresces in the presence of cisplatin to show that cisplatin accumulates in hair cell mitochondria. Lastly, we demonstrate that this accumulation occurs before mitochondrial dysregulation, Caspase-3 activation, and ultimately, hair cell death. Our findings provide additional evidence that suggest mitochondria are integral to cisplatin ototoxicity and cisplatin directly targets hair cell mitochondria.
PubMed: 38352581
DOI: 10.1101/2024.01.29.577846 -
Journal of Speech, Language, and... Aug 2023Distortion product otoacoustic emissions (DPOAEs) provide an objective assessment of cochlear function and are used for serial ototoxicity monitoring in pediatric cancer...
PURPOSE
Distortion product otoacoustic emissions (DPOAEs) provide an objective assessment of cochlear function and are used for serial ototoxicity monitoring in pediatric cancer patients. DPOAEs are modeled as having distortion (near ) and reflection (near 2-) component sources, and developmental changes are observed in these components' relative strengths in infants compared with adults. However, little is known about source component strengths in childhood or at extended high frequencies (EHFs; > 8 kHz). Thus, the purpose of this study was to describe the effects of age and stimulus frequency on DPOAE components in children.
METHOD
DPOAEs were collected with varied frequency ratios (/ = 1.1-1.25) for a wide range of frequencies (2-16 kHz) in 39 younger (3-6 years) and 41 older (10-12 years) children with constant levels (L/L) of 65/50 dB SPL. A depth-compensated simulator sound pressure level method of calibration was employed. A time waveform representation of the results across various ratios was created to estimate peak pressures and latencies of each DPOAE component.
RESULTS
Estimated peak pressures of DPOAE components revealed the greatest differences in DPOAE sources between children occurring at the highest frequencies tested, where the peak pressure of both components was largest for younger compared with older children. Latency differences between the children were only noted at higher frequencies for the distortion component.
CONCLUSIONS
These results suggest that DPOAE levels decrease with age and reflection emissions are vulnerable to cochlear change. This work guides optimization of protocols for pediatric ototoxicity monitoring, whereby including EHF otoacoustic emissions is clearly warranted and choosing to isolate DPOAE sources may prove beneficial.
SUPPLEMENTAL MATERIAL
https://doi.org/10.23641/asha.23669214.
Topics: Child; Humans; Acoustic Stimulation; Calibration; Cochlea; Otoacoustic Emissions, Spontaneous; Ototoxicity; Child, Preschool
PubMed: 37467378
DOI: 10.1044/2023_JSLHR-23-00013 -
ACS Infectious Diseases Aug 2023Complementing our earlier syntheses of the gentamicins B1, C1a, C2b, and X2, we describe the synthesis of gentamicins C1, C2, and C2a characterized by methyl...
Complementing our earlier syntheses of the gentamicins B1, C1a, C2b, and X2, we describe the synthesis of gentamicins C1, C2, and C2a characterized by methyl substitution at the 6'-position, and so present an alternative access to previous chromatographic methods for accessing these sought-after compounds. We describe the antiribosomal activity of our full set of synthetic gentamicin congeners against bacterial ribosomes and hybrid ribosomes carrying the decoding A site of the human mitochondrial, A1555G mutant mitochondrial, and cytoplasmic ribosomes and establish structure-activity relationships with the substitution pattern around ring I to antiribosomal activity, antibacterial resistance due to the presence of aminoglycoside acetyl transferases acting on the 6'-position in ring I, and literature cochlear toxicity data.
Topics: Humans; Gentamicins; Anti-Bacterial Agents; Aminoglycosides
PubMed: 37481733
DOI: 10.1021/acsinfecdis.3c00233 -
Turkish Archives of Otorhinolaryngology Sep 2023To investigate the effects of cross-linked hyaluronic acid (CLHA) in an experimental model of vestibulotoxicity and cochleotoxicity.
OBJECTIVE
To investigate the effects of cross-linked hyaluronic acid (CLHA) in an experimental model of vestibulotoxicity and cochleotoxicity.
METHODS
Twenty-eight female Wistar albino rats (200-250 g) were divided into four groups. Group A received 0.06 mL of 13.33 mg/mL gentamicin, Group B received 0.06 mL of CLHA, Group C received 0.03 mL of 26.66 mg/mL gentamicin and 0.03 mL CLHA, and Group D received 0.06 mL of 0.09% saline. All groups underwent auditory brainstem response testing at 4-32 kHz, signal-to-noise ratio of distortion product otoacoustic emission measurements at 1.5-8 kHz and vestibular tests on days 0,1,7,10. The rats were sacrificed, and their labyrinths were histologically assessed and scored.
RESULTS
The hearing thresholds of Groups A and C were similar and significantly higher than those of the other groups at all frequencies, beginning from day 1. The vestibular and histological scores of Groups A and C were similar and significantly higher than those of the other groups from day 1. The audiological results, vestibular scores, and histological scores of Groups B and D were similar, except for a temporary middle ear effusion and hearing threshold shift in Group B. No significant deterioration was observed in the audiological, vestibular, and histological analyses of Groups B and D.
CONCLUSION
That both Group A and Group C similarly showed worsening audiological, vestibular, and histological tests suggests that CLHA did not alter the pharmacokinetics and histologic results of gentamicin.
PubMed: 38020411
DOI: 10.4274/tao.2023.2023-5-14 -
Redox Report : Communications in Free... Dec 2023Cisplatin-induced ototoxicity is caused by reactive oxygen species. It has been recognized that estradiol (E2) regulates redox balance. However, little is known about...
Cisplatin-induced ototoxicity is caused by reactive oxygen species. It has been recognized that estradiol (E2) regulates redox balance. However, little is known about the protective mechanisms of E2 against cisplatin-induced ototoxicity. In this study, we investigated the effect of E2 on nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated hair cell protection using the organ of Corti isolated from mice. The organ of Corti collected from C57BL/6 mice at 3-5 postnatal days was used in all experiments. The organ of Corti was exposed to 20 μM cisplatin with/without 100 nM E2 to examine the effect of E2 on cisplatin-induced hair cell loss. The mRNA expression of Nrf2 and the phase II detoxification gene after E2 and cisplatin treatment was analyzed using quantitative real-time PCR. E2 significantly reduces cisplatin-induced cochlear hair cell death. In addition, 100 nM E2 increased the mRNA expression of Nrf2 and phase II detoxification genes in the organ of Corti under cisplatin treatment. Our results suggest that E2 activates Nrf2, phase II detoxification enzymes and exerts a protective effect against cisplatin-induced ototoxicity.
Topics: Mice; Animals; Cisplatin; NF-E2-Related Factor 2; Ototoxicity; Estradiol; Apoptosis; Mice, Inbred C57BL; Hair Cells, Auditory; Reactive Oxygen Species; RNA, Messenger; Antineoplastic Agents
PubMed: 36661237
DOI: 10.1080/13510002.2022.2161224 -
Audiology Research Oct 2023Ototoxic drugs can result in hearing loss and tinnitus. Early detection of the ototoxic process can help minimize or prevent these consequences. The American...
Ototoxic drugs can result in hearing loss and tinnitus. Early detection of the ototoxic process can help minimize or prevent these consequences. The American Speech-Language-Hearing Association has provided guidelines for monitoring ototoxicity, whereas Italy has not yet implemented a national monitoring protocol. This study aims to assess the current state of ototoxicity monitoring in patients receiving cisplatin therapy. A self-administered survey has been used to gather information from oncologists, audiologists, and ENT specialists. The research was conducted at Santa Maria della Misericordia hospital in Perugia. Two questionnaires were administered, one to ENT/audiology specialists and another to oncology specialists. Both questionnaires were used to collect information on awareness of chemotherapy-induced ototoxicity. A comprehensive understanding of cisplatin-induced ototoxicity has been widely established (100%). The most commonly reported audiological symptoms by patients were hearing loss (100%) and tinnitus (87.5%). The majority of ENT and audiologists (93.8%) and oncologists (92.9%) expressed the need for a specific ototoxic monitoring program. However, they noted the absence of a well-defined ototoxicity monitoring protocol. A well-established and efficient ototoxic monitoring system facilitates early detection of ototoxic hearing loss and subsequent rehabilitation of inevitable hearing impairment.
PubMed: 37887850
DOI: 10.3390/audiolres13050069 -
Journal of Investigative Medicine : the... Apr 2024Cisplatin use is often limited by its ototoxic side effects, which can lead to irreversible hearing loss. Preventing cisplatin-induced ototoxicity is crucial to improve...
Cisplatin use is often limited by its ototoxic side effects, which can lead to irreversible hearing loss. Preventing cisplatin-induced ototoxicity is crucial to improve patient outcomes. Fluoxetine and fluvoxamine, both selective serotonin reuptake inhibitors antidepressants, inhibit the NLR pyrin domain-containing protein 3 inflammasome, a potential therapeutic target for preventing ototoxicity. However, human studies have not evaluated if these antidepressants may protect against cisplatin-induced ototoxicity. The object of this study is to assess the association between fluoxetine or fluvoxamine use and incidence of hearing loss or tinnitus in a large cohort of patients receiving cisplatin chemotherapy. We use a retrospective cohort study within the U.S. Department of Veterans Affairs healthcare system. Adult patients with cancer who received cisplatin chemotherapy between 2000 and 2023 are included. Incidence of ototoxicity, defined by international classification of diseases revision 9-CM or international classification of diseases revision 10-CM diagnoses of hearing loss or tinnitus is compared between concurrent use of fluoxetine or fluvoxamine and cisplatin alone. A total of 20,552 patients were included. Of those, 489 received cisplatin and fluoxetine or fluvoxamine. After propensity score adjustment, the hazard of ototoxicity was lower in the group receiving fluoxetine or fluvoxamine compared to the group receiving cisplatin alone (HR = 0.62, 95% CI = (0.41-0.94)). Fluoxetine or fluvoxamine use may be associated with a reduced risk of cisplatin-induced ototoxicity. Randomized clinical trials are needed to confirm these findings and establish the efficacy of the medications in ototoxicity prevention. Further research is also warranted to investigate the potential mechanisms underlying this protective effect.
PubMed: 38597272
DOI: 10.1177/10815589241247796 -
BioMed Research International 2023The Kir4.1 channel, an inwardly rectifying potassium ion (K) channel, is located in the hair cells of the organ of Corti as well as the intermediate cells of the stria...
The Kir4.1 channel, an inwardly rectifying potassium ion (K) channel, is located in the hair cells of the organ of Corti as well as the intermediate cells of the stria vascularis. The Kir4.1 channel has a crucial role in the generation of endolymphatic potential and maintenance of the resting membrane potential. However, the role and functions of the Kir4.1 channel in the progenitor remain undescribed. To observe the role of Kir4.1 in the progenitor treated with the one-shot ototoxic drugs (kanamycin and furosemide), we set the proper condition in culturing Immortomouse-derived HEI-OC1 cells to express the potassium-related channels well. And also, that was reproduced in mice experiments to show the important role of Kir4.1 in the survival of hair cells after treating the ototoxicity drugs. In our results, when kanamycin and furosemide drugs were cotreated with HEI-OC1 cells, the Kir4.1 channel did not change, but the expression levels of the NKCC1 cotransporter and KCNQ4 channel are decreased. This shows that inward and outward channels were blocked by the two drugs (kanamycin and furosemide). However, noteworthy here is that the expression level of Kir4.1 channel increased when kanamycin was treated alone. This shows that Kir4.1, an inwardly rectifying potassium channel, acts as an outward channel in place of the corresponding channel when the KCNQ4 channel, an outward channel, is blocked. These results suggest that the Kir4.1 channel has a role in maintaining K homeostasis in supporting cells, with K concentration compensator when the NKCC1 cotransporter and Kv7.4 (KCNQ4) channels are deficient.
Topics: Mice; Animals; Potassium Channels, Inwardly Rectifying; Aminoglycosides; Ototoxicity; Solute Carrier Family 12, Member 2; Furosemide; Anti-Bacterial Agents; Kanamycin; Potassium; Hair
PubMed: 38143588
DOI: 10.1155/2023/4191999