Search Results (107)

The cochlea is susceptible to damage from ototoxic agents such as cisplatin, yet the mechanisms underlying cochlear injury remain incompletely understood. Mast cells (MCs), key immune players in allergic and inflammatory responses, have recently been identified in the rodent cochlea and implicated in cisplatin-induced ototoxicity. Our study investigated the role of MC degranulation in cochlear damage and evaluated the activation capacity of cochlear-resident MCs. Bone marrow-derived MCs (BMMCs) were cultured and induced to degranulate via IgE-anti-DNP/DNP stimulation, and the supernatants were applied to cochlear explants. Cochlear explants were also treated with Compound 48/80 (CP48/80) or cisplatin to assess MC activation. Morphological changes were assessed and hair cells (HC) quantified via phalloidin staining, while ELISA measured mediator release. Supernatants from degranulated BMMC induced a dose-dependent HC loss and tissue damage. A significant chymase and tryptase release was triggered by CP48/80 from cochlear MCs, with chymase elevation detected even at low concentrations. Cochlear MCs were rapidly activated by cisplatin exposure, elevating chymase and histamine levels, and the effects were attenuated by the MC stabilizer sodium cromolyn. Notably, tryptase remained undetectable post-cisplatin treatment, suggesting tissue-specific MC responses. These findings establish MC degranulation as an early event in cisplatin-induced cochlear injury, mediated by chymase and histamine. Our study highlights MCs as potential therapeutic targets for mitigating ototoxicity and underscores the need to explore MC-driven pathways in hearing loss. Full article

Many forms of damage to cochlear sensory cells involve reactive oxygen species (ROS). We previously screened 81 antioxidants in vitro for the ability to reduce cochlear hair cell (HC) damage by the ototoxic aminoglycoside gentamicin. Only 13 antioxidants produced significant reduction in HC loss, with the quinone antioxidants seratrodast and idebenone being most protective. Why so few antioxidants were protective is unclear, but most antioxidants have other properties that could enhance or detract from protection. In particular, seratrodast is a potent thromboxane A₂ (TXA2) antagonist, while idebenone also strongly supports cell metabolism by enhancing mitochondrial function. We therefore asked whether a different TXA2 inhibitor (SQ-29548) or mitochondrial function enhancer (mitochonic acid) exhibited any HC protective ability in the same assay. In both cases, no significant protection from gentamicin was observed, indicating that the ROS scavenging activity of seratrodast and idebenone accounted for HC protection. Additionally, to assess the generality of HC protection by the two antioxidants, we assessed their potential for protection against cisplatin, an ototoxic anti-cancer drug that produces HC damage through a different mechanism than aminoglycosides, but which also involves ROS. High-dose seratrodast tested protected HCs from cisplatin damage, but not to the extent observed for gentamicin. High-dose idebenone was also protective, but even less than for seratrodast. Neither mitochonic acid nor SQ-29548 was protective against cisplatin. The results indicate that seratrodast and idebenone provide HC protection from gentamicin and cisplatin due to their free radical scavenging properties, but protection from cisplatin was less effective, presumably due to its different mechanism of ototoxicity. Full article

Childhood cancer treatments, including chemotherapy, radiation therapy, and combined modalities, pose significant risks to auditory function due to their ototoxic effects. Cisplatin, a chemotherapeutic agent commonly used in pediatric oncology, causes dose-dependent irreversible sensorineural hearing loss by damaging the inner ear structures, primarily through the generation of reactive oxygen species and the activation of apoptotic pathways. Radiation therapy exacerbates these effects, contributing to both sensorineural and conductive hearing loss via mechanisms such as vascular injury, inflammation, and fibrosis. The severity of hearing loss is influenced by the treatment timing, the cumulative dose, patient age, genetics, and concurrent therapies. The damaging effects of chemotherapy and radiation extend beyond the cochlea, involving the surrounding temporal bone as well as multiple levels of the auditory pathway. While pediatric patients may be candidates for bone-anchored hearing devices or cochlear implants, the need for serial imaging and the potential for implant-related MRI artifacts can complicate the timing of hearing rehabilitation. Moreover, the impact on the subcortical and cortical auditory structures may further influence the rehabilitation outcomes. This scoping review lays the foundation for future clinical and research efforts focused on the development of comprehensive pediatric guidelines for hearing preservation, monitoring, and rehabilitation, while also fostering multidisciplinary collaboration. Full article

The role of nitric oxide (NO) in the onset and pathogenesis of hearing loss remains a matter of debate. To address this, we conducted a narrative review of the literature on the subject. We performed a literature search of SCOPUS, PubMed, Cochrane Library, EMBASE, and Google Scholar databases on the production and role of NO in hearing loss using the search terms/strategy “nitric oxide” AND “hearing loss” to ensure a comprehensive review of available studies. Results: Of 186 papers initially retrieved, 166 were unrelated to hearing loss and NO and were excluded. Of the 23 papers ultimately reviewed, 58% (12 articles) reported that NO caused or worsened hearing loss, 26% (5 articles) reported a beneficial effect of NO in the treatment of and/or defense against hearing loss, and 16% (3 articles) reached no firm conclusion on whether NO played a positive or negative role. This review highlights the dual role of NO in auditory health, where it is essential for normal cochlear function through regulation of blood flow and neurotransmission. However, excessive or dysregulated NO production, particularly via inducible nitric oxide synthase (iNOS), can lead to oxidative stress and hearing loss. Conversely, NO also exhibits protective effects in certain contexts, such as reducing noise-induced hearing damage through its antioxidant properties. These findings underscore the potential of NO modulation as a therapeutic strategy for hearing loss, emphasizing the need for further research to optimize its application and understand the conditions under which it is beneficial or harmful. Full article

Recreational noise-induced hearing loss (RNIHL) is a significant factor contributing to hearing loss in young people. Its process is irreversible, and early symptoms are hidden. Therefore, early identification is of great significance. Otoacoustic emissions (OAEs) are commonly used to detect the function of outer hair cells. It is widely used for early diagnosis of occupational noise-induced hearing loss, but it remains underutilized in RNIHL detection. In order to explore the characteristics of RNIHL and the early detection value of different types of OAEs, this study reviewed the detection results of OAEs in previous studies on noise-induced hearing loss and analyzed the differences and causes among the studies. The study found that, through the detection of distortion product otoacoustic emissions (DPOAEs), there were differences in the sensitive frequency bands of outer hair cell damage between recreational noise and occupational noise, particularly in the high-frequency region. Transient-evoked otoacoustic emissions (TEOAEs) can fully reflect the damage to cochlear outer hair cells caused by RNIHL. This study indicates that OAEs, particularly TEOAEs, can serve as a highly sensitive and objective detection tool for RNIHL, whereas DPOAEs are more appropriate for the early screening of occupational noise-induced hearing loss. Full article

Background: Sudden-onset bilateral mixed hearing loss in adults is an extremely rare condition but challenging to diagnose and treat. Conductive hearing loss is associated with otitis media, while the simultaneous presence of a sensorineural component requires supplementary investigation for possible shared pathophysiological mechanisms. Case Presentation: We report the case of a 41-year-old male who was admitted to our hospital with a 48 h history of bilateral, fast progressive hearing loss following a viral illness. The audiologic testing revealed bilateral severe mixed hearing loss. Tympanometry indicated the presence of middle-ear effusion, and myringotomy confirmed the existence of pressurized serous fluid. Treatment consisted of systemic and intratympanic corticosteroids, antibiotics, and supportive therapy. The patient had an unexpected full recovery of auditory function within one month. Discussion: Multiple hypotheses were considered. We hypothesized the coexistence of unrelated conductive and sensorineural hearing loss or a unifying pathological process. Theories discussed include a direct viral insult to the cochlear structures or even pressure-mediated damage to the basal cochlea due to the simultaneous inward displacement of the oval and round windows. The complete resolution of hearing loss is the indicator of a reversible etiology, possibly due to transient inner ear dysfunction secondary to middle-ear pathology or viral infection. Conclusions: This case illustrates the complexity of diagnosing acute mixed hearing loss. This report emphasizes a rare case of sudden-onset bilateral mixed hearing loss with a complete recovery, contributing valuable insight into under-reported and diagnostically complex presentations. Full article

Background: Cochlear implantation is widely used to provide auditory rehabilitation to individuals with severe-to-profound sensorineural hearing loss. However, electrode insertion during cochlear implantation leads to inner ear trauma, damage to sensory structures, and consequently, loss of residual hearing. There is very limited information regarding the target proteins involved in electrode insertion trauma (EIT) following cochlear implantation. Methods: The aim of our study was to identify target proteins and host molecular pathways involved in cochlear damage following EIT utilizing the iTRAQ™ (isobaric tags for relative and absolute quantification) technique using our ex vivo model. The organ of Corti (OC) explants were dissected from postnatal day 3 rats and subjected to EIT or left untreated (control). The proteins were extracted, labelled, and subjected to ultra-high performance liquid chromatography–tandem mass spectrometry. Results: We identified distinct molecular pathways involved in EIT-induced cochlear damage. Confocal microscopy confirmed the expression of these identified proteins in OC explants subjected to EIT. By separating the apical, middle, and basal cochlear turns, we deciphered a topographic array of host molecular pathways that extend from the base to the apex of the cochlea, which are activated post-trauma following cochlear implantation. Conclusions: The identification of target proteins involved in cochlear damage will provide novel therapeutic targets for the development of effective treatment modalities for the preservation of residual hearing in implanted individuals. Full article

Aminoglycoside antibiotics are critical in clinical use for treating severe infections, but they can occasionally cause irreversible sensorineural hearing loss. To establish a rational pathway for otoprotectant discovery, we provide an integrated, three-tier methodology—comprising cell-model selection, transcriptomic analysis, and a gentamicin–Texas Red (GTTR) uptake assay—to guide the development of otoprotective strategies. We first utilized two murine auditory cell lines—UB/OC-2 and HEI-OC1. We focused on TMC1 and OCT2 and further explored the underlying mechanisms of ototoxicity. UB/OC-2 exhibited a higher sensitivity to gentamicin, which correlated with elevated OCT2 expression confirmed via RT-PCR and Western blot. Transcriptomic analysis revealed upregulation of PI3K-Akt, calcium, and GPCR-related stress pathways in gentamicin-treated HEI-OC1 cells. Protein-level analysis further confirmed that gentamicin suppressed phosphorylated Akt while upregulating ER stress markers (GRP78, CHOP) and apoptotic proteins (cleaved caspase 3, PARP). Co-treatment with PI3K inhibitors (LY294002, wortmannin) further suppressed Akt phosphorylation, supporting the role of PI3K-Akt signaling in auditory cells. To visualize drug entry, we used GTTR to evaluate its applicability as a fluorescence-based uptake assay in these cell lines, which were previously employed mainly in cochlear explants. Sodium thiosulfate (STS) and N-acetylcysteine (NAC) significantly decreased GTTR uptake, suggesting a protective effect against gentamicin-induced hair cell damage. In conclusion, our findings showed a complex ototoxic cascade involving OCT2- and TMC1-mediated drug uptake, calcium imbalance, ER stress, and disruption of PI3K-Akt survival signaling. We believe that UB/OC-2 cells serve as a practical in vitro model for mechanistic investigations and screening of otoprotective compounds. Additionally, GTTR may be a simple, effective method for evaluating protective interventions in auditory cell lines. Overall, this study provides molecular-level insights into aminoglycoside-induced ototoxicity and introduces a platform for protective strategies. Full article

Background/Objectives: Electrocochleography (ECochG) is a promising tool to monitor preservation of cochlear structures and function during cochlear implant (CI) surgery. However, the interpretation of ECochG signal changes during insertion of the CI electrode array remains controversial. This study investigates the influence of the degree and localization of cochlear trauma on ECochG signal changes using a mouse model. Methods: C57BL/6J-Crl1 mice underwent intracochlear ECochG recordings during the insertion of a platinum–iridium electrode. Results: In case of grade 1 and 2 cochlear trauma, as determined by post-mortem histological analysis, we found that a reduction in intracochlear cochlear microphonic (CM) amplitude correlates more significantly with the location of the trauma than with its severity. The more basally a trauma is located, the larger the CM amplitude drop. Furthermore, the results revealed that grade 1 or 2 trauma was detectable through ECochG before more severe trauma developed. Conclusions: These findings suggest that intracochlear ECochG can serve as a reliable intraoperative tool for detecting early and possibly reversible cochlear trauma, preventing more severe damage and aiding hearing preservation. The results emphasize the need for a nuanced interpretation of CM signal drops, considering trauma location and cochlear structure integrity at the site of trauma and apical to it. Full article

Background/Objectives: Vestibular dysfunction is one of the main complications after cochlear implant (CI) surgery, and there are currently no standardized protocols for vestibular assessment in CI candidates. Our objectives were to investigate the incidence of vestibular impairment after CI surgery, anamnestic (age, known systemic pathologies and cause of deafness) and surgical (intraoperative complications, malposition of the CI) risk factors, and the role of vestibular assessment in the selection of the suitable ear for implantation. Methods: We included 68 adult patients (80 ears) affected by moderate-to-profound SNHL undergoing CI. The dizziness handicap inventory (DHI), the video head impulse test (VHIT), the caloric test, and dynamic posturography (DP) were used to study the vestibular function and balance before and one month after CI. The DHI was also administered 24 h after surgery. Results: Despite significative impairment 24 h after surgery (29.6 ± 30), the mean DHI score returned to preoperative values (17.9 ± 26) after one month. Dizziness persisted in case of age ≥ 65 years old, surgical difficulties, simultaneous bilateral CI, Meniere’s disease and otosclerosis, comorbidities ≥ 3, anxiety/depression, and neurological diseases. The VHIT significantly worsened in 25% of ears, while the caloric test SPV nystagmus significantly decreased in 30% of ears. In cases of preoperative unilateral weakness, the implantation of the better ear was significantly related to higher DHI scores. Only 4/68 patients had a significant persistent reduction in the postural composite score after surgery, with an increased risk of falls. Conclusions: Medical history and vestibular assessment predict the risk of vestibular damage and help to choose the CI’s side and to manage vertigo after surgery. Full article

Background/Objectives: Sudden sensorineural hearing loss (SSNHL) is an acute condition with unclear etiology, commonly hypothesized to be associated with viral infections. Acute respiratory tract infections (RTIs), particularly those of viral origin, have been implicated in SSNHL through proposed mechanisms such as cochlear invasion and immune-mediated damage. However, robust large-scale epidemiological evidence examining this association remains limited. This study aimed to investigate the potential association between acute RTIs and subsequent risk of developing SSNHL across diverse populations. Methods: We conducted a multinational retrospective cohort study using data from the TriNetX Global Collaborative Network. Adults diagnosed with acute RTIs between 1 January 2012 and 30 June 2023 were compared to matched controls without RTI exposure. Patients with predisposing conditions for SSNHL were excluded. Propensity score matching (1:1) was performed by age and sex. SSNHL diagnoses within 60 days post index were analyzed using Cox proportional hazards models. Subgroup and sensitivity analyses were conducted by race, sex, and age strata. Results: Among 37 million patients analyzed, individuals with acute RTIs had a lower incidence of SSNHL compared to matched controls. Hazard ratios (HRs) for SSNHL were significantly reduced across all racial groups: Whites (HR: 0.572), Blacks (HR: 0.563), and Asians (HR: 0.409). Subgroup analyses revealed stronger inverse associations in males and younger age groups, particularly those aged 18–25 years. Conclusions: Contrary to prior assumptions, acute RTIs were associated with a lower incidence of SSNHL in a large, diverse cohort. While the findings raise the possibility of immunological or physiological factors influencing this association, the results should be interpreted with caution due to unmeasured confounding and the observational nature of the study. Full article

Noise-induced hearing loss (NIHL) is a common type of sensorineural hearing loss caused by exposure to high-intensity noise that leads to irreversible cochlear damage. Despite extensive research on cochlear pathophysiology, the precise mechanisms remain unclear, and no established treatment exists. This is due to the challenges in imaging and the inability to perform biopsies in human patients. Consequently, animal models, particularly mice, have been widely used to study NIHL. Clinically, NIHL presents as either a temporary threshold shift, in which hearing recovers, or a permanent threshold shift, which results in an irreversible loss. Histopathological studies have identified the key features of NIHL, including outer hair cell loss, auditory nerve degeneration, and synaptic impairment. Recent findings suggest that oxidative stress and inflammation are major contributors to NIHL, highlighting the potential for therapeutic interventions, such as antioxidants and anti-inflammatory agents. Given the increasing prevalence of NIHL owing to occupational noise exposure and personal audio device use, addressing this issue is a pressing public health challenge. This review summarizes the clinical features, underlying mechanisms, and emerging treatment strategies for NIHL while identifying current knowledge gaps and future research directions. Full article

Age-related hearing loss (ARHL) is a highly prevalent, burdensome sensorineural hearing loss closely associated with impaired autophagic influx. Our previous studies revealed that neuritin, a neurotrophic factor primarily expressed in the central nervous system, could alleviate drug-induced damages in hair cells (HCs) and spiral ganglion neurons. However, its effects on ARHL and whether these effects are closely related to autophagy remain unclear. Using the Nrn1 knock-in mice and cultured cochlear basilar membrane (CBM) of the neonatal mouse, we show that neuritin could restore aging-associated hearing loss and alleviate senescence-associated damage in the cochlea. Overexpression of neuritin in support cells (SCs) alleviates the loss of cochlear HCs and nerve fibers, reducing the damage to spiral ganglion neurons and the shifts in ABR’s high-frequency threshold. Furthermore, conditional overexpression of neuritin in SCs improves autophagic influx by upregulating the expression of microtubule-associated protein 1 light chain 3 type B (LCB3) protein and downregulating the expression of p21 protein. In cultured neonatal mouse CBM, neuritin administration significantly inhibits D-galactose-induced HC loss, cellular apoptosis, and ROS production and promotes autophagic influx. These effects were weakened when the autophagy inhibitor 3-MA was added. In summary, our results confirm the therapeutic potential of neuritin treatment for ARHL. Full article

Hearing loss remains a significant but underexplored health challenge in individuals with HIV/AIDS, particularly those exposed to occupational noise. The ototoxic effects of antiretroviral therapy (ART) and comorbid conditions like tuberculosis (TB) further compound the risk. This narrative review examines the intersection of HIV/AIDS, ART, and occupational noise-induced hearing loss (ONIHL), emphasizing the South African and broader African contexts. The aim of the study was to map the existing literature on the association between HIV/AIDS, its treatments, and ONIHL, and to identify research gaps to inform policy and clinical practice. A narrative review approach was adopted, systematically searching databases including PubMed, Scopus, and Web of Science. Studies published between 2000 and 2024 were included, focusing on the effects of HIV/AIDS, ART, and occupational noise exposure on hearing health. Data extraction and thematic synthesis were performed to identify key findings and gaps. Twenty studies were included, covering diverse settings such as South Africa, Cameroon, Tanzania, and the USA. Three key themes emerged: (1) dual burden of HIV and occupational noise exposure: HIV-positive individuals in noise-intensive industries, such as mining, face amplified risks of hearing loss due to immunological compromise and ototoxic TB treatments; (2) ototoxicity of ART: older ART regimens, widely used in resource-limited settings, are associated with a higher prevalence of sensorineural hearing loss (SNHL); and (3) immunological susceptibility to ONIHL: HIV-related immune suppression exacerbates cochlear damage from noise and ototoxic agents, contributing to both peripheral and central auditory dysfunction. This review highlights the urgent need for integrated hearing health interventions in HIV care and occupational health frameworks, particularly in high-prevalence regions like South Africa. Routine audiological assessments, access to safer ART regimens, and enhanced workplace protections are essential to mitigate the dual burden of HIV/AIDS and ONIHL. Future research should prioritize longitudinal studies and innovative, low-cost solutions for resource-limited settings. Full article

Background: Cisplatin, a widely used chemotherapeutic agent, is associated with significant ototoxicity, leading to progressive and irreversible sensorineural hearing loss in up to 93% of patients. Cisplatin generates reactive oxygen species (ROS) in the cochlea, activating apoptotic and necroptotic pathways that result in hair cell death. Inflammatory processes and nitrative stress also contribute to cochlear damage. Methods: This literature review was conducted to explore the mechanisms underlying cisplatin-induced ototoxicity and evaluate protective strategies, including both current and emerging approaches. A structured search was performed in multiple scientific databases, including PubMed and ScienceDirect, for articles published up to November 2024. Results: Current otoprotective strategies include systemic interventions such as antioxidants, anti-inflammatory agents, and apoptosis inhibitors, as well as localized delivery methods like intratympanic injection and nanoparticle-based systems. However, these approaches have limitations, including potential interference with cisplatin’s antitumor efficacy and systemic side effects. Emerging strategies focus on genetic and biomarker-based risk stratification, novel otoprotective agents targeting alternative pathways, and combination therapies. Repurposed drugs like pravastatin also show promise in reducing cisplatin-induced ototoxicity. Conclusions: Despite these advancements, significant research gaps remain in translating preclinical findings to clinical applications and developing selective otoprotective agents that do not compromise cisplatin’s efficacy. This review examines the mechanisms of cisplatin-induced ototoxicity, current otoprotective strategies, and emerging approaches to mitigate this adverse effect. Full article