Opa1 Prevents Apoptosis and Cisplatin-Induced Ototoxicity in Murine Cochleae

Optic atrophy1 (OPA1) is crucial for inner mitochondrial membrane (IMM) fusion and essential for maintaining crista structure and mitochondrial morphology. Optic atrophy and hearing impairment are the most prevalent clinical features associated with mutations in the OPA1 gene, but the function of OPA1 in hearing is still unknown. In this study, we examined the ability of Opa1 to protect against cisplatin-induced cochlear cell death in vitro and in vivo. Our results revealed that knockdown of Opa1 affects mitochondrial function in HEI-OC1 and Neuro 2a cells, as evidenced by an elevated reactive oxygen species (ROS) level and reduced mitochondrial membrane potential. The dysfunctional mitochondria release cytochrome c, which triggers apoptosis. Opa1 expression was found to be significantly reduced after cell exposed to cisplatin in HEI-OC1 and Neuro 2a cells. Loss of Opa1 aggravated the apoptosis and mitochondrial dysfunction induced by cisplatin treatment, whereas overexpression of Opa1 alleviated cisplatin-induced cochlear cell death in vitro and in explant. Our results demonstrate that overexpression of Opa1 prevented cisplatin-induced ototoxicity, suggesting that Opa1 may play a vital role in ototoxicity and/or mitochondria-associated cochlear damage.

Antioxidant Effect of Curcumin on the Prevention of Oxidative Damage to the Cochlea in an Ototoxic Rat Model Based on Malondialdehyde Expression

Introduction Aminoglycoside, as an antimicrobial medication, also has side-effects on the inner ears, bringing about hearing disorders. Curcumin has been proven to be a strong scavenger against various reactive oxygen species (ROS), and the increase in ROS production is considered to play an important role in the process of hearing disorder. Objective To prove that curcumin is an effective antioxidant to prevent cochlear damage based on malondialdehyde (MDA) expression. Methods The present research used 32 Rattus norvegicus, of the Wistar lineage, randomly divided into 8 groups: negative control, ototoxic control (a single dose of 40 mg/ml of gentamicin via intratympanic injection), 2 groups submitted to ototoxic control + curcumin treatment (100 mg/kg, 200 mg/kg), 2 groups who iunderwent ototoxic control + curcumin treatment for 7 days, and two groups submitted to curcumin treatment as prevention for 3 days + ototoxic induction. Results The results showed that the lowest dosage of curcumin (100 mg/kg) could decrease MDA expression on the cochlear fibroblastic wall of the ototoxic model; however using greater doses of curcumin (200 mg/kg) for 7 days would provide a better effect. Curcumin could also significantly decrease MDA expression when it was administered during the preototoxic exposure. Conclusion Curcumin can be used as a therapy for ototoxic prevention based on the decrease in MDA expression.

Primed to die: an investigation of the genetic mechanisms underlying noise-induced hearing loss and cochlear damage in homozygous Foxo3-knockout mice

The prevalence of noise-induced hearing loss (NIHL) continues to increase, with limited therapies available for individuals with cochlear damage. We have previously established that the transcription factor FOXO3 is necessary to preserve outer hair cells (OHCs) and hearing thresholds up to two weeks following mild noise exposure in mice. The mechanisms by which FOXO3 preserves cochlear cells and function are unknown. In this study, we analyzed the immediate effects of mild noise exposure on wild-type, Foxo3 heterozygous (Foxo3+/−), and Foxo3 knock-out (Foxo3−/−) mice to better understand FOXO3’s role(s) in the mammalian cochlea. We used confocal and multiphoton microscopy to examine well-characterized components of noise-induced damage including calcium regulators, oxidative stress, necrosis, and caspase-dependent and caspase-independent apoptosis. Lower immunoreactivity of the calcium buffer Oncomodulin in Foxo3−/− OHCs correlated with cell loss beginning 4 h post-noise exposure. Using immunohistochemistry, we identified parthanatos as the cell death pathway for OHCs. Oxidative stress response pathways were not significantly altered in FOXO3’s absence. We used RNA sequencing to identify and RT-qPCR to confirm differentially expressed genes. We further investigated a gene downregulated in the unexposed Foxo3−/− mice that may contribute to OHC noise susceptibility. Glycerophosphodiester phosphodiesterase domain containing 3 (GDPD3), a possible endogenous source of lysophosphatidic acid (LPA), has not previously been described in the cochlea. As LPA reduces OHC loss after severe noise exposure, we treated noise-exposed Foxo3−/− mice with exogenous LPA. LPA treatment delayed immediate damage to OHCs but was insufficient to ultimately prevent their death or prevent hearing loss. These results suggest that FOXO3 acts prior to acoustic insult to maintain cochlear resilience, possibly through sustaining endogenous LPA levels.

Downregulation of GJB2 and SLC26A4 Genes Induced by Noise Exposure is Associated with Cochlear Damage

Noise can change the pattern of gene expression inducing sensorineural hearing impairment. There is no investigation on effects of noise frequency on the expression of GJB2 and SLC26A4 genes involved in congenital hearing impairment in cochlear tissue. This study investigated impacts of white and purple noise on gene expression and pathologic changes of cochlear tissue. In this study, 32 adult male Westar rats were selected and divided into experimental groups WN (animals exposed to white noise with a frequency range of 100-20000 Hz), PN (animals exposed to purple noise with a frequency range of 4-20 kHz) and control groups. All experimental groups were exposed to a sound pressure level of 118-120 dB for 8 hours per day. Cochlear tissue sampling was performed for tissue pathology studies, also RNA was extracted at 1 hour & 1 week after cessation of noise exposure. The results showed that Both white and purple noises caused permanent damage to the cortical, estrosilica systems of hair cells and ganglion of the hearing nerve. GJB2 and SLC26A4 were downregulated in both groups exposed with white and purple noise. However, differences are notably more significant in 1 weak post-exposure than 1 hour. Our Findings suggest GJB2 and SLC26A4 can be considered as biomarkers of response to noise frequency which is associated with the pathological response of cochlear tissue, leading to sensorineural hearing impairment. It would be suggested the demand for a more conventional approach to assessment of noise-induced hearing loss and subsequently the practice of hearing protection programs.

On the use of envelope following responses to estimate peripheral level compression in the auditory system

Individual estimates of cochlear compression may provide complementary information to traditional audiometric hearing thresholds in disentangling different types of peripheral cochlear damage. Here we investigated the use of the slope of envelope following response (EFR) magnitude-level functions obtained from four simultaneously presented amplitude modulated tones with modulation frequencies of 80–100 Hz as a proxy of peripheral level compression. Compression estimates in individual normal hearing (NH) listeners were consistent with previously reported group-averaged compression estimates based on psychoacoustical and distortion-product oto-acoustic emission (DPOAE) measures in human listeners. They were also similar to basilar membrane (BM) compression values measured invasively in non-human mammals. EFR-based compression estimates in hearing-impaired listeners were less compressive than those for the NH listeners, consistent with a reduction of BM compression. Cochlear compression was also estimated using DPOAEs in the same NH listeners. DPOAE estimates were larger (less compressive) than EFRs estimates, showing no correlation. Despite the numerical concordance between EFR-based compression estimates and group-averaged estimates from other methods, simulations using an auditory nerve (AN) model revealed that compression estimates based on EFRs might be highly influenced by contributions from off-characteristic frequency (CF) neural populations. This compromises the possibility to estimate on-CF (i.e., frequency-specific or “local”) peripheral level compression with EFRs.

Mitochondrial Dysfunction and Sirtuins: Important Targets in Hearing Loss

Mitochondrial dysfunction has been suggested to be a risk factor for sensorineural hearing loss (SNHL) induced by aging, noise, ototoxic drugs, and gene. Reactive oxygen species (ROS) are mainly derived from mitochondria, and oxidative stress induced by ROS contributes to cochlear damage as well as mitochondrial DNA mutations, which may enhance the sensitivity and severity of hearing loss and disrupt ion homeostasis (e.g., Ca2+ homeostasis). The formation and accumulation of ROS further undermine mitochondrial components and ultimately lead to apoptosis and necrosis. SIRT3–5, located in mitochondria, belong to the family of sirtuins, which are highly conserved deacetylases dependent on nicotinamide adenine dinucleotide (NAD+). These deacetylases regulate diverse cellular biochemical activities. Recent studies have revealed that mitochondrial sirtuins, especially SIRT3, modulate ROS levels in hearing loss pathologies. Although the precise functions of SIRT4 and SIRT5 in the cochlea remain unclear, the molecular mechanisms in other tissues indicate a potential protective effect against hearing loss. In this review, we summarize the current knowledge regarding the role of mitochondrial dysfunction in hearing loss, discuss possible functional links between mitochondrial sirtuins and SNHL, and propose a perspective that SIRT3–5 have a positive effect on SNHL.

Primed to Die: An Investigation of the Genetic Mechanisms Underlying Noise-Induced Hearing Loss and Cochlear Damage in Homozygous Foxo3-knockout Mice

The prevalence of noise-induced hearing loss (NIHL) continues to increase, with limited therapies available for individuals with cochlear damage. We have previously established that the transcription factor FOXO3 is necessary to preserve outer hair cells (OHCs) and hearing thresholds up to two weeks following a mild noise exposure in mice. The mechanisms by which FOXO3 preserves cochlear cells and function are unknown. In this study, we analyzed the immediate effects of mild noise exposure on wild-type, Foxo3 heterozygous (Foxo3+/KO), and Foxo3 knock-out (Foxo3KO/KO) mice to better understand FOXO3’s role(s) in the mammalian cochlea. We used confocal and multiphoton microscopy to examine well-characterized components of noise-induced damage including calcium regulators, oxidative stress, necrosis, and caspase-dependent and -independent apoptosis. Lower immunoreactivity of the calcium buffer oncomodulin in Foxo3KO/KO OHCs correlated with cell loss beginning 4 hours post-noise exposure. Using immunohistochemistry, we identified parthanatos as the cell death pathway for OHCs. Oxidative stress response pathways were not significantly altered in FOXO3’s absence. We used RNA sequencing to identify and RT-qPCR to confirm differentially expressed genes. We further investigated a gene downregulated in the unexposed Foxo3KO/KO mice that may contribute to OHC noise susceptibility. Glycerophosphodiester Phosphodiesterase Domain Containing 3 (GDPD3), a possible endogenous source of lysophosphatidic acid (LPA), has not previously been described in the cochlea. As LPA reduces OHC loss after severe noise exposure, we treated noise exposed Foxo3KO/KO mice with exogenous LPA. LPA treatment delayed immediate damage to OHCs but was insufficient to ultimately prevent their death or prevent hearing loss. These results suggest that FOXO3 acts prior to acoustic insult to maintain cochlear resilience, possibly through sustaining endogenous LPA levels.

Audiovestibular symptoms and sequelae in COVID-19 patients

BACKGROUND: since the beginning of COVID-19 outbreak a growing number of symptoms and deficits associated with the new pathology have emerged, among them cochlear damage in otherwise asymptomatic COVID-19 patients has been described. OBJECTIVE: to investigate general and audiovestibular symptoms and sequelae in healed patients, and to seek for any sign of residual or permanent hearing or vestibular loss. METHODS: we reviewed the data coming from 48 Covid-19 patients whose nasopharyngeal swabs have turned negative, all employed at our facility, that opted in for a free screening of audiovestibular symptoms offered by our hospital after the aforementioned report was published. The screening included a tonal pure tone audiometry, a vHIT and SHIMP test, as well as a survey including known symptoms and audiovestibular symptoms. RESULTS: general symptoms as reported by our patients largely reflect what reported by others in the literature. 4 (8.3%) patients reported hearing loss, 2 (4.2%) tinnitus, 4 dizziness (8.3%), 1 spinning vertigo (2%), 1 dynamic imbalance (2%), 3 static imbalance (6.3%). Most audiovestibular symptoms have regressed. Thresholds at pure tone audiometry and vHIT gain were within normality range in all post-Covid-19 patients. CONCLUSIONS: even if some patients suffer from audiovestibular symptoms, these are mostly transitory and there is no clear evidence of clinically relevant persistent cochlear or vestibular damage after recovery.