Ultrasound Microbubbles Enhance the Efficacy of Insulin-Like Growth Factor-1 Therapy for the Treatment of Noise-Induced Hearing Loss

The application of insulin-like growth factor 1 (IGF-1) to the round window membrane (RWM) is an emerging treatment for inner ear diseases. RWM permeability is the key factor for efficient IGF-1 delivery. Ultrasound microbubbles (USMBs) can increase drug permeation through the RWM. In the present study, the enhancing effect of USMBs on the efficacy of IGF-1 application and the treatment effect of USMB-mediated IGF-1 delivery for noise-induced hearing loss (NIHL) were investigated. Forty-seven guinea pigs were assigned to three groups: the USM group, which received local application of recombinant human IGF-1 (rhIGF-1, 10 µg/µL) following application of USMBs to the RWM; the RWS group, which received IGF-1 application alone; and the saline-treated group. The perilymphatic concentration of rhIGF-1 in the USM group was 1.95- and 1.67- fold of that in the RWS group, 2 and 24 h after treatment, respectively. After 5 h of 118 dB SPL noise exposure, the USM group had the lowest threshold shift in auditory brainstem response, least loss of cochlear outer hair cells, and least reduction in the number of synaptic ribbons on postexposure day 28 among the three groups. The combination of USMB and IGF-1 led to a better therapeutic response to NIHL. Two hours after treatment, the USM group had significantly higher levels of Akt1 and Mapk3 gene expression than the other two groups. The most intense immunostaining for phosphor-AKT and phospho-ERK1/2 was detected in the cochlea in the USM group. These results suggested that USMB can be applied to enhance the efficacy of IGF-1 therapy in the treatment of inner ear diseases.

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Constant Light Dysregulates Cochlear Circadian Clock and Exacerbates Noise-Induced Hearing Loss

International Journal of Molecular Sciences ◽

10.3390/ijms21207535 ◽

2020 ◽

Vol 21 (20) ◽

pp. 7535

Author(s):

Chao-Hui Yang ◽

Chung-Feng Hwang ◽

Jiin-Haur Chuang ◽

Wei-Shiung Lian ◽

Feng-Sheng Wang ◽

...

Keyword(s):

Hearing Loss ◽

Circadian Clock ◽

Auditory System ◽

High Intensity ◽

Noise Exposure ◽

Clock Genes ◽

Outer Hair Cells ◽

Constant Light ◽

Noise Induced Hearing Loss ◽

Brainstem Response

Noise-induced hearing loss is one of the major causes of acquired sensorineural hearing loss in modern society. While people with excessive exposure to noise are frequently the population with a lifestyle of irregular circadian rhythms, the effects of circadian dysregulation on the auditory system are still little known. Here, we disturbed the circadian clock in the cochlea of male CBA/CaJ mice by constant light (LL) or constant dark. LL significantly repressed circadian rhythmicity of circadian clock genes Per1, Per2, Rev-erbα, Bmal1, and Clock in the cochlea, whereas the auditory brainstem response thresholds were unaffected. After exposure to low-intensity (92 dB) noise, mice under LL condition initially showed similar temporary threshold shifts to mice under normal light–dark cycle, and mice under both conditions returned to normal thresholds after 3 weeks. However, LL augmented high-intensity (106 dB) noise-induced permanent threshold shifts, particularly at 32 kHz. The loss of outer hair cells (OHCs) and the reduction of synaptic ribbons were also higher in mice under LL after noise exposure. Additionally, LL enhanced high-intensity noise-induced 4-hydroxynonenal in the OHCs. Our findings convey new insight into the deleterious effect of an irregular biological clock on the auditory system.

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Analysis of Chronic Tinnitus in Noise-Induced Hearing Loss and Presbycusis

Journal of Clinical Medicine ◽

10.3390/jcm10081779 ◽

2021 ◽

Vol 10 (8) ◽

pp. 1779

Author(s):

Hee Jin Kang ◽

Dae Woong Kang ◽

Sung Su Kim ◽

Tong In Oh ◽

Sang Hoon Kim ◽

...

Keyword(s):

Hearing Loss ◽

Otoacoustic Emissions ◽

Pure Tone Audiometry ◽

Auditory Brainstem ◽

Outer Hair Cells ◽

Chronic Tinnitus ◽

Noise Induced Hearing Loss ◽

Distortion Product ◽

Hearing Thresholds ◽

Brainstem Response

The most frequent causes of tinnitus associated with hearing loss are noise-induced hearing loss and presbycusis. The mechanism of tinnitus is not yet clear, although several hypotheses have been suggested. Therefore, we aimed to analyze characteristics of chronic tinnitus between noise-induced hearing loss and presbycusis. Materials and Methods: This paper is a retrospective chart review and outpatient clinic-based study of 248 patients with chronic tinnitus from 2015 to 2020 with noise-induced or presbycusis. Pure tone audiometry (PTA), auditory brainstem response (ABR), distortion product otoacoustic emissions (DPOAE), transient evoked otoacoustic emissions (TEOAE), and tinnitograms were conducted. Results: PTA showed that hearing thresholds at all frequencies were higher in patients with noise-induced hearing loss than the presbycusis group. ABR tests showed that patients with presbycusis had longer wave I and III latencies (p < 0.05 each) than patients with noise-induced hearing loss. TEOAE tests showed lower values in patients with noise-induced hearing loss than presbycusis at 1.5, 2, 3, and 4 kHz (p < 0.05 each). DPOAE tests showed that response rates in both ears at 1.5, 2, and 3 kHz were significantly higher in patients with presbycusis than noise-induced hearing loss (p < 0.05 each). Discussion: This study showed that hearing thresholds were higher, the loudness of tinnitus was smaller, and the degree of damage to outer hair cells was lower in patients with presbycusis than with noise-induced hearing loss. Moreover, wave I and III latencies were more prolonged in patients with presbycusis despite their having lower hearing thresholds. These phenomena may reflect the effects of aging or degeneration of the central nervous system with age. Further studies are needed to evaluate the etiologies of tinnitus.

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Inhibition of Cochlear HMGB1 Expression Attenuates Oxidative Stress and Inflammation in an Experimental Murine Model of Noise-Induced Hearing Loss

Cells ◽

10.3390/cells10040810 ◽

2021 ◽

Vol 10 (4) ◽

pp. 810

Author(s):

Cheng-Ping Shih ◽

Chao-Yin Kuo ◽

Yuan-Yung Lin ◽

Yi-Chun Lin ◽

Hang-Kang Chen ◽

...

Keyword(s):

Oxidative Stress ◽

Hearing Loss ◽

Noise Exposure ◽

Outer Hair Cells ◽

Control Group ◽

Noise Induced Hearing Loss ◽

Post Exposure ◽

Nadph Oxidase 4 ◽

Brainstem Response ◽

Ros Formation

Noise-induced hearing loss (NIHL) is a common inner ear disease but has complex pathological mechanisms, one of which is increased oxidative stress in the cochlea. The high-mobility group box 1 (HMGB1) protein acts as an inflammatory mediator and shows different activities with redox modifications linked to the generation of reactive oxygen species (ROS). We aimed to investigate whether manipulation of cochlear HMGB1 during noise exposure could prevent noise-induced oxidative stress and hearing loss. Sixty CBA/CaJ mice were divided into two groups. An intraperitoneal injection of anti-HMGB1 antibodies was administered to the experimental group; the control group was injected with saline. Thirty minutes later, all mice were subjected to white noise exposure. Subsequent cochlear damage, including auditory threshold shifts, hair cell loss, expression of cochlear HMGB1, and free radical activity, was then evaluated. The levels of HMGB1 and 4-hydroxynonenal (4-HNE), as respective markers of reactive nitrogen species (RNS) and ROS formation, showed slight increases on post-exposure day 1 and achieved their highest levels on post-exposure day 4. After noise exposure, the antibody-treated mice showed markedly less ROS formation and lower expression of NADPH oxidase 4 (NOX4), nitrotyrosine, inducible nitric oxide synthase (iNOS), and intercellular adhesion molecule-1 (ICAM‑1) than the saline-treated control mice. A significant amelioration was also observed in the threshold shifts of the auditory brainstem response and the loss of outer hair cells in the antibody-treated versus the saline-treated mice. Our results suggest that inhibition of HMGB1 by neutralization with anti-HMGB1 antibodies prior to noise exposure effectively attenuated oxidative stress and subsequent inflammation. This procedure could therefore have potential as a therapy for NIHL.

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Effect of Phlorofucofuroeckol A and Dieckol Extracted from Ecklonia cava on Noise-induced Hearing Loss in a Mouse Model

Marine Drugs ◽

10.3390/md19080443 ◽

2021 ◽

Vol 19 (8) ◽

pp. 443

Author(s):

Hyunjun Woo ◽

Min-Kyung Kim ◽

Sohyeon Park ◽

Seung-Hee Han ◽

Hyeon-Cheol Shin ◽

...

Keyword(s):

Hearing Loss ◽

Hair Cell ◽

Noise Exposure ◽

Radical Scavenging ◽

Threshold Shift ◽

Ecklonia Cava ◽

Control Group ◽

Noise Induced Hearing Loss ◽

Antioxidant Agents ◽

Brainstem Response

One of the well-known causes of hearing loss is noise. Approximately 31.1% of Americans between the ages of 20 and 69 years (61.1 million people) have high-frequency hearing loss associated with noise exposure. In addition, recurrent noise exposure can accelerate age-related hearing loss. Phlorofucofuroeckol A (PFF-A) and dieckol, polyphenols extracted from the brown alga Ecklonia cava, are potent antioxidant agents. In this study, we investigated the effect of PFF-A and dieckol on the consequences of noise exposure in mice. In 1,1-diphenyl-2-picrylhydrazyl assay, dieckol and PFF-A both showed significant radical-scavenging activity. The mice were exposed to 115 dB SPL of noise one single time for 2 h. Auditory brainstem response(ABR) threshold shifts 4 h after 4 kHz noise exposure in mice that received dieckol were significantly lower than those in the saline with noise group. The high-PFF-A group showed a lower threshold shift at click and 16 kHz 1 day after noise exposure than the control group. The high-PFF-A group also showed higher hair cell survival than in the control at 3 days after exposure in the apical turn. These results suggest that noise-induced hair cell damage in cochlear and the ABR threshold shift can be alleviated by dieckol and PFF-A in the mouse. Derivatives of these compounds may be applied to individuals who are inevitably exposed to noise, contributing to the prevention of noise-induced hearing loss with a low probability of adverse effects.

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A Human Inner Ear Model for assessment of Noise Induced Hearing Loss via energy methods

IFAC-PapersOnLine ◽

10.1016/j.ifacol.2020.12.727 ◽

2020 ◽

Vol 53 (2) ◽

pp. 16424-16429

Author(s):

Milka C.I. Madahana ◽

Otis T.C. Nyandoro ◽

John E.D. Ekoru

Keyword(s):

Hearing Loss ◽

Inner Ear ◽

Energy Methods ◽

Noise Induced Hearing Loss ◽

Human Inner Ear

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Local application of hepatocyte growth factor using gelatin hydrogels attenuates noise-induced hearing loss in guinea pigs

Acta Oto-Laryngologica ◽

10.1080/00016480902725197 ◽

2009 ◽

Vol 129 (4) ◽

pp. 453-457 ◽

Cited By ~ 30

Author(s):

Takatoshi Inaoka ◽

Takayuki Nakagawa ◽

Yayoi S. Kikkawa ◽

Yasuhiko Tabata ◽

Kazuya Ono ◽

...

Keyword(s):

Hearing Loss ◽

Growth Factor ◽

Hepatocyte Growth Factor ◽

Guinea Pigs ◽

Local Application ◽

Noise Induced Hearing Loss ◽

Hepatocyte Growth

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

Cell Death and Disease ◽

10.1038/s41419-021-03972-6 ◽

2021 ◽

Vol 12 (7) ◽

Author(s):

Holly J. Beaulac ◽

Felicia Gilels ◽

Jingyuan Zhang ◽

Sarah Jeoung ◽

Patricia M. White

Keyword(s):

Oxidative Stress ◽

Hearing Loss ◽

Noise Exposure ◽

Multiphoton Microscopy ◽

Cell Loss ◽

Outer Hair Cells ◽

Noise Induced Hearing Loss ◽

Knock Out ◽

Cell Death Pathway ◽

Cochlear Damage

AbstractThe 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.

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Outer hair cells in the mammalian cochlea and noise-induced hearing loss

Nature ◽

10.1038/315662a0 ◽

1985 ◽

Vol 315 (6021) ◽

pp. 662-665 ◽

Cited By ~ 77

Author(s):

A. R. Cody ◽

I. J. Russell

Keyword(s):

Hearing Loss ◽

Hair Cells ◽

Outer Hair Cells ◽

Noise Induced Hearing Loss

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Direct drug application to the round window: A comparative study of ototoxicity in rats

Otolaryngology ◽

10.1016/j.otohns.2009.07.014 ◽

2009 ◽

Vol 141 (5) ◽

pp. 584-590 ◽

Cited By ~ 10

Author(s):

Silvia Murillo-Cuesta ◽

Fernando García-Alcántara ◽

Elena Vacas ◽

Jon Alexander Sistiaga ◽

Guadalupe Camarero ◽

...

Keyword(s):

Hearing Loss ◽

Cell Damage ◽

Round Window ◽

Drug Application ◽

Local Drug Delivery ◽

Saline Control ◽

Round Window Membrane ◽

Cochlear Function ◽

Profound Hearing Loss ◽

Brainstem Response

Objective: To assess the validity of inducing ototoxicity in rats by applying a sponge soaked in kanamycin and furosemide on the round window. Study Design: Basic, randomized, nonblind experimental study. Setting: Animal models of cochlear damage and reliable methods of local drug delivery are fundamental to study hearing loss and to design new therapies. Subjects and Methods: Four experimental groups of six Wistar rats with different methods of drug administration were used: (1) injection of subcutaneous kanamycin (400 mg/kg) and intravenous furosemide (100 mg/kg); (2) local application of a sponge soaked in saline close to the round window; (3) animals for which the sponge was soaked in a solution containing kanamycin (200 mg/mL) and furosemide (50 mg/mL); and (4) sham-operated rats. The tympanic bulla was exposed using a ventral approach, and a bullostomy was performed to visualize the round window membrane. Cochlear function was assessed by measuring the auditory brainstem response, and hearing thresholds in response to click and tone burst stimuli were determined as peak and interpeak latencies. At the end of the study, cochlear histology was analyzed. Results: Systemic administration of kanamycin and furosemide induced profound hearing loss and severe hair cell damage. Local delivery of these ototoxic drugs caused comparable damage but avoided the systemic side effects of the drug. Sham-operated and saline control animals did not experience functional alterations. Conclusion: Situating a sponge soaked in kanamycin and furosemide on the round window membrane through the ventral approach is a reliable method to provoke local ototoxicity in rats.

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