Cochlear zinc signaling dysregulation is associated with noise-induced hearing loss, and zinc chelation enhances cochlear recovery.

Exposure to loud noise triggers sensory organ damage and degeneration that, in turn, leads to hearing loss. Despite the troublesome impact of noise-induced hearing loss (NIHL) in individuals and societies, treatment strategies that protect and restore hearing are few and insufficient. As such, identification and mechanistic understanding of the signaling pathways involved in NIHL are required. Biological zinc is mostly bound to proteins, where it plays major structural or catalytic roles; however, there is also a pool of unbound, mobile (labile) zinc. Labile zinc is mostly found in vesicles in secretory tissues, where it is released and plays a critical signaling role. In the brain, labile zinc fine-tunes neurotransmission and sensory processing. However, injury-induced dysregulation of labile zinc signaling contributes to neurodegeneration. Here, we tested whether zinc dysregulation occurs and contributes to NIHL in mice. We found that ZnT3, the vesicular zinc transporter responsible for loading zinc into vesicles, is expressed in cochlear hair cells and the spiral limbus, with labile zinc also present in the same areas. Soon after noise trauma, ZnT3 and zinc levels are significantly increased, and their subcellular localization is vastly altered. Disruption of zinc signaling, either via ZnT3 deletion or pharmacological zinc chelation, mitigated NIHL, as evidenced by enhanced auditory brainstem responses, distortion product otoacoustic emissions, and number of hair cell synapses. These data reveal that noise-induced zinc dysregulation is associated with cochlear dysfunction and recovery after NIHL, and point to zinc chelation as a potential treatment for mitigating NIHL.

Gelatin-Encapsulated Tetrahedral DNA Nanostructure Enhances Cellular Internalization for Treating Noise-Induced Hearing Loss.

Nanoparticle-based drug delivery strategies have emerged as a crucial avenue for comprehensive sensorineural hearing loss treatment. Nevertheless, developing therapy vectors crossing both biological and cellular barriers has encountered significant challenges deriving from various external factors. Herein, the rational integration of gelatin nanoparticles (GNPs) with tetrahedral DNA nanostructures (TDNs) to engineer a distinct drug-delivery nanosystem (designed as TDN@GNP) efficiently enhances the biological permeability and cellular internalization, further resolving the dilemma of noise-induced hearing loss via loading epigallocatechin gallate (EGCG) with anti-lipid peroxidation property. Rationally engineering of TDN@GNP demonstrates dramatic alterations in the physicochemical key parameters of TDNs that are pivotal in cell-particle interactions and promote cellular uptake through multiple endocytic pathways. Furthermore, the EGCG-loaded nanosystem (TDN-EGCG@GNP) facilitates efficient inner ear drug delivery by superior permeability through the biological barrier (round window membrane), maintaining high drug concentration within the inner ear. The TDN-EGCG@GNP actively overcomes the cell membrane, exhibiting hearing protection from noise insults via reduced lipid peroxidation in outer hair cells and spiral ganglion neurons. This work exemplifies how integrating diverse vector functionalities can overcome biological and cellular barriers in the inner ear, offering promising applications for inner ear disorders.

Norepinephrine protects against cochlear outer hair cell damage and noise-induced hearing loss via α2A-adrenergic receptor.

BACKGROUND: The cochlear sympathetic system plays a key role in auditory function and susceptibility to noise-induced hearing loss (NIHL). The formation of reactive oxygen species (ROS) is a well-documented process in NIHL. In this study, we aimed at investigating the effects of a superior cervical ganglionectomy (SCGx) on NIHL in Sprague-Dawley rats. METHODS: We explored the effects of unilateral and bilateral Superior Cervical Ganglion (SCG) ablation in the eight-ten weeks old Sprague-Dawley rats of both sexes on NIHL. Auditory function was evaluated by auditory brainstem response (ABR) testing and Distortion product otoacoustic emissions (DPOAEs). Outer hair cells (OHCs) counts and the expression of α2A-adrenergic receptor (AR) in the rat cochlea using immunofluorescence analysis. Cells culture and treatment, CCK-8 assay, Flow cytometry staining and analysis, and western blotting were to explore the mechanisms of SCG fibers may have a protective role in NIHL. RESULTS: We found that neither bilateral nor unilateral SCGx protected the cochlea against noise exposure. In HEI-OC1 cells, H2O2-induced oxidative damage and cell death were inhibited by the application of norepinephrine (NE). NE may prevent ROS-induced oxidative stress in OHCs and NIHL through the α2A-AR. CONCLUSION: These results demonstrated that sympathetic innervation mildly affected cochlear susceptibility to acoustic trauma by reducing oxidative damage in OHCs through the α2A-AR. NE may be a potential therapeutic strategy for NIHL prevention.

Therapeutic effect of intraperitoneal dexamethasone on noise-induced permanent threshold shift in mice model.

The purpose of the study was to which investigate whether dexamethasone, which has anti-inflammatory and immune response suppression roles, could treat noise-induced hearing loss caused by damage to hair cells in the cochlea. The experiment used 8-week-old CBA mice exposed to white noise at an intensity of 110 dB SPL for 2 h, with hearing loss confirmed by the auditory brainstem response test. Dexamethasone was administered by intraperitoneal injection for 5 days, and the therapeutic effect was investigated for 3 weeks. The experimental groups were 3 mg/kg of dexamethasone (3 mpk) and 10 mg/kg of dexamethasone (10 mpk), and the control group was a saline-administered group. The results showed that compared to the control group, the hearing threshold value was recovered by 10 dB SPL compared to the saline group from the 14th day in the 3 mpk group. In the 10 mpk group, thresholds were recovered from the 7th day compared to the saline group. This difference was similar at 4 kHz, and in the case of the 10 mpk group, the threshold was recovered by 20 dB SPL compared to the saline group. The study also confirmed the restoration of nerve cell activity and showed a recovery effect of about 20 µV in the amplitude value change in the 10 mpk group. In conclusion, the study suggests that dexamethasone has a therapeutic effect for noise-induced hearing loss by increasing the activity of nerve cells and showing a recovery effect from hair cells damaged by noise.

ERK1/2 Inhibition via the Oral Administration of Tizaterkib Alleviates Noise-Induced Hearing Loss While Tempering down the Immune Response.

Noise-induced hearing loss (NIHL) is a major cause of hearing impairment and is linked to dementia and mental health conditions, yet no FDA-approved drugs exist to prevent it. Downregulating the mitogen-activated protein kinase (MAPK) cellular pathway has emerged as a promising approach to attenuate NIHL, but the molecular targets and the mechanism of protection are not fully understood. Here, we tested specifically the role of the kinases ERK1/2 in noise otoprotection using a newly developed, highly specific ERK1/2 inhibitor, tizaterkib, in preclinical animal models. Tizaterkib is currently being tested in phase 1 clinical trials for cancer treatment and has high oral bioavailability and low predicted systemic toxicity in mice and humans. In this study, we performed dose-response measurements of tizaterkib's efficacy against permanent NIHL in adult FVB/NJ mice, and its minimum effective dose (0.5 mg/kg/bw), therapeutic index (>50), and window of opportunity (<48 h) were determined. The drug, administered orally twice daily for 3 days, 24 h after 2 h of 100 dB or 106 dB SPL noise exposure, at a dose equivalent to what is prescribed currently for humans in clinical trials, conferred an average protection of 20-25 dB SPL in both female and male mice. The drug shielded mice from the noise-induced synaptic damage which occurs following loud noise exposure. Equally interesting, tizaterkib was shown to decrease the number of CD45- and CD68-positive immune cells in the mouse cochlea following noise exposure. This study suggests that repurposing tizaterkib and the ERK1/2 kinases' inhibition could be a promising strategy for the treatment of NIHL.

Role of Oxidative Stress in Sensorineural Hearing Loss.

Hearing is essential for communication, and its loss can cause a serious disruption to one's social life. Hearing loss is also recognized as a major risk factor for dementia; therefore, addressing hearing loss is a pressing global issue. Sensorineural hearing loss, the predominant type of hearing loss, is mainly due to damage to the inner ear along with a variety of pathologies including ischemia, noise, trauma, aging, and ototoxic drugs. In addition to genetic factors, oxidative stress has been identified as a common mechanism underlying several cochlear pathologies. The cochlea, which plays a major role in auditory function, requires high-energy metabolism and is, therefore, highly susceptible to oxidative stress, particularly in the mitochondria. Based on these pathological findings, the potential of antioxidants for the treatment of hearing loss has been demonstrated in several animal studies. However, results from human studies are insufficient, and future clinical trials are required. This review discusses the relationship between sensorineural hearing loss and reactive oxidative species (ROS), with particular emphasis on age-related hearing loss, noise-induced hearing loss, and ischemia-reperfusion injury. Based on these mechanisms, the current status and future perspectives of ROS-targeted therapy for sensorineural hearing loss are described.

C-Phycocyanin Attenuates Noise-Induced Cochlear Synaptopathy via the Inhibition of Oxidative Stress and Intercellular Adhesion Molecule-1 in the Cochlea.

The synapses between inner hair cells (IHCs) and spiral ganglion neurons (SGNs) are the most vulnerable structures in the noise-exposed cochlea. Cochlear synaptopathy results from the disruption of these synapses following noise exposure and is considered the main cause of poor speech understanding in noisy environments, even when audiogram results are normal. Cochlear synaptopathy leads to the degeneration of SGNs if damaged IHC-SGN synapses are not promptly recovered. Oxidative stress plays a central role in the pathogenesis of cochlear synaptopathy. C-Phycocyanin (C-PC) has antioxidant and anti-inflammatory activities and is widely utilized in the food and drug industry. However, the effect of the C-PC on noise-induced cochlear damage is unknown. We first investigated the therapeutic effect of C-PC on noise-induced cochlear synaptopathy. In vitro experiments revealed that C-PC reduced the H2O2-induced generation of reactive oxygen species in HEI-OC1 auditory cells. H2O2-induced cytotoxicity in HEI-OC1 cells was reduced with C-PC treatment. After white noise exposure for 3 h at a sound pressure of 118 dB, the guinea pigs intratympanically administered 5 µg/mL C-PC exhibited greater wave I amplitudes in the auditory brainstem response, more IHC synaptic ribbons and more IHC-SGN synapses according to microscopic analysis than the saline-treated guinea pigs. Furthermore, the group treated with C-PC had less intense 4-hydroxynonenal and intercellular adhesion molecule-1 staining in the cochlea compared with the saline group. Our results suggest that C-PC improves cochlear synaptopathy by inhibiting noise-induced oxidative stress and the inflammatory response in the cochlea.

Efficacy of Oral Steroids for Acute Acoustic Trauma.

OBJECTIVE: This study aimed to study the effect of steroid treatment on new-onset sensorineural hearing loss (SNHL) in subjects presenting shortly after an audiometry-confirmed acute acoustic trauma (AAT) injury. STUDY DESIGN: This is a case-control study. METHODS: We identified healthy military personnel who presented with AAT injury to the Israeli Defense Forces Medical Corps Otolaryngology/Audiology Services during 2016-2020. Patients were nonrandomly allocated to a treatment arm, where they received steroids (prednisone, 1 mg/kg, 60 mg maximal daily dose), administered for either ≥7 days or <7 days, or to a control arm, in which no treatment was offered besides loud noise avoidance. Audiometries were conducted within 7 days following the AAT and within 1 month later. We compared changes in bone conduction (BC) and air conduction (AC) thresholds at 2-8 kHz. RESULTS: Of the 263 enrolled subjects, 137 (52%) received steroids and 126 (48%) received no treatment. Subjects who were treated early (<24 h) with high-dose steroids and for ≥7 days demonstrated significantly better hearing outcomes, compared with the nontreatment group. Subjects in the steroids group demonstrated 13-14 dB average improvement in BC thresholds at 3 and 4 kHz (p = 0.001) and additional 7-8 dB average improvement in AC thresholds at 6 and 8 kHz, compared with the nontreatment group (p < 0.0001). These observations were more compelling in patients who initially presented with worse hearing losses (>35 dB). No statistically significant differences were observed in AC/BC pure tone average between the two groups. CONCLUSIONS: Early oral steroids are recommended in AAT injuries and were shown to improve hearing outcomes within 1 month.

A PRMT5 inhibitor protects against noise-induced hearing loss by alleviating ROS accumulation.

The aim of this study was to investigate the effect of LLY-283, a selective inhibitor of protein arginine methyltransferase 5 (PRMT5), on a noise-induced hearing loss (NIHL) mouse model and to identify a potential target for a therapeutic intervention against NIHL. Eight-week-old male C57BL/6 mice were used. The auditory brainstem response was measured 2 days after noise exposure. The apoptosis of hair cells (HCs) was detected by caspase-3/7 staining, whereas the accumulation of reactive oxygen species (ROS) was measured by 4-HNE staining. We demonstrated that the death of HCs and loss of cochlear synaptic ribbons induced by noise exposure could be significantly reduced by the presence of LLY-283. LLY-283 pretreatment before noise exposure notably decreased 4-HNE and caspase-3/7 levels in the cochlear HCs. We also noticed that the number of spiral ganglion neurons (SGNs) was notably increased after LLY-283 pretreatment. Furthermore, we showed that LLY-283 could increase the expression level of p-AKT in the SGNs. The underlying mechanism involves alleviation of ROS accumulation and activation of the PI3K/AKT pathway, indicating that LLY-283 might be a potential candidate for therapeutic intervention against NIHL.

Integrating pharmacogenomics into clinical trials of hearing disorders.

In 2019, the U.S. Food and Drug Administration issued guidance to increase the efficiency of drug development and support precision medicine, including tailoring treatments to those patients who will benefit based on genetic variation even in the absence of a documented mechanism of action. Although multiple advancements have been made in the field of pharmacogenetics (PGx) for other disease conditions, there are no approved PGx guidelines in the treatment of hearing disorders. In studies of noise-induced hearing loss (NIHL), some progress has been made in the last several years associating genomic loci with susceptibility to noise damage. However, the power of such studies is limited as the underlying physiological responses may vary considerably among the patient populations. Here, we have summarized previous animal studies to argue that NIHL subtyping is a promising strategy to increase the granularity of audiological assessments. By coupling this enhanced phenotyping capability with genetic association studies, we suggest that drug efficacy will be better predicted, increasing the likelihood of success in clinical trials when populations are stratified based on genetic variation or designed with multidrug combinations to reach a broader segment of individuals suffering or at risk from NIHL.

[Preliminary observation on the differential expression of metformin in preventing noise-induced hearing loss in inner ear protein group of rats].

Objective: To study the protective effects of metformin on noise-induced hearing loss (NIHL) and its differential protein omics expression profile. Methods: In January 2021, 39 male Wistar rats were randomly divided into control group, noise exposure group and metformin+noise exposure group, with 13 rats in each group. Rats in the noise exposure group and metformin+noise exposure group were continuously exposed to octave noise with sound pressure level of 120 dB (A) and center frequency of 8 kHz for 4 h. Rats in the metformin+noise exposure group were treated with 200 mg/kg/d metformin 3 d before noise exposure for a total of 7 d. Auditory brainstem response (ABR) was used to test the changes of hearing thresholds before noise exposure and 1, 4, 7 d after noise exposure in the right ear of rats in each group. Tandem mass tag (TMT) quantitative proteomics was used to identify and analyze the differentially expressed protein in the inner ear of rats in each group, and it was verified by immunofluorescence staining with frozen sections. Results: The click-ABR thresholds of right ear in the noise exposure group and metformin+noise exposure group were significantly higher than those in the control group 1, 4, 7 d after noise exposure (P<0.05) . The click-ABR threshold of right ear in the metformin+noise exposure group were significantly lower than that in the noise exposure group (P<0.05) . Compared with the noise exposure group, 1035 up-regulated proteins and 1145 down-regulated proteins were differentially expressed in the metformin+noise exposure group. GO enrichment analysis showed that the significantly differentially expressed proteins were mainly involved in binding, molecular function regulation, signal transduction, and other functions. Enrichment analysis of KEGG pathway revealed that the pathways for significant enrichment of differentially expressed proteins included phosphatidylinositol 3-kinase-protein kinase B (PI3K-Akt) signaling pathway, focal adhesion, diabetic cardiomyopathy, mitogen, and mitogen-activated protein kinase (MAPK) signaling pathway. Immunofluorescence experiments showed that compared with the noise exposure group, the fluorescence intensity of insulin-like growth factor 1 receptor (IGF1R) in the metformin+noise exposure group was increased, and the fluorescence intensity of eukaryotic translation initiation factor 4E binding protein 1 (eIF4EBP1) was decreased. Conclusion: Noise exposure can lead to an increase in rat hearing threshold, and metformin can improve noise-induced hearing threshold abnormalities through multiple pathways and biological processes.

The preparation of dexamethasone sodium phosphate multivesicular liposomes thermosensative hydrogel and its impact on noise-induced hearing loss in the Guinea pigs.

OBJECTIVE: The aim of this study is to establish the dexamethasone sodium phosphate multivesicular liposomes thermosensative hydrogel (DEX-MVLs-Gel) drug delivery system and to analyze the pharmacodynamics, pharmacokinetics and safety of DEX-MVLs-Gel as well as to explore whether the prepared DEX-MVLs-Gel can protect the hearing in the guinea pigs following noise exposure. METHODS: DEX-MVLs formulations were constructed by double emulsion method, and the DEX-MVLs-Gel was prepared after adding P407 and P188 into the DEX-MVLs. A total of 20 adult albino guinea pigs were chosen to establish the animal models with noise-induced hearing loss. After animals were treated with DEX-MVLs-Gel at concentrations of 20, 6 and 2 mg/mL, and 5 mg/mL Dexamethasone Sodium Phosphate (DEX-P) solution, respectively, the hearing function, drug concentration in the peripheral lymph fluid, and hair cell morphology were assessed. RESULTS: The ABR threshold of the 20 mg/mL DEX-MVLs-Gel treated group at the frequencies of 4, 8, 16 and 24 kHz were measured as 47.5 ± 5.2, 48.3 ± 4.1, 55.8 ± 3.8 and 57.5 5 ± 5.2 dB SPL, respectively. Statistical significances were noted between the 20 mg/mL DEX-MVLs-Gel treated group and control group at each frequency (all P < 0.05), between the 2 mg/mL and 6 mg/mL DEX-MVLs-Gel treated groups at the frequencies of 4 and 8 kHz (both P < 0.05). High Performance Liquid Chromatography (HPLC) demonstrated that the drug concentrations in the peripheral lymph in all groups were gradually decreased on the 1st, 3rd and 7th d after intratympanic injection. Scattered hair cell loss could be observed mainly in the basal and middle turn in the saline administrated group and the 20 mg/mL DEX-MVLs-Gel administration group, and the hair cell loss was not identified in the apical turn. CONCLUSIONS: A high concentration (20 mg/mL) of DEX-MVLs-Gel exerts significant protective effects upon the guinea pigs with noise-induced hearing loss. The prepared DEX-MVLs-Gel can be effectively maintained in the peripheral lymph fluid of guinea pigs for 3-7 d and MVLs-Gel causes no obvious ototoxicity.

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

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.

Noise-Induced Hearing Loss: Updates on Molecular Targets and Potential Interventions.

Noise overexposure leads to hair cell loss, synaptic ribbon reduction, and auditory nerve deterioration, resulting in transient or permanent hearing loss depending on the exposure severity. Oxidative stress, inflammation, calcium overload, glutamate excitotoxicity, and energy metabolism disturbance are the main contributors to noise-induced hearing loss (NIHL) up to now. Gene variations are also identified as NIHL related. Glucocorticoid is the only approved medication for NIHL treatment. New pharmaceuticals targeting oxidative stress, inflammation, or noise-induced neuropathy are emerging, highlighted by the nanoparticle-based drug delivery system. Given the complexity of the pathogenesis behind NIHL, deeper and more comprehensive studies still need to be fulfilled.

Combination photobiomodulation/N-acetyl-L-cysteine treatment appears to mitigate hair cell loss associated with noise-induced hearing loss in rats.

Sensorineural hearing loss is an intractable disease. Acoustic overstimulation creates hearing loss; many patients exhibit social and emotional dysfunctions. In a model of noise-induced hearing loss (NIHL), low-level laser photobiomodulation (PBM) at a near-infrared wavelength significantly improved auditory brainstem response (ABR) thresholds. In addition, both N-acetyl-L-cysteine (NAC) and acetyl-L-carnitine (ALCAR) attenuated NIHL, reducing the effects of noise trauma in the cochlea and the central auditory system. Here, we combined PBM with antioxidants to explore hearing threshold recovery and morphological hair cell changes after rats were exposed to noise. The average auditory brainstem response thresholds after PBM/NAC combination treatment were reduced from the apex to the basal turn at all of 8, 16, and 32 kHz compared to the noise-only group. The PBM/NAC combination treated group exhibited intact outer hair cells in all turns, and significantly greater hair cell numbers in the middle and basal cochlear turns, than did controls. Thus, PBM/NAC treatment may prevent hearing dysfunction caused by NIHL.

Effect and Biocompatibility of a Cross-Linked Hyaluronic Acid and Polylactide-co-glycolide Microcapsule Vehicle in Intratympanic Drug Delivery for Treating Acute Acoustic Trauma.

The treatment of acute hearing loss is clinically challenging due to the low efficacy of drug delivery into the inner ear. Local intratympanic administration of dexamethasone (D) and insulin-like growth factor 1 (IGF1) has been proposed for treatment, but they do not persist in the middle ear because they are typically delivered in fluid form. We developed a dual-vehicle drug delivery system consisting of cross-linked hyaluronic acid and polylactide-co-glycolide microcapsules. The effect and biocompatibility of the dual vehicle in delivering D and IGF1 were evaluated using an animal model of acute acoustic trauma. The dual vehicle persisted 10.9 times longer (8.7 days) in the middle ear compared with the control (standard-of-care vehicle, 0.8 days). The dual vehicle was able to sustain drug release over up to 1 to 2 months when indocyanine green was loaded as the drug. One-third of the animals experienced an inflammatory adverse reaction. However, it was transient with no sequelae, which was validated by micro CT findings, endoscopic examination, and histological assessment. Hearing restoration after acoustic trauma was satisfactory in both groups, which was further supported by comparable numbers of viable hair cells. Overall, the use of a dual vehicle for intratympanic D and IGF1 delivery may maximize the effect of drug delivery to the target organ because the residence time of the vehicle is prolonged.

Junctional Modulation of Round Window Membrane Enhances Dexamethasone Uptake into the Inner Ear and Recovery after NIHL.

Delivery of substances into the inner ear via local routes is increasingly being used in clinical treatment. Studies have focused on methods to increase permeability through the round window membrane (RWM) and enhance drug diffusion into the inner ear. However, the clinical applications of those methods have been unclear and few studies have investigated the efficacy of methods in an inner ear injury model. Here, we employed the medium chain fatty acid caprate, a biologically safe, clinically applicable substance, to modulate tight junctions of the RWM. Intratympanic treatment of sodium caprate (SC) induced transient, but wider, gaps in intercellular spaces of the RWM epithelial layer and enhanced the perilymph and cochlear concentrations/uptake of dexamethasone. Importantly, dexamethasone co-administered with SC led to significantly more rapid recovery from noise-induced hearing loss at 4 and 8 kHz, compared with the dexamethasone-only group. Taken together, our data indicate that junctional modulation of the RWM by SC enhances dexamethasone uptake into the inner ear, thereby hastening the recovery of hearing sensitivity after noise trauma.

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.

Biocompatibility and Therapeutic Effect of 3 Intra-Tympanic Drug Delivery Vehicles in Acute Acoustic Trauma.

INTRODUCTION: The aim of this study was to assess the biocompatibility of several intra-tympanic (IT) drug delivery vehicles and to compare hearing outcomes. MATERIALS AND METHODS: After acute acoustic trauma, rats were treated with IT 10 mg/mL dexamethasone phosphate (D) and divided into the following groups for drug delivery: saline + D (n = 15), hyaluronic acid (HA) + D (n = 17), and methoxy polyethylene glycol-b-polycaprolactone block copolymer (MP) + D (n = 24). RESULTS: No inflammation was found in the saline + D or HA + D groups. The duration of vehicle/drug persistence in the bulla was significantly longer for the MP + D (47.5 days) and HA + D groups (1.8 days) than for the saline + D group (<1 day). The tympanic membrane was significantly thicker in the MP + D group than in the saline + D and HA + D groups. The proportion of ears with good hearing outcome was significantly higher (63.6%) in the HA + D group than in the MP + D group. The number of hair cells in the hearing loss (HL) control group was significantly lower than in the MP + D group. DISCUSSION/CONCLUSION: HA shows great potential as a biocompatible vehicle for D delivery via the IT route, without an inflammatory reaction and with better hearing outcomes. Considering inflammation and hearing, MP may not be a good candidate for IT drug delivery.

Therapeutic effects of metformin for noise induced hearing loss.

OBJECTIVE: This study aimed to investigate the healing effect of metformin on noise induced hearing loss (NIHL) by measuring audiological, biochemical and histological parameters. MATERIALS AND METHODS: 32 rats were divided into four groups (Group 1: Noise, Group 2: Noise + Metformin, Grup 3: Metformin, Grup 4: Control). Broadband noise was applied to Group 1 and Group 2 after basal measurements. Measuring audiological (distortion product otoacoustic emission (DPOAE) and Auditory Brainstem Response (ABR)), biochemical (total antioxidant status (TAS), total oxidant status (TOS), oxidative status index (OSI), DNA damage, IL-1 beta, IL-6, TNF alfa, HSF-1 and COX-2) and histological parameters. RESULTS: Group 2 had significant decreases in ABR thresholds on day 7 and day 14 compared to day 1. DPOAE values of Group 2 on the 7th and 14th days were significantly higher than the post-noise levels. DNA damage, TOS and OSI values of Group 1 were significantly higher than the other groups. The Cox-2 value of Group 1 was higher than all other groups. The HSF-1 value of Group 2 was significantly higher than that of Group 1. In terms of IL-1 Beta, IL-6 and TNF-alpha values, there was no significant difference between groups 2, 3 and 4 and these values were significantly lower than group 1. In histopathological results of our study, no significant difference was found between the groups being exposed to noise and the control group. CONCLUSION: This study showed that early period of Metformin treatment has therapeutic effect on NIHL.