Thymoquinone ameliorates age-related hearing loss in C57BL/6J mice by modulating Sirt1 activity and Bak1 expression.

Age-related hearing loss (AHL) is the most common sensory disorder of aged population. Currently, one of the most important sources of experimental medicine for AHL is medicinal plants. This study performed the first investigation of the effect of thymoquinone (TQ), a potent antioxidant, on AHL. Here, we used inbred C57BL/6J mice (B6 mice) as a successful experimental model of the early onset of AHL. The behavioral assessment of hearing revealed that the injection of a high dose of TQ (40 mg/kg; TQ40) significantly improved the auditory sensitivity of B6 mice at all tested frequencies (8, 16 and 22 kHz). Histological sections of cochlea from B6 mice injected with a low dose (20 mg/kg; TQ20) and high dose showed relatively less degenerative signs in the modiolus, hair cells and spiral ligaments, the main constituents of the cochlea. In addition, TQ40 completely restored the normal pattern of hair cells in B6 mice, as shown in scanning electron micrographs. Our data indicated that TQ20 and TQ40 reduced levels of Bak1-mediated apoptosis in the cochlea of B6 mice. Interestingly, the level of Sirt1, a positive regulator of autophagy, was significantly increased in B6 mice administered TQ40. In conclusion, TQ relieves the symptoms of AHL by downregulating Bak1 and activating Sirt1 in the cochlea of B6 mice.

Inhibition of Histone Methyltransferase G9a Attenuates Noise-Induced Cochlear Synaptopathy and Hearing Loss.

Posttranslational modification of histones alters their interaction with DNA and nuclear proteins, influencing gene expression and cell fate. In this study, we investigated the effect of G9a (KMT1C, EHMT2), a major histone lysine methyltransferase encoded by the human EHMT2 gene and responsible for histone H3 lysine 9 dimethylation (H3K9me2) on noise-induced permanent hearing loss (NIHL) in adult CBA/J mice. The conditions of noise exposure used in this study led to losses of cochlear synapses and outer hair cells (OHCs) and permanent auditory threshold shifts. Inhibition of G9a with its specific inhibitor BIX 01294 or with siRNA significantly attenuated these pathological features. Treatment with BIX 01294 also prevented the noise-induced decrease of KCNQ4 immunolabeling in OHCs. Additionally, G9a was increased in cochlear cells, including both outer and inner sensory hair cells, some spiral ganglion neurons (SGNs), and marginal cells, 1 h after the completion of the noise exposure. Also subsequent to noise exposure, immunoreactivity for H3K9me2 appeared in some nuclei of OHCs following a high-to-low frequency gradient with more labeled OHCs in the 45-kHz than the 32-kHz region, as well as in the marginal cells and in some SGNs of the basal turn. These findings suggest that epigenetic modifications of H3K9me2 are involved in NIHL and that pharmacological targeting of G9a may offer a strategy for protection against cochlear synaptopathy and NIHL.

Effect of antioxidant supplementation on the auditory threshold in sensorineural hearing loss: a meta-analysis / Efeito da suplementação de antioxidantes sobre o limiar auditivo na perda auditiva neurosensorial: uma metanálise

Abstract Introduction: Hearing loss is conceptualized as any impairment of the ability to hear and/or detect speech or environment sounds, regardless of cause, type, or degree. It may occur at different stages of life; during pregnancy or childbirth, in childhood, adulthood or old age. It should be noted that aging is the most common cause of sensorineural hearing loss followed by noise-induced hearing loss, and both are closely related to the formation of reactive oxygen species. Dietary antioxidant supplementation has been employed as a therapeutic strategy to prevent and/or delay the risks of major human diseases. Objective: To assess randomized clinical trials to determine the effect of antioxidant supplementation on the auditory thresholds in patients of different age groups with sensorineural hearing loss. Methods: This systematic review consisted of a search in the following databases: MEDLINE, CENTRAL, ScienceDirect, Scopus, Web of Science, LILACS, SciELO and ClinicalTrials.gov. Additionally, the gray literature was also searched. The search strategy included terms related to the intervention (antioxidant supplementation), primary outcome (sensorineural hearing loss), as well as terms related to randomized clinical trials to improve search sensitivity. Results: Based on 977 potentially relevant records identified through the search in the databases, ten full-text publications were retrieved for further evaluation. The increase in threshold at the 4 kHz frequency was statistically higher in the control group (1.89 [1.01-2.78], p < 0.0001) when compared to the NAC group and the ginseng group, whereas at 6 kHz, the threshold increase was higher in the control group (1.42 [−1.14-3.97], p = 0.28), but no statistically significant differences were found between groups. Conclusion: Ginseng was the antioxidant agent that showed the best effect in preventing auditory threshold worsening at the frequency of 4 kHz, but not at 6 kHz in patients with sensorineural hearing loss caused by exposure to high sound pressure levels. There was no improvement in the thresholds with vitamin E supplementation.

Resumo Introdução: A perda auditiva é conceituada como qualquer diminuição da capacidade de ouvir e/ou detectar sons da fala ou do ambiente, independentemente da causa, tipo ou grau e pode ocorrer em diversos estágios da vida, durante a gestação ou parto, na infância, vida adulta ou na terceira idade. Convém destacar que o envelhecimento é a primeira causa de perda auditiva do tipo sensorioneural e em segundo lugar a perda auditiva induzida pelo ruído, ambas estão intimamente relacionadas com a formação de espécies reativas de oxigênio. Evidências têm sido acumuladas indicando que a suplementação com antioxidantes via alimentação tornou-se estratégia terapêutica para prevenir e/ou retardar os riscos das principais doenças humanas. Objetivo: Avaliar ensaios clínicos aleatórios para determinar qual o efeito da suplementação com antioxidantes sobre o limiar auditivo na perda auditiva sensorioneural em pacientes de diversas faixas etárias. Método: A formulação desta revisão sistemática consistiu na busca dos estudos nas seguintes bases de dados: MEDLINE, CENTRAL, ScienceDirect, Scopus, Web of Science, LILACS, SciELO e ClinicalTrials.gov. Adicionalmente, a literatura cinzenta também foi pesquisada. A estratégia de busca incluiu termos relacionados à intervenção (suplementação de antioxidantes), o desfecho primário (perda auditiva sensorioneural), bem como termos relacionados aos ensaios clínicos randomizados para melhorar e a sensibilidade da busca. Resultados: A partir de 977 registros potencialmente relevantes identificados através da busca nas bases de dados, dez publicações em texto completo foram recuperadas para avaliação mais aprofundada. O aumento no limiar na frequência de 4 kHz foi estatisticamente maior no Grupo Controle (1,89 [1,01-2,78], p < 0,0001) quando comparados com o Grupo NAC e o Grupo Ginseng, já na frequência de 6 kHz o aumento no limiar foi maior no Grupo Controle (1,42 [-1,14-3,97], p = 0,28), porém, não foram encontradas diferenças estatisticamente significativas entre grupos. Conclusão: O Ginseng foi o antioxidante que evitou a piora do limiar auditivo na frequência de 4 kHz, mas não em 6 kHz, em pacientes com perda auditiva sensorioneural causada por exposição a elevados níveis de pressão sonora. Não foi observada melhora nos limiares com a suplementação com Vitamina E.

Effect of antioxidant supplementation on the auditory threshold in sensorineural hearing loss: a meta-analysis.

INTRODUCTION: Hearing loss is conceptualized as any impairment of the ability to hear and/or detect speech or environment sounds, regardless of cause, type, or degree. It may occur at different stages of life; during pregnancy or childbirth, in childhood, adulthood or old age. It should be noted that aging is the most common cause of sensorineural hearing loss followed by noise-induced hearing loss, and both are closely related to the formation of reactive oxygen species. Dietary antioxidant supplementation has been employed as a therapeutic strategy to prevent and/or delay the risks of major human diseases. OBJECTIVE: To assess randomized clinical trials to determine the effect of antioxidant supplementation on the auditory thresholds in patients of different age groups with sensorineural hearing loss. METHODS: This systematic review consisted of a search in the following databases: MEDLINE, CENTRAL, ScienceDirect, Scopus, Web of Science, LILACS, SciELO and ClinicalTrials.gov. Additionally, the gray literature was also searched. The search strategy included terms related to the intervention (antioxidant supplementation), primary outcome (sensorineural hearing loss), as well as terms related to randomized clinical trials to improve search sensitivity. RESULTS: Based on 977 potentially relevant records identified through the search in the databases, ten full-text publications were retrieved for further evaluation. The increase in threshold at the 4kHz frequency was statistically higher in the control group (1.89 [1.01-2.78], p<0.0001) when compared to the NAC group and the ginseng group, whereas at 6kHz, the threshold increase was higher in the control group (1.42 [-1.14-3.97], p=0.28), but no statistically significant differences were found between groups. CONCLUSION: Ginseng was the antioxidant agent that showed the best effect in preventing auditory threshold worsening at the frequency of 4kHz, but not at 6kHz in patients with sensorineural hearing loss caused by exposure to high sound pressure levels. There was no improvement in the thresholds with vitamin E supplementation.

Trigonelline promotes auditory function through nerve growth factor signaling on diabetic animal models.

BACKGROUND: Protection of cochlear function and reconstruction of neuronal networks in damaged auditory sensory structures is crucial for therapeutic treatment of diabetic hearing loss. Nerve growth factor (NGF) has been used as a novel therapeutic target to protect against the neurodegenerative effects of Diabetes Mellitus (DM). PURPOSE: We aimed to evaluate the potential effect of trigonelline (TRG) on reducing auditory damage produced by DM using NGF as a potential marker. METHOD: Docking simulations were carried out using Autodock Vina software and visualized using Discovery Studio. Morphological analysis of hair cells and neuromasts was performed on alloxan-induced diabetic zebrafish by fluorescence and scanning electron microscopy. Blockage of NGF receptor phosphorylation with K-252a was used to evaluate TRG and NGF action. Further assessment of NGF by ELISA on a primary culture of spiral ganglion cells was performed as a marker of neuronal function on the hearing system. Finally, auditory function was assessed in LepR(db/db) mice using auditory brainstem response (ABR) and transient evoked otoacoustic emission (TEOAE) during 8 weeks. RESULTS: Docking simulations showed that TRG binds to the active site of NGF through molecular interactions with Lysine88 (Lys88) and Tyrosine52 (Tyr52). TRG treatment significantly reduced hair cell loss and neuromast damage in diabetic zebrafish (P < .05). Further evaluation revealed a significant increase in the number of neuromasts after NGF administration (P < .001). TRG and NGF action was suppressed during blockage of NGF receptor phosphorylation. Moreover, spiral ganglion cells revealed significant elevation on NGF values after TRG treatment (P < .05). In vivo evaluation of LepR(db/db) mice revealed a significant reduction in the auditory damage produced under diabetic progression, characterized by reduced ABR hearing threshold shifts and increased signal-to-noise ratio in TEOAE (P < .05). CONCLUSIONS: This study suggests that the enhanced hearing function produced by TRG may be mediated by NGF, providing a potential therapeutic strategy for diabetic hearing loss.

The effects of postnatal phthalate exposure on the development of auditory temporal processing in rats.

OBJECTIVE: The central auditory pathway is known to continue its development during the postnatal critical periods and is shaped by experience and sensory inputs. Phthalate, a known neurotoxic material, has been reported to be associated with attention deficits in children, impacting many infant neurobehaviors. The objective of this study was to investigate the potential effects of neonatal phthalate exposure on the development of auditory temporal processing. METHODS: Neonatal Sprague-Dawley rats were randomly assigned into two groups: The phthalate group (n = 6), and the control group (n = 6). Phthalate was given once per day from postnatal day 8 (P8) to P28. Upon completion, at P28, the Auditory Brainstem Response (ABR) and Gap Prepulse Inhibition of Acoustic Startle response (GPIAS) at each gap duration (2, 5, 10, 20, 50 and 80 ms) were measured, and gap detection threshold (GDT) was calculated. These outcomes were compared between the two groups. RESULTS: Hearing thresholds by ABR showed no significant differences at all frequencies between the two groups. Regarding GPIAS, no significant difference was observed, except at a gap duration of 20 ms (p = 0.037). The mean GDT of the phthalate group (44.0 ms) was higher than that of the control group (20.0 ms), but without statistical significance (p = 0.065). Moreover, the phthalate group tended to demonstrate more of a scattered distribution in the GDT group than the in the control group. CONCLUSION: Neonatal phthalate exposure may disrupt the development of auditory temporal processing in rats.

[Diagnostics and Therapy of Idiopathic Sudden Sensorineural Hearing Loss]. / Diagnostik und Therapie des Hörsturzes.

This article reviews recent aspects of diagnostics, differential diagnostics and evidence in systemic and local therapy of idiopathic, sudden, sensorineural hearing loss (ISSHL). Since a number of disorders can be accompanied by sudden hearing loss a meaningful and targeted diagnostic strategy is of utmost importance. An important differential diagnosis of sudden hearing loss are intralabyrinthine schwannomas (ILS). The incidence of ILS is probably significantly underestimated. This may be due to the lack of awareness or lack of explicit search for an intralabyrinthine tumor on MRI or an inappropriate MRI technique ('head-MRI' instead of 'temporal bone-MRI' with too high slice thickness) for the evaluation of sudden hearing loss. Therefore, the request to the radiologist should specifically include the question for (or exclusion of) an ILS. With special MRI techniques, it is today possible to visualize an endolymphatic hydrops. The evidence in the therapy of ISSHL is - with respect to quality not quantity of studies - unsatisfying. The value of systemically (low dose) or intratympanically applied corticosteroids in the primary treatment of ISSHL is still unclear. In order to investigate the efficacy and safety of high dose corticosteroids in primary treatment for ISSHL a national, multicenter, three-armed, randomized, triple-blind controlled clinical trial is currently performed in Germany (http://hodokort-studie.hno.org/). After insufficient recovery of threshold with systemic therapy of ISSHL, intratympanic corticosteroid therapy appears to be associated with a significantly higher chance of improvement of hearing threshold than no therapy or placebo. Both, hearing gain and final hearing thresholds, however, appear to be independent of the start of secondary therapy. Based on the currently available data from clinical studies, no recommendation can be made with respect to type of corticosteroid and specifics of the intratympanic application protocol.

Carbon disulfide potentiates the effects of impulse noise on the organ of Corti.

Occupational noise can damage workers' hearing, and the phenomenon is even more dangerous when noise is associated with an ototoxic solvent. Aromatic solvents are known to provoke chemical-induced hearing loss, but little is known about the effects on hearing of carbon disulfide (CS2) when combined with noise. Co-exposure to CS2 and noise may have a harmful effect on hearing, but the mechanisms involved are not well understood. For instance, CS2 is not thought to have a cochleotoxic effect, but rather it is thought to cause retrocochlear hearing impairment. In other words, CS2 could have a distal neuropathic effect on the auditory pathway. However, a possible pharmacological effect of CS2 on the central nervous system (CNS) has never been mentioned in the literature. The aim of this study was to assess, in rats, the effects of a noise (continuous vs. impulse), associated with a low concentration of CS2 [(short-term threshold limit value) x 10 as a safety factor] on the peripheral auditory receptor. The noise, whatever its nature, was an octave band noise centered at 8kHz, and the 250-ppm CS2 exposure lasted 15min per hour, 6h per day, for 5 consecutive days. The impact of the different experimental conditions on hearing loss was assessed using distortion product oto-acoustic emissions and histological analyses. Although the LEX,8h (8-h time-weighted average exposure) for the impulse noise was lower (84dB SPL) than that for the continuous noise (89dB SPL), it appeared more damaging to the organ of Corti, in particular to the outer hair cells. CS2 exposure alone did not have any effect on the organ of Corti, but co-exposure to continuous noise with CS2 was less damaging than exposure to continuous noise alone. In contrast, the cochleo-traumatic effects of impulse noise were significantly enhanced by co-exposure to CS2. Therefore, CS2 can clearly modulate the middle-ear reflex function. In fact, CS2 may have two distinct effects: firstly, it has a pharmacological effect on the CNS, modifying the trigger of the acoustic reflex; and secondly, it can make the organ of Corti more susceptible to impulse noise. The pharmacological effects on the CNS and the effects of CS2 on the organ of Corti are discussed to try to explain the overall effect of the solvent on hearing. Once again, the results reported in this article show that the temporal structure (continuous vs. impulse) of noise should be taken into consideration as a key parameter when establishing hearing conservation regulations.

Quercetin protects against hair cell loss in the zebrafish lateral line and guinea pig cochlea.

Eighteen supplement drugs were screened using hair cells to determine a protective effect against the adverse effects of neomycin by using the zebrafish lateral line. The zebrafish were administered the supplement drugs 1 h before neomycin exposure. One hour later, animals were fixed in paraformaldehyde. Dose-response curves were generated to evaluate the protective effect on hair cells. The screen identified 3 supplements (quercetin, catechin and tannic acid). Three minutes after exposure to neomycin, increased antioxidant activity was found in the lateral line hair cells, as determined by the analysis of oxidative stress. Quercetin decreases antioxidant activity. The identified drugs were also investigated to determine whether they protect the cochlea against noise-induced hearing loss in guinea pigs. The drugs were administered via the intraperitoneal route in the guinea pigs 3 days before and 4 days after noise exposure. Seven days after noise exposure (130-dB sound pressure level for 3 h), the auditory brainstem response threshold shifts were assessed. We observed that the auditory brainstem response threshold shift was significantly less in the quercetin group than in the vehicle control group. The results of our study indicate that screening drugs using zebrafish can determine additional protective drugs for the inner ear.

Extended use of systemic steroid is beneficial in preserving hearing in guinea pigs after cochlear implant.

CONCLUSION: Seven-day administration of systemic steroids was more effective in preserving hearing for 12 weeks after cochlear implantation (CI) than a 3-day delivery. OBJECTIVES: To determine the effectiveness of extended delivery of systemic steroids to preserve hearing in guinea pigs after CI. METHODS: Dexamethasone (4 mg/ml) was delivered parenterally via a mini-osmotic pump for either 3 or 7 days. A dummy CI electrode was inserted via cochleostomy approach in 8-week-old guinea pigs. Auditory thresholds were assessed from tone burst auditory brainstem responses (2, 8, 16, 24, and 32 kHz) at 1 day prior to CI, and 1, 4, and 12 weeks after implantation. Histologic evaluation of the cochleae was carried out. RESULTS: No differences were observed in hearing thresholds among groups before CI. Significant hearing preservation was achieved at 8, 16, 24, and 32 kHz only in the 7-day infusion group compared with the control group at 1 week after CI. The same trend was maintained at 4 weeks (16, 24 kHz) and 12 weeks (16, 24, and 32 kHz). Histologic review of the 7-day infusion group revealed less fibrosis and ossification in the scala tympani and the preservation of more spiral ganglion cells, compared with the control group.

Auditory Tones and Foot-Shock Recapitulate Spontaneous Sub-Threshold Activity in Basolateral Amygdala Principal Neurons and Interneurons.

In quiescent states such as anesthesia and slow wave sleep, cortical networks show slow rhythmic synchronized activity. In sensory cortices this rhythmic activity shows a stereotypical pattern that is recapitulated by stimulation of the appropriate sensory modality. The amygdala receives sensory input from a variety of sources, and in anesthetized animals, neurons in the basolateral amygdala (BLA) show slow rhythmic synchronized activity. Extracellular field potential recordings show that these oscillations are synchronized with sensory cortex and the thalamus, with both the thalamus and cortex leading the BLA. Using whole-cell recording in vivo we show that the membrane potential of principal neurons spontaneously oscillates between up- and down-states. Footshock and auditory stimulation delivered during down-states evokes an up-state that fully recapitulates those occurring spontaneously. These results suggest that neurons in the BLA receive convergent input from networks of cortical neurons with slow oscillatory activity and that somatosensory and auditory stimulation can trigger activity in these same networks.

Association of Caffeine and Hearing Recovery After Acoustic Overstimulation Events in a Guinea Pig Model.

IMPORTANCE: Noise-induced hearing loss is an increasingly worrisome problem. Although caffeine intake is common in people involved in noise-related environments, the effect of caffeine on the recovery of hearing after a temporary threshold shift requires further understanding. OBJECTIVES: To determine whether caffeine impairs hearing recovery in a guinea pig model exposed to acoustic overstimulation. DESIGN, SETTING, AND SUBJECTS: This experiment at the McGill University Auditory Sciences Laboratory used 24 female albino guinea pigs (age, 6 months; weight, 500-600 g) divided randomly into 3 groups of 8 animals each. Group 1 was exposed to caffeine; group 2, acoustic overstimulation events (AOSEs); and group 3, both. Data were collected from July 1, 2013, to March 30, 2014, and analyzed from April 1 to August 1, 2014. INTERVENTIONS: Daily caffeine dose for groups 1 and 3 consisted of 25 mg/kg administered intraperitoneally for 15 days. The AOSEs were administered on days 1 and 8 and consisted of 1 hour of 110-dB pure-tone sound. MAIN OUTCOMES AND MEASURES: Serial auditory brainstem response (ABR) tests to determine the audiological threshold shift and recovery were obtained at baseline and on days 1 (1 hour after the first AOSE), 4, 8 (before and 1 hour after the second AOSE), 11, and 15. Scanning electron and light microscopy of the cochleas were performed to determine morphologic changes. RESULTS: The day 1 post-AOSE measurement resulted in a similar threshold shift in all animals in groups 2 and 3 at all frequencies tested (8, 16, 20, and 25 kHz). The maximum threshold shift was at 16 kHz, with a mean of 66.12 dB. By day 8, the threshold shift in group 2 recovered completely at all frequencies except 20 kHz, where a mean threshold shift of 20.63 dB of sound pressure level (SPL) was present. Hearing impairment in group 3 persisted in 8-, 16-, and 25-kHz frequencies with thresholds of 21.88, 28.13, and 26.25 dB SPL, respectively (P = .001). After a second AOSE at day 8, similar threshold shift and outcome were recorded on day 15 compared with day 8, with a mean threshold shift at 20 kHz of 29.38 dB SPL in group 2 and mean threshold shifts at 8, 16, 20, and 25 kHz of 29.38, 35.63, 40.63, and 38.75 dB SPL, respectively, in group 3. The difference in ABR threshold recovery was in concordance with scanning electronic and light microscopy findings for each group. CONCLUSIONS AND RELEVANCE: A daily dose of caffeine was found to impair the recovery of hearing after an AOSE.

Gentamicin-induced ototoxicity and nephrotoxicity vary with circadian time of treatment and entail separate mechanisms.

The aminoglycoside antibiotic gentamicin can cause both ototoxicity and nephrotoxicity, the severity of which varies with circadian time of daily treatment. However, it is not yet resolved if such drug-induced adverse effects are independent or interdependent phenomena. Two groups of 9 female Sprague-Dawley rats (200-250 g), each housed separately and entrained to a 12 h light (06:00-18:00 h) - 12 h dark cycle, received a daily subcutaneous injection of 100 mg/kg gentamicin. One group was treated at the beginning of the activity span, 2 Hours After Lights On (HALO), and the other at the beginning of the rest span, 14 HALO. Global toxicity was gauged by both body weight loss relative to the pre-treatment baseline and number of deaths. Ototoxicity, i.e., hearing loss, was assessed by changes in auditory brainstem response (ABR) for pure tone stimuli of 8, 16, 24, and 32 kHz before and after 2 and 4 weeks of gentamicin treatment. Renal toxicity was evaluated by changes in urinary N-acetyl-ß-glucosaminidase (NAG)/creatinine (CR) concentration ratio before and after each week of treatment. In a complementary substudy of separate but comparable 2 and 14 HALO groups of rats, blood samples were obtained before and 30, 60, 120, and 240 min post-subcutaneous injection of 100 mg/kg gentamicin. Number of animal deaths was greater in the 2 (4 deaths) than 14 HALO (1 death) group, mirroring more severe initial (first two weeks of treatment) body weight losses from baseline, being more than 2-fold greater in animals of the 2 than 14 HALO group. Ototoxicity progressively worsened during the treatment; although, the extent of hearing loss varied according to circadian time of treatment across all frequencies (p < 0.05), particularly the 24 and 32 kHz ones (both p < 0.005), both at the 2 and 4 week assessments. At 32 kHz after 4 weeks of gentamicin dosing, the 2 HALO group showed an average 42 dB hearing loss, while the 14 HALO group exhibited only an average 10 dB loss. ABR response latencies were longer for the 2 than 14 HALO rats. The time course of nephrotoxicity differed from that of ototoxicity. The mean urinary NAG/CR ratio peaked after the first week of treatment, averaging 13.64-fold greater than baseline for the 2 HALO-treated animals compared to 7.38-fold greater than baseline for the 14 HALO-treated ones. Ratio values declined thereafter; although, even after the second week of dosing, they remained greater in the 2 than 14 HALO group (averaging 8.15-fold greater and 2.23-fold greater than baseline, respectively). Pharmacokinetic analysis of the blood gentamicin values revealed slower clearance, on average by ∼25% (p < 0.001), in the rats of the 14 than 2 HALO group (x ± S.E.: 3.22 ± 0.49 and 4.53 ± 0.63 mL/min/kg, respectively). The study findings indicate robust difference of the time course in rats of both treatment groups of gentamicin-induced ototoxicity and nephrotoxicity, supporting the hypothesis these organ toxicities are independent of one another, and further suggest the observed treatment-time differences in gentamicin adverse effects may be more dependent on local cell, tissue, or organ circadian (chrono) pharmacodynamic than (chrono) pharmacokinetic mechanisms.

Atrial natriuretic peptide modulates auditory brainstem response of rat.

CONCLUSION: These findings suggest that Atrial natriuretic peptide (ANP) exhibits an inhibitory effect on auditory brainstem response (ABR) and is involved in the neuromodulation of the auditory nervous system. OBJECTIVES: ANP may alter electrophysiological properties of the cochlea and play a role in auditory action. METHODS: This study was undertaken to examine and clarify the role of ANP in the rat auditory system using ABR audiometry. The mean ABR thresholds and the latencies for wave II at the ABR threshold altered at given frequencies throughout the study. RESULTS: Intra-arterial infusion of ANP (0.1 mg/kg, 4 mg/kg, and 8 mg/kg; bolus injection) resulted in a significant increase in ABR thresholds. A significant shift in the ABR wave II latency was observed at lower frequency (1 kHz and 2 kHz). There was a little change in latency at 20 kHz. Increased amount of ANP significantly altered the ABR in rats.

Effects of a dexamethasone-releasing implant on cochleae: A functional, morphological and pharmacokinetic study.

AIM: This study evaluated the impact of a dexamethasone-releasing silicone implant on hearing function preservation, cochlear morphology and perilymph pharmacokinetics after cochlear implantation. METHODS: Guinea pigs were implanted unilaterally with silicone rods containing either 2% dexamethasone (DEXA group, n = 18) or no dexamethasone (control group, n = 17). Auditory brainstem response (ABR) and distortion product otoacoustic emissions (DPOAEs) were measured preoperatively and over 6 months postoperatively. Cochlear histology using standard hematoxylin and eosin (H&E) staining and tumor necrosis factor (TNF)-alpha staining was performed 1 month postoperatively. Twenty-two guinea pigs were involved in the pharmacokinetic study, and real-time drug concentrations in perilymph were investigated using high-performance liquid chromatography (HPLC). The Mann-Whitney U test (1-tailed) was used for statistical analyses. RESULTS: ABR and DPOAE testing demonstrated decreased hearing function immediately postoperatively followed by a progressive hearing loss within the first day postoperatively. There was almost no observable hearing improvement in the control group from 1 week to 6 months postoperatively, but hearing levels in the DEXA group improved gradually from 1 week to 12 weeks. Hearing loss in the DEXA and control group was 5.0 ± 3.4 dB and 21.7 ± 5.3 dB, respectively at a 16-kHz stimulus frequency 6 months postoperatively. The difference in threshold shifts was present throughout all measured frequencies, and it was significant at 4-24 kHz. The morphological study revealed new fibrosis formation in the scala tympani, which encapsulated the implanted electrode. TNF-alpha positive staining in the cochleae of the DEXA group was less evident than the control group. The pharmacokinetic study revealed a peak perilymph concentration 30 min postoperatively and sustained dexamethasone release at least 1 week postoperatively. CONCLUSION: Cochlear implants that incorporate dexamethasone can release drug chronically in the inner ear and induce significant long-term recovery and preservation of auditory function after implantation.

Hearing Status in Pediatric Renal Transplant Recipients.

OBJECTIVES: Renal transplant provides a long-term survival. Hearing impairment is a major factor in subjective health status. Status of hearing and the cause of hearing impairment in the pediatric renal transplant group have not been evaluated. Here, we studied to evaluate hearing status in pediatric renal transplant patients and to determine the factors that cause hearing impairment. MATERIALS AND METHODS: Twenty-seven pediatric renal transplant recipients were investigated. All patients underwent audiologic assessment by means of pure-tone audiometry. The factors on hearing impairment were performed. RESULTS: Sensorineural hearing impairment was found in 17 patients. There was marked hearing impairment for the higher frequencies between 4000 and 8000 Hz. Sudden hearing loss developed in 2 patients, 1 of them had tinnitus. Decrease of speech understanding was found in 8 patients. The cyclosporine level was significantly high in patients with hearing impairment compared with group without hearing impairment. Cyclosporine levels also were found to be statistically significantly high when compared with the group with decrease of speech understanding and the group without decrease of speech understanding. Similar relations cannot be found between tacrolimus levels and hearing impairment and speech understanding. CONCLUSIONS: Sensorineural hearing impairment prevalence was high in pediatric renal transplant recipients when compared with the general population of children. Cyclosporine may be responsible for causing hearing impairment after renal transplant. We suggest that this effect is a dose-dependent toxicity.

Assessment of ototoxicity of tea tree oil in a chinchilla animal model.

OBJECTIVE: The aim of the present study is to examine the effects of tea tree oil on hearing function and cochlear morphology after intratympanic administration in a chinchilla animal model. METHODS: Nine chinchillas received intratympanic injection of 3% tea tree oil dissolved in olive oil in one ear, whereas the contralateral control ear received olive oil only. Outcome measures included auditory brainstem responses conducted before treatment and at 10 days and 30 days following the injection. Post-mortem cochlear morphology was assessed using scanning electron microscopy. RESULTS: At 10 and 30 days following the injection, there was no significant change in auditory brain response thresholds at 8, 16, 20 or 25kHz. Scanning electron microscopy imaging showed no damage to auditory hair cells. CONCLUSION: Tea tree oil (3%) does not appear to be ototoxic in a chinchilla animal model. Future preclinical and clinical studies are required to establish the effectiveness of TTO in treating otitis.

[Lack of protection against gentamicin ototoxicity by auditory conditioning with noise]. / Falta de proteção contra a ototoxicidade da gentamicina pelo condicionamentoauditivo com ruído.

INTRODUCTION: Auditory conditioning consists of the pre-exposure to low levels of a potential harmful agent to protect against a subsequent harmful exposure. OBJECTIVE: To confirm if conditioning with an agent different from that used to cause the trauma can also be effective. METHODS: This was an experimental study with 17 guinea pigs, divided into three groups: an ototoxic control group (Cont) that received intramuscular administration of gentamicin 160 mg/kg/day for ten consecutive days, but no sound exposure; a sound control group (Sound) that was exposed to 85 dB broadband noise centered at 4 kHz, 30 min each day for ten consecutive days, but received no ototoxic medications; and an experimental group (Expt) that received sound exposure identical to the Sound group and after each noise presentation, received gentamicin similarly to Cont group. The animals were evaluated by distortion product otoacoustic emissions (DPOAEs), brainstem auditory evoked potentials (BAEPs), and scanning electron microscopy. RESULTS: The animals that were conditioned with noise did not show any protective effect compared with the ones that received only the ototoxic gentamicin administration. This lack of protection was observed functionally and morphologically. CONCLUSION: Conditioning with 85 dB broadband noises, 30 min a day for ten consecutive days does not protect against an ototoxic gentamicin administration of 160 mg/kg/day for ten consecutive days in the guinea pig.

Lack of protection against gentamicin ototoxicity by auditory conditioning with noise / Falta de proteção contra a ototoxicidade da gentamicina pelo condicionamento auditivo com ruído

INTRODUCTION: Auditory conditioning consists of the pre-exposure to low levels of a potential harmful agent to protect against a subsequent harmful presentation. OBJECTIVE: To confirm if conditioning with an agent different from the used to cause the trauma can also be effective. METHOD: Experimental study with 17 guinea pigs divided as follows: group Som: exposed to 85 dB broadband noise centered at 4 kHz, 30 minutes a day for 10 consecutive days; group Cont: intramuscular administration of gentamicin 160 mg/kg a day for 10 consecutive days; group Expt: conditioned with noise similarly to group Som and, after each noise presentation, received gentamicin similarly to group Cont. The animals were evaluated by distortion product otoacoustic emissions (DPOAEs), brainstem auditory evoked potentials (BAEPs) and scanning electron microscopy. RESULTS: The animals that were conditioned with noise did not show any protective effect compared to the ones that received only the ototoxic gentamicin administration. This lack of protection was observed functionally and morphologically. CONCLUSION: Conditioning with 85 dB broadband noise, 30 min a day for 10 consecutive days does not protect against an ototoxic gentamicin administration of 160 mg/kg a day for 10 consecutive days in the guinea pig. .

INTRODUÇÃO: O condicionamento auditivo consiste da pré-exposição de um agente lesivo em baixos níveis para proteger contra uma posterior apresentação lesiva. OBJETIVO: Confirmar se o condicionamento com um agente diferente do utilizado para causar o trauma pode ser efetivo. MÉTODO: Estudo experimental com 17 cobaias albinas divididas como a seguir- grupo Som: exposto a um ruído branco de 85 dB centrado em 4 kHz, 30 minutos por dia, por 10 dias consecutivos; grupo Cont: administração intramuscular de gentamicina 160 mg/kg por dia, por 10 dias consecutivos; grupo Expt: condicionado com ruído como o grupo Som. Após cada exposição ao ruído, recebeu gentamicina similarmente ao grupo Cont. Os animais foram avaliados por emissões otoacústicas produto de distorção (EOAPDs), potencial evocado auditivo de tronco encefálico (PEATE) e microscopia eletrônica de varredura (MEV). RESULTADOS: Os animais que foram condicionados com ruído não mostraram qualquer efeito protetor quando comparados com os que receberam apenas a gentamicina em doses ototóxicas. Esta ausência de proteção foi observada tanto funcionalmente quanto morfologicamente. CONCLUSÃO: Os autores concluíram que o condicionamento com ruído branco a 85 dB por 30 minutos, por dia por 10 dias consecutivos, não protege contra uma administração de gentamicina 160 mg/kg/dia, por 10 dias consecutivos. .

Protective effects of Ginkgo biloba extract EGb 761 against noise trauma-induced hearing loss and tinnitus development.

Noise-induced hearing loss (NIHL) and resulting comorbidities like subjective tinnitus are common diseases in modern societies. A substance shown to be effective against NIHL in an animal model is the Ginkgo biloba extract EGb 761. Further effects of the extract on the cellular and systemic levels of the nervous system make it a promising candidate not only for protection against NIHL but also for its secondary comorbidities like tinnitus. Following an earlier study we here tested the potential effectiveness of prophylactic EGb 761 treatment against NIHL and tinnitus development in the Mongolian gerbil. We monitored the effects of EGb 761 and noise trauma-induced changes on signal processing within the auditory system by means of behavioral and electrophysiological approaches. We found significantly reduced NIHL and tinnitus development upon EGb 761 application, compared to vehicle treated animals. These protective effects of EGb 761 were correlated with changes in auditory processing, both at peripheral and central levels. We propose a model with two main effects of EGb 761 on auditory processing, first, an increase of auditory brainstem activity leading to an increased thalamic input to the primary auditory cortex (AI) and second, an asymmetric effect on lateral inhibition in AI.