Several studies suggest that hearing loss results in changes in the balance between inhibition and excitation in the inferior colliculus (IC). The IC is an integral nucleus within the auditory brainstem. The majority of ascending pathways from the lateral lemniscus (LL), superior olivary complex (SOC), and cochlear nucleus (CN) synapse in the IC before projecting to the thalamus and cortex. Many of these ascending projections provide inhibitory innervation to neurons within the IC. However, the nature and the distribution of this inhibitory input have only been partially elucidated in the rat. The inhibitory neurotransmitter, gamma aminobutyric acid (GABA), from the ventral nucleus of the lateral lemniscus (VNLL), provides the primary inhibitory input to the IC of the rat with GABA from other lemniscal and SOC nuclei providing lesser, but prominent innervation. There is evidence that hearing related conditions can result in dysfunction of IC neurons. These changes may be mediated in part by changes in GABA inputs to IC neurons. We have previously used gene micro-arrays in a study of deafness-related changes in gene expression in the IC and found significant changes in GAD as well as the GABA transporters and GABA receptors (Holt 2005). This is consistent with reports of age and trauma related changes in GABA (Bledsoe et al., 1995; Mossop et al., 2000; Salvi et al., 2000). Ototoxic lesions of the cochlea produced a permanent threshold shift. The number, intensity, and density of GABA positive axon terminals in the IC were compared in normal hearing and deafened rats. While the number of GABA immunolabeled puncta was only minimally different between groups, the intensity of labeling was significantly reduced. The ultrastructural localization and distribution of labeling was also examined. In deafened animals, the number of immuno gold particles was reduced by 78 % in axodendritic and 82 % in axosomatic GABAergic puncta. The affected puncta were primarily associated with small IC neurons. These results suggest that reduced inhibition to IC neurons contribute to the increased neuronal excitability observed in the IC following noise or drug induced hearing loss. Whether these deafness diminished inhibitory inputs originate from intrinsic or extrinsic CNIC sources awaits further study.

Evidence suggests that otologic injury from ototopical aminoglycoside preparations is infrequent when used to treat ear infections with an intact tympanic membrane. Meanwhile, parenteral administration of aminoglycosides, is well known to be associated with a significant incidence of cochlear and vestibular damage. The discrepancy between topical and parenteral ototoxic effects is thought to result from a combination of factors, including the protective function of debris overlying the round window membrane, low antibiotic concentrations of topical antibiotic preparations, length of exposure and inability to detect subtle hearing or vestibular changes. Herein, we present a case of acute vestibulopathy following a 2-week course of topical gentamicin otic drops. Awareness of vestibulotoxicity following topical gentamicin therapy is prudent as vestibulopathic symptoms can be severely debilitating.

UNASSIGNED: Chemotherapeutic agents can have both serious side effects and ototoxicity, which can be caused by direct toxic effects or by metabolic derangement by the agents. Cabazitaxel (CBZ) is a next-generation semi-synthetic taxane derivative that is effective in both preclinical models of human tumors that are sensitive or resistant to chemotherapy and in patients suffering from progressive prostate cancer despite docetaxel treatment. The primary aim of this study is to investigate the ototoxicity of CBZ in a rat model.
UNASSIGNED: : A total of 24 adult male Wistar-Albino rats were equally and randomly divided into four groups. CBZ (Jevtana, Sanofi-Aventis USA) was intraperitoneally administered to Groups 2, 3, and 4 at doses of 0.5, 1.0, and 1.5 mg/kg/week, respectively, for 4 consecutive weeks; Group 1 received only i.p. saline at the same time. At the end of the study, the animals were sacrificed and their cochlea removed for histopathological examination.
UNASSIGNED: : Intraperitoneal administration of CBZ exerted an ototoxic effect on rats, and the histopathological results became worse in a dose-dependent manner (P < 0.05).
UNASSIGNED: : Our findings suggest that CBZ may be an ototoxic agent and can damage the cochlea. More clinical studies should be conducted to understand its ototoxicity.

Aminoglycoside antibiotics are lifesaving medicines, crucial for the treatment of chronic or drug resistant infections. However, aminoglycosides are toxic to the sensory hair cells in the inner ear. As a result, aminoglycoside-treated individuals can develop permanent hearing loss and vestibular impairment. There is considerable evidence that reactive oxygen species (ROS) production and the subsequent phosphorylation of c-Jun N-terminal kinase (JNK) and P38 mitogen-activated protein kinase (P38) drives apoptosis in aminoglycoside-treated hair cells. However, treatment strategies that directly inhibit ROS, JNK, or P38 are limited by the importance of these molecules for normal cellular function. Alternatively, the upstream regulator apoptosis signal-regulating kinase 1 (ASK1/MAP3K5) is a key mediator of ROS-induced JNK and P38 activation under pathologic but not homeostatic conditions. We investigated ASK1 as a mediator of drug-induced hair cell death using cochlear explants from Ask1 knockout mice, demonstrating that Ask1 deficiency attenuates neomycin-induced hair cell death. We then evaluated pharmacological inhibition of ASK1 with GS-444217 as a potential otoprotective therapy. GS-444217 significantly attenuated hair cell death in neomycin-treated explants but did not impact aminoglycoside efficacy against P. aeruginosa in the broth dilution test. Overall, we provide significant pre-clinical evidence that ASK1 inhibition represents a novel strategy for preventing aminoglycoside ototoxicity. KEY MESSAGES: ASK1 is an upstream, redox-sensitive regulator of P38 and JNK, which are known mediators of hair cell death. Ask1 knockout does not affect hair cell development in vivo, but significantly reduces aminoglycoside-induced hair cell death in vitro. A small-molecule inhibitor of ASK1 attenuates neomycin-induced hair cell death, and does not impact antibiotic efficacy in vitro. ASK1 may be a novel molecular target for preventing aminoglycoside-induced hearing loss.

2-hydroxypropyl-β-cyclodextrin (HPβCD), a cholesterol chelator used to treat Niemann-Pick C1 (NPC1) lysosomal storage disease, causes hearing loss in mammals by preferentially destroying outer hair cells. Because cholesterol plays an important role in early neural development, we hypothesized that HPβCD would cause more extensive damage to postnatal cochlear and vestibular structures in than adult rats. This hypothesis was tested by administering HPβCD to adult rats and postnatal day 3 (P3) cochlear and vestibular organ cultures. Adult rats treated with HPβCD developed hearing impairment and outer hair cell loss 3-day post-treatment; damage increased with dose from the high frequency base toward the low-frequency apex. The HPβCD-induced histopathologies were more severe and widespread in cochlear and vestibular cultures at P3 than in adults. HPβCD destroyed both outer and inner hair cells, auditory nerve fibers and spiral ganglion neurons as well as type I and type II vestibular hair cells and vestibular ganglion neurons. The early stage of HPβCD damage involved disruption of hair cell mechanotransduction and destruction of stereocilia. HPβCD-mediated apoptosis in P3 cultures was most-strongly initiated by activation of the extrinsic caspase-8 cell death pathway in cochlear and vestibular hair cells and neurons followed by activation of executioner caspase-3. Thus, HPβCD is toxic to all types of postnatal cochlear and vestibular hair cells and neurons in vitro whereas in vivo it only appears to destroy outer hair cells in adult cochleae. The more severe HPβCD-induced damage in postnatal cultures could be due to greater drug bioavailability in vitro and/or greater vulnerability of the developing inner ear.

2-Hydroxypropyl-β-cyclodextrin (HPβCD), a cholesterol chelator, is being used to treat diseases associated with abnormal cholesterol metabolism such as Niemann-Pick C1 (NPC1). However, the high doses of HPβCD needed to slow disease progression may cause hearing loss. Previous studies in mice have suggested that HPβCD ototoxicity results from selective outer hair cell (OHC) damage. However, it is unclear if HPβCD causes the same type of damage or is more or less toxic to other species such as rats, which are widely used in toxicity research. To address these issues, rats were given a subcutaneous injection of HPβCD between 500 and 4000 mg/kg. Distortion product otoacoustic emissions (DPOAE), the cochlear summating potential (SP), and compound action potential (CAP) were used to assess cochlear function followed by quantitative analysis of OHC and inner hair cell (IHC) loss. The 3000- and 4000-mg/kg doses abolished DPOAE and greatly reduced SP and CAP amplitudes. These functional deficits were associated with nearly complete loss of OHC as well as ~ 80% IHC loss over the basal two thirds of the cochlea. The 2000-mg/kg dose abolished DPOAE and significantly reduced SP and CAP amplitudes at the high frequencies. These deficits were linked to OHC and IHC losses in the high-frequency region of the cochlea. Little or no damage occurred with 500 or 1000 mg/kg of HPβCD. The HPβCD-induced functional and structural deficits in rats occurred suddenly, involved damage to both IHC and OHC, and were more severe than those reported in mice.

Many drugs on the World Health Organization\'s list of critical medicines are ototoxic, destroying sensory hair cells within the ear. These drugs preserve life, but patients can experience side effects including permanent hearing loss and vestibular dysfunction. Aminoglycoside ototoxicity was first recognised 80 years ago. However, no preventative treatments have been developed. In order to develop such treatments, we must identify the factors driving hair cell death. In vivo, studies of cell death are typically conducted using mouse models. However, a robust model of aminoglycoside ototoxicity does not exist. Previous studies testing aminoglycoside delivery via intraperitoneal or subcutaneous injection have produced variable ototoxic effects in the mouse. As a result, surgical drug delivery to the rodent ear is often used to achieve ototoxicity. However, this technique does not accurately model clinical practice. In the clinic, aminoglycosides are administered to humans intravenously (i.v.). However, repeated i.v. delivery has not been reported in the mouse. This study evaluated whether repeated i.v. administration of amikacin or tobramycin would induce hearing loss. Daily i.v. injections over a two-week period were well tolerated and transient low frequency hearing loss was observed in the aminoglycoside treatment groups. However, the hearing changes observed did not mimic the high frequency patterns of hearing loss observed in humans. Our results indicate that the i.v. delivery of tobramycin or amikacin is not an effective technique for inducing ototoxicity in mice. This result is consistent with previously published reports indicating that the mouse cochlea is resistant to systemically delivered aminoglycoside ototoxicity.

Ototoxic drug-induced hair cell (HC) damage is one of the main causes of sensorineural hearing loss, which is one of the most common sensory disorders in humans. Aminoglycoside antibiotics are common ototoxic drugs, and these can cause the accumulation of intracellular oxygen free radicals and lead to apoptosis in HCs. Fasudil is a Rho kinase inhibitor and vasodilator that has been widely used in the clinic and has been shown to have neuroprotective effects. However, the possible application of fasudil in protecting against aminoglycoside-induced HC loss and hearing loss has not been investigated. In this study, we investigated the ability of fasudil to protect against neomycin-induced HC loss both in vitro and in vivo. We found that fasudil significantly reduced the HC loss in cochlear whole-organ explant cultures and reduced the cell death of auditory HEI-OC1 cells after neomycin exposure in vitro. Moreover, we found that fasudil significantly prevented the HC loss and hearing loss of mice in the in vivo neomycin damage model. Furthermore, we found that fasudil could significantly inhibit the Rho signaling pathway in the auditory HEI-OC1 cells after neomycin exposure, thus further reducing the neomycin-induced accumulation of reactive oxygen species and subsequent apoptosis in HEI-OC1 cells. This study suggests that fasudil might contribute to the increased viability of HCs after neomycin exposure by inhibition of the Rho signaling pathway and suggests a new therapeutic target for the prevention of aminoglycoside-induced HC loss and hearing loss.

Information is summarized from the overall body of published literature regarding ototoxic chemicals encountered outside of clinical exposures, largely in occupational settings. While summarizing the most common non-pharmaceutical ototoxins, this review provides clinically relevant information and recommendations such that hearing health professionals may adopt a more comprehensive and appropriate diagnostic case history, test battery, documentation scheme, and education delivery.
Solvents, metals, and asphyxiants literature was reviewed using PubMed, national and international agency websites, and communications with known ototoxicity experts.
Initial intentions to summarize the existing programs for occupational ototoxicity monitoring fell short when it was discovered that such programs have not yet formalized across the major oversight agencies in the United States. Instead, recommended guidance documents and fact sheets, which highlight existing occupational exposure limits and suggest monitoring and education are discussed.
While evidence in humans is limited, potentially ototoxic substances are worthy of improved surveillance and further research to understand their ototoxic mechanisms, effects, and possible mitigation strategies. A triad approach of monitoring, protecting, and educating is recommended for effective prevention of hearing loss: the Department of Defense Hearing Center of Excellence\'s Comprehensive Hearing Health Program model employs such an approach.

Sensorineural hearing loss due to ototoxic cancer therapy is well established; effects on the vestibular system are unknown. We examined the feasibility of implementing vestibular screens for pediatric cancer survivors exposed to ototoxic agents. The prevalence of screening failures is reported.
Cancer survivors who were 6-17 years, at least 1-month posttreatment, and received ototoxic therapy (radiation to the head/neck, cisplatin, carboplatin) were eligible. Screening measures included (1) Pediatric Vestibular Symptom Questionnaire, (2) Modified Clinical Test of Sensory Interaction on Balance, and (3) Dynamic Visual Acuity.
Vestibular screening failures were observed in 30 participants (60%). Patients with a brain tumor diagnosis were at increased risk for failures compared to nonbrain tumor patients (74.2% vs. 36.8%, P = 0.009). Patients who underwent brain surgery were at increased risk for failures compared to patients without brain surgery (71% vs. 42%, P = 0.043). Patients with a longer duration between end of treatment and vestibular screening had a reduced risk of failures, with an almost 20% decrease for each year between the time points (odds ratio = 0.812; 95% confidence interval: 0.683-0.964, P = 0.018). Receiving carboplatin correlated with a decreased risk of failure (P = 0.016), due to a negative correlation with other clinical risk factors (diagnosis of a brain tumor, major brain surgery) that are associated with vestibular screening failure.
Vestibular screening failures are highly prevalent in childhood cancer survivors who received ototoxic therapy. Broad screening of this population and further characterization of these patients are warranted.