Oxidative stress has been established as the key mechanism of the cochlear damage underlying noise-induced hearing loss, however, emerging evidence suggests that cochlear inflammation may also be a ...major contributor. This study aimed to improve our understanding of the cochlear inflammatory response associated with acute and chronic noise exposure. C57BL/6 mice were exposed to acute traumatic noise (100 dBSPL, 8–16 kHz for 24 h) and their cochleae collected at various intervals thereafter, up to 7 days. Using quantitative RT-PCR and immunohistochemistry, changes in expression levels of proinflammatory cytokines (TNF-α, IL-1β), chemokines (CCL2) and cell adhesion molecules (ICAM-1) were studied. All gene transcripts displayed similar dynamics of expression, with an early upregulation at 6 h post-exposure, followed by a second peak at 7 days. ICAM-1 immunoexpression increased significantly in the inferior region of the spiral ligament, peaking 24 h post-exposure. The early expression of proinflammatory mediators likely mediates the recruitment and extravasation of inflammatory cells into the noise-exposed cochlea. The occurrence of the latter expression peak is not clear, but it may be associated with reparative processes initiated in response to cochlear damage. Chronic exposure to moderate noise (90 dBSPL, 8–16 kHz, 2 h/day, up to 4 weeks) also elicited an inflammatory response, reaching a maximum after 2 weeks, suggesting that cochlear damage and hearing loss associated with chronic environmental noise exposure may be linked to inflammatory processes in the cochlea. This study thus provides further insight into the dynamics of the cochlear inflammatory response induced by exposure to acute and chronic noise.
Cisplatin is a commonly used chemotherapeutic agent with proven efficacy in treating various malignancies, including testicular, ovarian, cervical, breast, bladder, head and neck, and lung cancer. ...Cisplatin is also used to treat tumors in children, such as neuroblastoma, osteosarcoma, and hepatoblastoma. However, its clinical use is limited by severe side effects, including ototoxicity, nephrotoxicity, neurotoxicity, hepatotoxicity, gastrointestinal toxicity, and retinal toxicity. Cisplatin-induced ototoxicity manifests as irreversible, bilateral, high-frequency sensorineural hearing loss in 40–60% of adults and in up to 60% of children. Hearing loss can lead to social isolation, depression, and cognitive decline in adults, and speech and language developmental delays in children. Cisplatin causes hair cell death by forming DNA adducts, mitochondrial dysfunction, oxidative stress, and inflammation, culminating in programmed cell death by apoptosis, necroptosis, pyroptosis, or ferroptosis. Contemporary medical interventions for cisplatin ototoxicity are limited to prosthetic devices, such as hearing aids, but these have significant limitations because the cochlea remains damaged. Recently, the U.S. Food and Drug Administration (FDA) approved the first therapy, sodium thiosulfate, to prevent cisplatin-induced hearing loss in pediatric patients with localized, non-metastatic solid tumors. Other pharmacological treatments for cisplatin ototoxicity are in various stages of preclinical and clinical development. This narrative review aims to highlight the molecular mechanisms involved in cisplatin-induced ototoxicity, focusing on cochlear inflammation, and shed light on potential antioxidant and anti-inflammatory therapeutic interventions to prevent or mitigate the ototoxic effects of cisplatin. We conducted a comprehensive literature search (Google Scholar, PubMed) focusing on publications in the last five years.
•Mitochondrial dysfunction and oxidative stress play a central etiological role in the development of sensorineural hearing loss, either inherited or acquired.•Cochlear cells are susceptible to ...oxidative damage due to their high metabolic demands.•Many promising antioxidant therapies for the prevention and treatment of acquired sensorineural hearing loss are in preclinical and clinical development.
Sensorineural hearing loss (SNHL) can either be genetically inherited or acquired as a result of aging, noise exposure, or ototoxic drugs. Although the precise pathophysiological mechanisms underlying SNHL remain unclear, an overwhelming body of evidence implicates mitochondrial dysfunction and oxidative stress playing a central etiological role. With its high metabolic demands, the cochlea, particularly the sensory hair cells, stria vascularis, and spiral ganglion neurons, is vulnerable to the damaging effects of mitochondrial reactive oxygen species (ROS). Mitochondrial dysfunction and consequent oxidative stress in cochlear cells can be caused by inherited mitochondrial DNA (mtDNA) mutations (hereditary hearing loss and aminoglycoside-induced ototoxicity), accumulation of acquired mtDNA mutations with age (age-related hearing loss), mitochondrial overdrive and calcium dysregulation (noise-induced hearing loss and cisplatin-induced ototoxicity), or accumulation of ototoxic drugs within hair cell mitochondria (drug-induced hearing loss). In this review, we provide an overview of our current knowledge on the role of mitochondrial dysfunction and oxidative stress in the development of SNHL caused by genetic mutations, aging, exposure to excessive noise, and ototoxic drugs. We also explore the advancements in antioxidant therapies for the different forms of acquired SNHL that are being evaluated in preclinical and clinical studies.
The mammalian outer hair cell (OHC) protein prestin (Slc26a5) differs from other Slc26 family members due to its unique piezoelectric-like property that drives OHC electromotility, the putative ...mechanism for cochlear amplification. Here, we use cryo-electron microscopy to determine prestin's structure at 3.6 Å resolution. Prestin is structurally similar to the anion transporter Slc26a9. It is captured in an inward-open state which may reflect prestin's contracted state. Two well-separated transmembrane (TM) domains and two cytoplasmic sulfate transporter and anti-sigma factor antagonist (STAS) domains form a swapped dimer. The transmembrane domains consist of 14 transmembrane segments organized in two 7+7 inverted repeats, an architecture first observed in the bacterial symporter UraA. Mutation of prestin's chloride binding site removes salicylate competition with anions while retaining the prestin characteristic displacement currents (Nonlinear Capacitance), undermining the extrinsic voltage sensor hypothesis for prestin function.
Abstract
The outer hair cell (OHC) membrane harbors a voltage-dependent protein, prestin (SLC26a5), in high density, whose charge movement is evidenced as a nonlinear capacitance (NLC). NLC is ...bell-shaped, with its peak occurring at a voltage, V
h
, where sensor charge is equally distributed across the plasma membrane. Thus, V
h
provides information on the conformational state of prestin. V
h
is sensitive to membrane tension, shifting to positive voltage as tension increases and is the basis for considering prestin piezoelectric (PZE). NLC can be deconstructed into real and imaginary components that report on charge movements in phase or 90 degrees out of phase with AC voltage. Here we show in membrane macro-patches of the OHC that there is a partial trade-off in the magnitude of real and imaginary components as interrogation frequency increases, as predicted by a recent PZE model (Rabbitt in Proc Natl Acad Sci USA 17:21880–21888, 2020). However, we find similar behavior in a simple 2-state voltage-dependent kinetic model of prestin that lacks piezoelectric coupling. At a particular frequency, F
is
, the complex component magnitudes intersect. Using this metric, F
is
, which depends on the frequency response of each complex component, we find that initial V
h
influences F
is
; thus, by categorizing patches into groups of different V
h
, (above and below − 30 mV) we find that F
is
is lower for the negative V
h
group. We also find that the effect of membrane tension on complex NLC is dependent, but differentially so, on initial V
h
. Whereas the negative group exhibits shifts to higher frequencies for increasing tension, the opposite occurs for the positive group. Despite complex component trade-offs, the low-pass roll-off in absolute magnitude of NLC, which varies little with our perturbations and is indicative of diminishing total charge movement, poses a challenge for a role of voltage-driven prestin in cochlear amplification at very high frequencies.
Fragile X syndrome (FXS) is characterized by hypersensitivity to sensory stimuli, including environmental sounds. We compared the auditory brainstem response (ABR) recorded
in mice lacking the gene (
...) for fragile X mental retardation protein (FMRP) with that in wild-type animals. We found that ABR wave I, which represents input from the auditory nerve, is reduced in
animals, but only at high sound levels. In contrast, wave IV, which represents the activity of auditory brainstem nuclei is enhanced at all sound levels, suggesting that loss of FMRP alters the central processing of auditory signals. Current-clamp recordings of neurons in the medial nucleus of the trapezoid body in the auditory brainstem revealed that, in contrast to neurons from wild-type animals, sustained depolarization triggers repetitive firing rather than a single action potential. In voltage-clamp recordings, K
currents that activate at positive potentials ("high-threshold" K
currents), which are required for high-frequency firing and are carried primarily by Kv3.1 channels, are elevated in
mice, while K
currents that activate near the resting potential and inhibit repetitive firing are reduced. We therefore tested the effects of AUT2 ((4-({5-(4R)-4-ethyl-2,5-dioxo-1-imidazolidinyl-2-pyridinyl}oxy)-2-(1-methylethyl) benzonitrile, a compound that modulates Kv3.1 channels. AUT2 reduced the high-threshold K
current and increased the low-threshold K
currents in neurons from
animals by shifting the activation of the high-threshold current to more negative potentials. This reduced the firing rate and,
, restored wave IV of the ABR. Our results from animals of both sexes suggest that the modulation of the Kv3.1 channel may have potential for the treatment of sensory hypersensitivity in patients with FXS.
mRNA encoding the Kv3.1 potassium channel was one of the first described targets of the fragile X mental retardation protein (FMRP). Fragile X syndrome is caused by loss of FMRP and, in humans and mice, causes hypersensitivity to auditory stimuli. We found that components of the auditory brain response (ABR) corresponding to auditory brainstem activity are enhanced in mice lacking FMRP. This is accompanied by hyperexcitability and altered potassium currents in auditory brainstem neurons. Treatment with a drug that alters the voltage dependence of Kv3.1 channels normalizes the imbalance of potassium currents, as well as ABR responses
, suggesting that such compounds may be effective in treating some symptoms of fragile X syndrome.
-Electromotility is derived from conformational changes in the membrane protein prestin.-Voltage drives conformational changes in prestin by moving charged moieties of the protein.-The coupling of ...prestin charge movement and electromotility is not fixed.-The weakest coupling is at the voltage (Vh) where prestin frequency response is slowest.-Molecular loads within the membrane are revealed in prestin's cryo-EM structure.
The OHC drives cochlear amplification, and prestin activity is the basis. The frequency response of nonlinear capacitance (NLC), which is a ratiometric measure of prestin's voltage-sensor charge movement (dQp/dVm), depends on the location of AC voltage excitation along prestin's operating voltage range, being slowest at the voltage (Vh) where NLC peaks. Here we directly investigate the coupling between prestin charge movement (Qp) and electromotility (eM) at frequencies up to 6.25 kHz, and find tight correspondence between the two at operating voltages displaced from Vh. Near Vh, however, eM shows a slower frequency response than Qp. We reason that coupling is more susceptible to molecular/cellular loads at Vh, where prestin compliance is expected to be maximal. Recent cryo-EM studies have begun to shed light on structural features of prestin that impact its performance against loads.
This article is part of the Special Issue Outer hair cell Edited by Joseph Santos-Sacchi and Kumar Navaratnam
Acquired hearing loss is a worldwide epidemic that affects all ages. It is multifactorial in etiology with poorly characterized molecular mechanisms. Mitochondria are critical components in hearing. ...Here, we aimed to identify the mechanisms of mitochondria-dependent hearing loss using Fus1 KO mice, our novel model of mitochondrial dysfunction/oxidative stress.
Using auditory brainstem responses (ABRs), we characterized the Fus1 KO mouse as a novel, clinically relevant model of age-related hearing loss (ARHL) of metabolic etiology. We demonstrated early decline of the endocochlear potential (EP) that may occur due to severe mitochondrial and vascular pathologies in the Fus1 KO cochlear stria vascularis. We showed that pathological alterations in antioxidant (AO) and nutrient and energy sensing pathways (mTOR and PTEN/AKT) occur in cochleae of young Fus1 KO mice before major hearing loss. Importantly, short-term AO treatment corrected pathological molecular changes, while longer AO treatment restored EP, improved ABR parameters, restored mitochondrial structure, and delayed the development of hearing loss in the aging mouse.
Currently, no molecular mechanisms linked to metabolic ARHL have been identified. We established pathological and molecular mechanisms that link the disease to mitochondrial dysfunction and oxidative stress.
Since chronic mitochondrial dysfunction is common in many patients, it could lead to developing hearing loss that can be alleviated/rescued by AO treatment. Our study creates a framework for clinical trials and introduces the Fus1 KO model as a powerful platform for developing novel therapeutic strategies to prevent/delay hearing loss associated with mitochondrial dysfunction. Antioxid. Redox Signal. 27, 489-509.
To provide evidence-based guidance on the clinical management of cancer cachexia in adult patients with advanced cancer.
A systematic review of the literature collected evidence regarding ...nutritional, pharmacologic, and other interventions, such as exercise, for cancer cachexia. PubMed and the Cochrane Library were searched for randomized controlled trials (RCTs) and systematic reviews of RCTs published from 1966 through October 17, 2019. ASCO convened an Expert Panel to review the evidence and formulate recommendations.
The review included 20 systematic reviews and 13 additional RCTs. Dietary counseling, with or without oral nutritional supplements, was reported to increase body weight in some trials, but evidence remains limited. Pharmacologic interventions associated with improvements in appetite and/or body weight include progesterone analogs and corticosteroids. The other evaluated interventions either had no benefit or insufficient evidence of benefit to draw conclusions on efficacy. Limitations of the evidence include high drop-out rates, consistent with advanced cancer, as well as variability across studies in outcomes of interest and methods for outcome assessment.
Dietary counseling may be offered with the goals of providing patients and caregivers with advice for the management of cachexia. Enteral feeding tubes and parenteral nutrition should not be used routinely. In the absence of more robust evidence, no specific pharmacological intervention can be recommended as the standard of care; therefore, clinicians may choose not to prescribe medications specifically for the treatment of cancer cachexia. Nonetheless, when it is decided to trial a drug to improve appetite and/or improve weight gain, currently available pharmacologic interventions that may be used include progesterone analogs and short-term (weeks) corticosteroids.
Neuronal calcium sensor 1 (NCS1) regulates a wide range of cellular functions throughout the mammalian nervous systems. Altered NCS1 expression is associated with neurodevelopmental and ...neurodegenerative diseases. Previous studies focused on affective and cognitive behaviors in NCS1 knockout (KO) mice, but little is known about the physiological and pathological states associated with the loss of NCS1 in the peripheral nervous system. We previously reported that NCS1 expression was reduced following paclitaxel-induced peripheral neuropathy. Here, we comprehensively investigated the phenotypes of NCS1-KO mice through a battery of behavioral tests examining both central and peripheral nervous systems. Generally, only mild differences were observed in thermal sensation and memory acquisition between NCS1-WT and -KO male mice, but not in female mice. No differences were observed in motor performance, affective behaviors, and hearing in both sexes. These results suggest that NCS1 plays a modulatory role in sensory perceptions and cognition, particularly in male mice. NCS1 has been proposed as a pharmacological target for various diseases. Therefore, the sex-specific effects of NCS1 loss may be of clinical interest. As we examined a constitutive KO model, future studies focusing on various conditional KO models will further elucidate the precise physiological significance of NCS1.
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