Post exposure treatment with a Src-PTK inhibitor in combination with N-l-acetyl cysteine to reduce noise-induced hearing loss

Both the antioxidant, N-l-acetyl cysteine (NAC), and the Src inhibitor, KX1-004, have been used to protect the cochlea from hazardous noise. In order to extend our previous work on KX1-004 with noise exposure, the current studies were undertaken with two goals: (1) to test the effectiveness of NAC and KX1-004 in combination with one another when given in a protection paradigm, and (2) to test the NAC+KX1-004 combination in a postexposure rescue paradigm. The noise exposure for the first experiment consisted of a 4-kHz octave band of noise at 107 dB SPL for 2 hours. The combination of NAC and KX1-004 were administered either prior to the noise exposure or post exposure (rescue). The second experiment was undertaken to extend the findings of the first experiment’s rescue paradigm. The 4 kHz octave band noise was delivered at 112 dB SPL for 1 hour, with the experimental drugs delivered only in a rescue paradigm. In Experiment 1, animals treated before the 2-hour noise exposure with the combination of NAC and KX1-004 had from 12 to 17 dB less permanent threshold shift when compared to control saline treated animals. Treatment in the rescue paradigm did not produce any reductions in threshold shift from the 2-hour exposure. In the second experiment, with the 1-hour noise, rescue with KX1-004 or KX1-004 plus NAC yielded small, but significant, reductions in threshold shift. There was no additional benefit from the combination of NAC and KX1-004 over KX1-004 by itself.

from Noise & Health

Maternal smoking during pregnancy: Impact on otoacoustic emissions in neonates

Conclusions
Maternal smoking during pregnancy had a negative effect on cochlear function, as determined by otoacoustic emissions testing. Therefore, pregnant women should be warned of this additional hazard of smoking. It is important that smoking control be viewed as a public health priority and that strategies for treating tobacco dependence be devised.

from the International Journal of Pediatric Otorhinolaryngology

Protecting the auditory system with glucocorticoids

Glucocorticoids are hormones released following stress-related events and function to maintain homeostasis. Glucocorticoid receptors localize, among others, to hair cells, spiral ligament and spiral ganglion neurons. Glucocorticoid receptor-induced protection against acoustic trauma is found by i) pretreatment with glucocorticoid agonists; ii) acute restraint stress; and iii) sound conditioning. In contrast, glucocorticoid receptor antagonists exacerbate hearing loss. These findings have important clinical significance since synthetic glucocorticoids are commonly used to treat hearing loss. However, this treatment has limited success since hearing improvement is often not maintained once the treatment has ended, a fact that reduces the overall appeal for this treatment. It must be realized that despite the wide-spread use of glucocorticoids to treat hearing disorders, the molecular mechanisms underlying this treatment are not well characterized. This review will give insight into some physiological and biochemical mechanisms underlying glucocorticoid treatment for preventing hearing loss

from Hearing Research

Protective effects of brain-derived neurotrophic factor on the noise-damaged cochlear spiral ganglion

Conclusion: When administered via cochlear infusion following noise damage, brain-derived neurotrophic factor appears to improve the auditory threshold, and to have a protective effect on the spiral ganglion cells.

from the Journal of Laryngology and Otology

Ion Flow In Cochlear Hair Cells And The Regulation Of Hearing Sensitivity

This paper discusses how ion transport proteins in the hair cells of the mammalian cochlea work to produce a sensitive but stable hearing organ. The transport proteins in the inner and outer hair cells are summarized (including their current voltage characteristics), and the roles of these proteins in determining intracellular Ca2+, membrane potential, and ultimately cochlear sensitivity are discussed. The paper also discusses the role of the Ca2+ sequestration sacs in outer hair cells in the autoregulation of hair cell membrane potential and cochlear gain, and how the underdamped control of Ca2+ within these sacs may produce the observed slow oscillations in cochlear sensitivity and otoacoustic emissions after cochlear perturbations, including perilymphatic perfusions and prolonged low-frequency tones. The relative insensitivity of cochlear gain to short-term changes in the endocochlear potential is also discussed.

from Hearing Research

TAK1 Expression in the Cochlea: A Specific Marker for Adult Supporting Cells

Transforming growth factor-β-activated kinase-1 (TAK1) is a mitogen activated protein kinase kinase kinase that is involved in diverse biological roles across species. Functioning downstream of TGF-β and BMP signaling, TAK1 mediates the activation of the c-Jun N-terminal kinase signaling pathway, serves as the target of pro-inflammatory cytokines, such as TNF-α, mediates NF-κβ activation, and plays a role in Wnt/Fz signaling in mesenchymal stem cells. Expression of TAK1 in the cochlea has not been defined. Data mining of previously published murine cochlear gene expression databases indicated that TAK1, along with TAK1 interacting proteins 1 (TAB1), and 2 (TAB2), is expressed in the developing and adult cochlea. The expression of TAK1 in the developing cochlea was confirmed using RT-PCR and immunohistochemistry. Immunolabeling of TAK1 in embryonic, neonatal, and mature cochleas via DAB chromogenic and fluorescent immunohistochemistry indicated that TAK1 is broadly expressed in both the developing otocyst and periotic mesenchyme at E12.5 but becomes more restricted to specific types of supporting cells as the organ of Corti matures. By P1, TAK1 immunolabeling is found in cells of the stria vascularis, hair cells, supporting cells, and Kölliker’s organ. By P16, TAK1 labeling is limited to cochlear supporting cells. In the adult cochlea, TAK1 immunostaining is only present in the cytoplasm of Deiters’ cells, pillar cells, inner phalangeal cells, and inner border cells, with no expression in any other cochlear cell types. While the role of TAK1 in the inner ear is unclear, TAK1 expression may be used as a novel marker for specific sub-populations of supporting cells.

from JARO — Journal of the Association for Research in Otolaryngology

Adipose tissue-derived stromal cells protect hair cells from aminoglycoside

Conclusion:
These findings demonstrate that ADSCs have the capacity to protect auditory hair cells, and can be a useful strategy to develop therapy for deafness in the clinic. The multiple paracrine growth factors and cytokines secreted by ADSCs might be involved in this effect.

from The Laryngoscope

Prognosis of patients with idiopathic sudden hearing loss: role of vestibular assessment

In patients with idiopathic sudden hearing loss, the extent of the inner ear lesion tends to correlate with the severity of cochlear damage. Vestibular assessment may be valuable in predicting the final outcome.

from the Journal of Laryngology and Otology

Dissecting the molecular basis of organ of Corti development: Where are we now?

This review summarizes recent progress in our understanding of the molecular basis of cochlear duct growth, specification of the organ of Corti, and differentiation of the different types of hair cells. Studies of multiple mutations suggest that developing hair cells are involved in stretching the organ of Corti through convergent extension movements.However, Atoh1 null mutants have only undifferentiated and dying organ of Corti precursors but show a near normal extension of the cochlear duct, implying that organ of Corti precursor cells can equally drive this process. Some factors influence cochlear duct growth by regulating the cell cycle and proliferation. Shortened cell cycle and premature cell cycle exit can lead to a shorter organ of Corti with multiple rows of hair cells (e.g., Foxg1 null mice). Other genes affect the initial formation of a cochlear duct with or without affecting the organ of Corti. Such observations are consistent with evolutionary data that suggest some developmental uncoupling of cochlear duct from organ of Corti formation. Positioning the organ of Corti requires multiple genes expressed in the organ of Corti and the flanking region. Several candidate factors have emerged but how they cooperate to specify the organ of Corti and the topology of hair cells remains unclear. Atoh1 is required for differentiation of all hair cells, but regulation of inner versus outer hair cell differentiation is still unidentified. In summary, the emerging molecular complexity of organ of Corti development demands further study before a rational approach towards regeneration of unique types of hair cells in specific positions is possible.

from Hearing Research

Hypoxia enhances the stemness markers of cochlear stem/progenitor cells and expands sphere formation through activation of hypoxia-inducible factor-1alpha

Unlike neural stem cells that maintain populations in the adult brains of both rodents and humans, cochlear stem cells appear to diminish in number after birth and may become quiescent in adult mammalian cochleae. Hypoxia has been observed to promote an undifferentiated cell state in various stem cell populations; however, little is know about such an effect on cochlear stem/progenitor cells (SPCs). The aims of this study were to assess the effect of hypoxia on cochlear SPCs and to examine the impact of hypoxia-inducible factor-1alpha (Hif-1a) on regulating such an effect. Our data demonstrate that hypoxic culturing for 24 h significantly increased sphere formation and viability of cochlear SPCs compared with those cultured under normoxic conditions. Concurrent with these proliferation promotion effects are changes in the expression of multiple stemness and cell-cycle quiescent associated gene targets, including Abcg2, nestin, p27Kip1and Vegf. Knockdown of Hif-1a expression by small interfering RNA inhibited hypoxia-induced cochlear SPC expansion and resulted in downregulation of Vegf, Abcg2, and nestin and upregulation of p27Kip1 gene expression. These results suggest that Hif-1a plays an important role in the stimulation of the proliferation of cochlear SPCs, which confers a great benefit of expanding cochlear SPCs via hypoxic conditions.

from Hearing Research

Cochlear implant patients’ speech understanding in background noise: effect of mismatch between electrode assigned frequencies and perceived pitch

Conclusion: The mismatch between frequencies allocated to electrodes and the pitch perceived on stimulation of the same electrodes could partially account for our subjects’ difficulties with speech understanding in noisy conditions. We suggest that these subjects could benefit from mismatch correction, through a procedure allowing individualised reallocation of frequency bands to electrodes.

from the Journal of Laryngology and Otology

Reduced Electromotility of Outer Hair Cells Associated with Connexin-Related Forms of Deafness: An In silico Study of a Cochlear Network Mechanism

Mutations in the GJB2 gene encoding for the connexin 26 (Cx26) protein are the most common source of nonsyndromic forms of deafness. Cx26 is a building block of gap junctions (GJs) which establish electrical connectivity in distinct cochlear compartments by allowing intercellular ionic (and metabolic) exchange. Animal models of the Cx26 deficiency in the organ of Corti seem to suggest that the hearing loss and the degeneration of outer hair cells (OHCs) and inner hair cells is due to failed K+ and metabolite homeostasis. However, OHCs can develop normally in some mutants, suggesting that the hair cells death is not the universal mechanism. In search for alternatives, we have developed an in silico large scale three-dimensional model of electrical current flow in the cochlea in the small signal, linearised, regime. The effect of mutations was analysed by varying the magnitude of resistive components representing the GJ network in the organ of Corti. The simulations indeed show that reduced GJ conductivity increases the attenuation of the OHC transmembrane potential at frequencies above 5 kHz from 6.1 dB/decade in the wild-type to 14.2 dB/decade. As a consequence of increased GJ electrical filtering, the OHC transmembrane potential is reduced by up to 35 dB at frequencies >10 kHz. OHC electromotility, driven by this potential, is crucial for sound amplification, cochlear sensitivity and frequency selectivity. Therefore, we conclude that reduced OHC electromotility may represent an additional mechanism underlying deafness in the presence of Cx26 mutations and may explain lowered OHC functionality in particular reported Cx26 mutants.

from JARO — Journal of the Association for Research in Otolaryngology

Corticotropin-releasing factor-2 activation prevents gentamicin-induced oxidative stress in cells derived from the inner ear

Generation of reactive oxygen species (ROS) is a common denominator in many conditions leading to cell death in the cochlea, yet little is known of the cochlea’s endogenous mechanisms involved in preventing oxidative stress and its consequences in the cochlea. We have recently described a corticotropin-releasing factor (CRF) signaling system in the inner ear involved in susceptibility to noise-induced hearing loss. We use biochemical and proteomics assays to define further the role of CRF signaling in the response of cochlear cells to aminoglycoside exposure. We demonstrate that activity via the CRF2 class of receptors protects against aminoglycoside-induced ROS production and activation of cell death pathways. This study suggests for the first time a role for CRF signaling in protecting the cochlea against oxidative stress, and our proteomics data suggest novel mechanisms beyond induction of free radical scavengers that are involved in its protective mechanisms. © 2010 Wiley-Liss, Inc.

from the Journal of Neuroscience Research

Heat shock protein 70 and cellular disturbances in cochlear cisplatin ototoxicity model

Conclusions: Seven days after cisplatin exposure, we found disturbances of the cochlear cellular machinery involving heat shock protein 70, other apoptotic proteins and total superoxide dismutase.

from the Journal of Laryngology and Otology

Somatic motility and hair bundle mechanics, are both necessary for cochlear amplification?

Hearing organs have evolved to detect sounds across several orders of magnitude of both intensity and frequency. Detection limits are at the atomic level despite the energy associated with sound being limited thermodynamically. Several mechanisms have evolved to account for the remarkable frequency selectivity, dynamic range, and sensitivity of these various hearing organs, together termed the active process or cochlear amplifier. Similarities between hearing organs of disparate species provides insight into the factors driving the development of the cochlear amplifier. These properties include: a tonotopic map, the emergence of a two hair cell system, the separation of efferent and afferent innervations, the role of the tectorial membrane, and the shift from intrinsic tuning and amplification to a more end organ driven process. Two major contributors to the active process are hair bundle mechanics and outer hair cell electromotility, the former present in all hair cell organs tested, the latter only present in mammalian cochlear outer hair cells. Both of these processes have advantages and disadvantages, and how these processes interact to generate the active process in the mammalian system is highly disputed. A hypothesis is put forth suggesting that hair bundle mechanics provides amplification and filtering in most hair cells, while in mammalian cochlea, outer hair cell motility provides the amplification on a cycle by cycle basis driven by the hair bundle that provides frequency selectivity (in concert with the tectorial membrane) and compressive nonlinearity. Separating components of the active process may provide additional sites for regulation of this process.

from Hearing Research