Yeasmin Tahera

Estrogen receptor β protects against acoustic trauma in mice

The hormone estradiol affects the auditory system both by itself and by its interaction with neuroprotective factors. In this study, we examined the role of estrogen receptors (ERs) in response to auditory trauma. We found a ligand-dependent protective role for ERbeta in the auditory system by investigating mice deficient in ERalpha (ERKO mice), ERbeta (BERKO mice), and aromatase (ARKO mice). Basal auditory brainstem response (ABR) thresholds were similar in all animals. An acoustic trauma causing a temporary hearing loss raised ABR thresholds in male and female BERKO and ARKO mice compared with WT and ERKO mice. The ERalpha-selective agonist, propyl(1H) pyrazole-1,3,5-triyl-trisphenol (PPT), partially protected ARKO mice from trauma, while the ERbeta-selective agonist, 2,3-bis (4-hydroxyphenyl)-propionitrile (DPN), protected WT and ARKO mice. Immunohistochemistry and western blotting confirmed the expression of ERbeta in cochlea of WT males and females. Levels of brain-derived neurotrophic factor (BDNF), a neuroprotective peptide that can be induced by estrogen, was lower in BERKO and ARKO mice compared with WT. DPN treatment increased BDNF expression in ARKO mice. These data indicate ERbeta-mediated neuroprotection involving BDNF in the auditory system of males and females.

NF-κB mediated glucocorticoid response in the inner ear after acoustic trauma

The inner ear of humans and experimental animals demonstrate an abundance of glucocorticoid receptors (GR). Glucocorticoids (GC) are widely used to treat different hearing disorders; yet the mechanisms of GC action on the inner ear are unknown. We demonstrate how GR can directly modulate hearing sensitivity in response to a moderate acoustic trauma that results in a hearing loss (10–30 dB). The GC agonist (dexamethasone) and the drugs (metyrapone + RU 486) showed opposing effects on hearing threshold shifts. GC agonist (dexamethasone) decreased the hearing threshold whereas pre‐treatment with a GC synthesis inhibitor (metyrapone) in combination with a GR antagonist (RU 486) exacerbated auditory threshold shifts (25–60 dB) after acoustic trauma with statistically significant increase in GR mRNA and GR protein compared with the vehicle and acoustic trauma group. Acoustic trauma caused a significant increase in the nuclear transport of NF‐κB, whereas pre‐treatment with the drugs (metyrapone and RU 486) blocked NF‐κB nuclear transport into spiral ganglion nuclei. An NF‐κB inhibitor, pyrrolidine dithiocarbamate ammonium blocked the trauma‐induced translocation of NF‐κB and resulted in a hearing loss (45–60) dB. These results indicate that several factors define the responsiveness of the inner ear to GC, including the availability of ligand or receptor, and the nuclear translocation of GR and NF‐κB. These findings will further our understanding of individual GC responsiveness to steroid treatment, and will help improve the development of pharmaceuticals to selectively target GR in the inner ear for individuals with increased sensitivity to acoustic trauma.

Glucocorticoid receptors modulate auditory sensitivity to acoustic trauma.

Glucocorticoids are widely used to treat different hearing disorders yet the exact mechanisms of glucocorticoid action on the inner ear are not known. The inner ear of both humans and experimental animals demonstrate an abundance of glucocorticoid receptors (GRs) in both neuronal and non-neuronal tissues. In this review, we discuss how activation of the hypothalamic-pituitary-adrenal axis can directly modulate hearing sensitivity. Recent findings indicate that several factors define the responsiveness of the peripheral auditory system to glucocorticoids including the concentration of agonist, availability of the GR, and the activation of GR and NF-kappaB. These findings will further our understanding of individual glucocorticoid responsiveness to steroid treatment, and will help improve the development of pharmaceuticals to selectively target GR in the inner ear for individuals with increased sensitivity to acoustic trauma.

Sound conditioning protects hearing by activating the hypothalamic-pituitary-adrenal axis

Sound conditioning primes the auditory system to low levels of acoustic stimuli and reduces damage caused by a subsequent acoustic trauma. This priming activates the HPA axis resulting in the elevation of plasma corticosterone with a consequent upregulation of glucocorticoid receptors (GR) in the cochlea and the paraventricular nucleus (PVN) of the hypothalamus in the mouse. This protective effect is blocked by adrenalectomy or pharmacological treatment with RU486 + metyrapone. Sound conditioning prevents GR down-regulation induced by acoustic trauma and subsequently enhances GR activity in spiral ganglion neurons. Increased SRC-1 expression, triggered by sound conditioning, positively correlates with the upregulation of GR in the cochlea. These findings will help to define the cellular mechanisms responsible for protecting the auditory system from hearing loss by sound conditioning.

Functional responses of estrogen receptors in the male and female auditory system.

Recently significant progress was made in understanding the mechanisms by which the two estrogen receptors (alpha and beta) are involved in different pathways of estrogen action in a wide variance of tissues. Divergent responses of cells and tissues to estrogens or their ligands have been attributed to various isoforms and signaling pathways of estrogen receptors. Both subtypes of estrogen receptors have been identified in the cochlea and there are indications that they have neuroprotective effects but there is still limited information on the role and specific mechanisms of these two receptors in the auditory system. This review will examine the molecular and functional actions of the two estrogen receptor subtypes, the pivotal role they play in the auditory system and their therapeutic strategies for protecting against hearing loss.

Glucocorticoid Receptor and Mitogen-Activated Protein Kinase Activity after Restraint Stress and Acoustic Trauma

Restraint stress (RS) protects auditory function against acoustic trauma by activating glucocorticoid receptors (GR) in the cochlea. In a search for the signaling pathways downstream to GR that may be involved in RS-induced protection we report here (1) a downregulation of phosphorylated extracellular signal-regulated kinases 1 and 2 (pERK 1/2) after the combined treatment of RS and acoustic trauma; (2) activation of phospho-p38 in the auditory nerve after RS; (3) the abolition of these two effects by pretreatment with metyrapone (an inhibitor of corticosterone synthesis) and RU486 (a GR antagonist); and (4) no activation of c-jun-N-terminal kinases 1 and 2 (JNK 1/2), ERK, or p38 after acoustic trauma alone. Thus we demonstrate a GR-dependent ERK-mediated pathway that modulates auditory function after RS and acoustic trauma. These findings reveal new mechanisms that underlie hearing loss and will have implications for the development of pharmacological strategies for protecting against acoustic trauma.

Protection against Acoustic Trauma by Forward and Backward Sound Conditioning

The purpose of the present study was to determine if short-term sound conditioning provides protection when delivered either before (forward sound conditioning) or after (backward sound conditioning) a traumatic exposure in the guinea pig. Two different sound conditioning paradigms were studied (1 kHz, 81 dB SPL, 24 h; 6.3 kHz, 78 dB SPL, 24 h). The 1-kHz forward sound conditioning paradigm (81 dB SPL, 24 h) protected distortion product otoacoustic emissions (DPOAEs) against a short-duration acoustic trauma (2.7 kHz, 103 dB SPL, 5 min) compared to the group exposed to the acoustic trauma alone. The 1-kHz forward sound conditioning paradigm (81 dB SPL, 24 h) also protected both the auditory brainstem response (ABR) thresholds and DPOAEs against a longer-duration acoustic trauma (2.7 kHz, 103 dB SPL, 30 min). The group exposed to the acoustic trauma alone showed ABR threshold shifts between 15 and 24 dB, and DPOAE amplitude shifts between 11 and 24 dB, while the group with 1-kHz forward sound conditioning showed statistically significant protection at all ABR frequencies and at all DPOAE frequencies. The 1-kHz backward sound conditioning paradigm protected against acoustic trauma (2.7 kHz, 103 dB SPL, 30 min). The ABR thresholds were protected at 1, 2 and 4 kHz, and DPOAEs at all frequencies (except 8 kHz) when compared to the group exposed only to the acoustic trauma. The 6.3-kHz forward sound conditioning paradigm protected against acoustic trauma (5.5 kHz, 109 dB SPL, 30 min) at 6.3, 8 and 10 kHz. The 6.3-kHz backward sound conditioning paradigm showed no protection against acoustic trauma at any DPOAE frequency. Taken together, these findings are important for understanding how the auditory system can be modulated by acoustic stimulation and highlights the importance of the acoustic environment during the recovery process of the auditory system.

Differential activation of mitogen-activated protein kinases and brain-derived neurotrophic factor after temporary or permanent damage to a sensory system.

Functional and morphological differences between temporary (TTS) and permanent (PTS) hearing loss induced by acoustic trauma are well characterized whereas molecular differences remain to be elucidated. A comparative analysis of the expression of the phosphorylated forms of extracellular signal-regulated kinase (ERK1/2), c-jun-N-terminal kinases 1/2 (JNK1/2) and p38 in the mouse cochlea after acoustic trauma resulting in either a temporary or permanent damage is presented. In the acute phase of PTS an upregulation of phosphorylated p38, JNK1/2, and ERK1/2 was found while in the acute phase of TTS a downregulation of phospho-p38 occurred and no immediate change of pJNK1/2 and pERK1/2 was noted. After a 24 h recovery from TTS JNK1/2 and ERK1/2 was activated while the expression of phospho-p38 was downregulated. In contrast PTS group showed complete recovery to control values for all three MAPKs by 24 h post. The level of brain-derived neurotrophic factor (BDNF), a potent otoprotective agent, was elevated after both types of acoustic trauma but the elevation after permanent trauma was of a longer duration. The expression of BDNF receptors TrkB (truncated form) was downregulated only after permanent hearing loss. Thus, temporary and permanent hearing loss demonstrate different expression patterns and temporal aspects of MAPK, BDNF and TrkB in the cochlea. The results of this study will help reveal the cellular mechanisms underlying hearing loss induced by acoustic trauma.

Environmental enrichment to sound activates dopaminergic pathways in the auditory system

Environmental enrichment to sound stimulation, in the adult, can promote physiological changes and protection against trauma in the auditory peripheral and central nervous system. Sound enrichment, or sound conditioning is a method that utilizes a low-level, non-damaging acoustic stimulus as a protective agent. Pre-treating subjects to a moderate or low-level acoustic stimulus reduces the damaging effects of a subsequent traumatic stimulus. The intention of this review is to describe how environmental enrichment to sound affords protection against a subsequent trauma, and the role that the dopaminergic pathways in the cochlea and the auditory brainstem play in this protection. Dopamine is released from the lateral efferents and exerts a tonic inhibition of auditory nerve activity thus preserving auditory sensitivity and protecting against excitotoxicity. Sound conditioning up-regulated tyrosine hydroxylase in the lateral efferents under the inner hair cells and acoustic trauma reduced these levels. Thus, sound conditioning triggers an up-regulation of tyrosine hydroxylase both in the lateral efferent of cochlea and in the lateral superior olivary complex. These findings expand our understanding of the neurochemical balance and regulation between the lateral olivocochlear neurons and the lateral efferent terminals in the cochlea during sound stimulation.