Dataset Information

Pioglitazone Represents an Effective Therapeutic Target in Preventing Oxidative/Inflammatory Cochlear Damage Induced by Noise Exposure.

ABSTRACT: Recent progress in hearing loss research has provided strong evidence for the imbalance of cellular redox status and inflammation as common predominant mechanisms of damage affecting the organ of Corti including noise induced hearing loss. The discovery of a protective molecule acting on both mechanisms is challenging. The thiazolidinediones, a class of antidiabetic drugs including pioglitazone and rosiglitazone, have demonstrated diverse pleiotrophic effects in many tissues where they exhibit anti-inflammatory, anti-proliferative, tissue protective effects and regulators of redox balance acting as agonist of peroxisome proliferator-activated receptors (PPARs). They are members of the family of ligand regulated nuclear hormone receptors that are also expressed in several cochlear cell types, including the outer hair cells. In this study, we investigated the protective capacity of pioglitazone in a model of noise-induced hearing loss in Wistar rats and the molecular mechanisms underlying this protective effects. Specifically, we employed a formulation of pioglitazone in a biocompatible thermogel providing rapid, uniform and sustained inner ear drug delivery via transtympanic injection. Following noise exposure (120 dB, 10 kHz, 1 h), different time schedules of treatment were employed: we explored the efficacy of pioglitazone given immediately (1 h) or at delayed time points (24 and 48 h) after noise exposure and the time course and extent of hearing recovery were assessed. We found that pioglitazone was able to protect auditory function at the mid-high frequencies and to limit cell death in the cochlear basal/middle turn, damaged by noise exposure. Immunofluorescence and western blot analysis provided evidence that pioglitazone mediates both anti-inflammatory and anti-oxidant effects by decreasing NF-?B and IL-1? expression in the cochlea and opposing the oxidative damage induced by noise insult. These results suggest that intratympanic pioglitazone can be considered a valid therapeutic strategy for attenuating noise-induced hearing loss and cochlear damage, reducing inflammatory signaling and restoring cochlear redox balance.

SUBMITTER: Paciello F

PROVIDER: S-EPMC6187064 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Pioglitazone Represents an Effective Therapeutic Target in Preventing Oxidative/Inflammatory Cochlear Damage Induced by Noise Exposure.

Paciello Fabiola F Fetoni Anna Rita AR Rolesi Rolando R Wright Matthew B MB Grassi Claudio C Troiani Diana D Paludetti Gaetano G

Frontiers in pharmacology 20181008

Recent progress in hearing loss research has provided strong evidence for the imbalance of cellular redox status and inflammation as common predominant mechanisms of damage affecting the organ of Corti including noise induced hearing loss. The discovery of a protective molecule acting on both mechanisms is challenging. The thiazolidinediones, a class of antidiabetic drugs including pioglitazone and rosiglitazone, have demonstrated diverse pleiotrophic effects in many tissues where they exhibit a ...[more]

PMID: 30349478

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Project description:Cochlear inflammatory response to various environmental insults, including acoustic and ototoxic overexposures, has been increasingly become a topic of interest. As the immune response is associated with both pathology and protection, targeting specific components of the immune response is expected to dissect the relationships between cellular damage and inflammation-associated protection and repair in the cochlea. Duffy antigen receptor for chemokines (DARC) is a member of a group of atypical chemokine receptors, and essential for chemokine-regulated leukocyte/neutrophil trafficking during inflammation. Previous studies have reported that Darc deficiency alters chemokine bioavailability and leukocyte homeostasis, leading to significant anti-inflammatory effects in tissues following injury. In this study, we have used Darc knockout mice to determine the impact of a deficiency in this gene on cochlear development, as well as function in cochlea subjected to various stresses. We observed that DARC is not required for normal development of cochlear function, as evidenced by typical hearing sensitivity in juvenile Darc-KO mice, as compared to wild type (WT) C57BL/6 mice. However, Darc-KO mice exhibited improved hearing recovery after intense noise exposure when compared to wild-type. The auditory brainstem response (ABR) threshold shift between KO and WT mice was most obvious at 1-week post-noise exposure. At cochlear locations above the frequency range of the energy band of damaging noise, both hair cell survival and ribbon synapse density were improved in Darc deficient animals. In addition, the mRNA levels of some major inflammatory effectors, including Mcp-1 and Gdf15, were altered in Darc-KO mice compared to control mice at 1, 3 and 7 days post-noise exposure. These data collectively suggest that the normal Darc-dependent inflammatory response slows down the process of hearing recovery, and exacerbates cellular damage in the cochlea after noise exposure.

Project description:Noise-induced hearing loss has gained relevance as one of the most common forms of hearing impairment. The anatomical correlates of hearing loss, principally cell damage and/or death, are relatively well-understood histologically. However, much less is known about the physiological aspects of damaged, surviving cells. Here we addressed the functional consequences of noise exposure on the capacity of inner hair cells (IHCs) to release synaptic vesicles at synapses with spiral ganglion neurons (SGNs). Mice of either sex at postnatal day (P) 15-16 were exposed to 1-12 kHz noise at 120 dB sound pressure level (SPL), for 1 h. Exocytosis was measured by tracking changes in membrane capacitance (ΔCm) from IHCs of the apical cochlea. Upon IHC depolarization to different membrane potentials, ΔC m showed the typical bell-shaped curve that mirrors the voltage dependence of Ca2+ influx, in both exposed and unexposed cells. Surprisingly, from IHCs at 1-day after exposure (d.a.e.), we found potentiation of exocytosis at the peak of the bell-shaped curve. The increase in exocytosis was not accompanied by changes in whole-cell Ca2+ influx, suggesting a modification in coupling between Ca2+ channels and synaptic vesicles. Consistent with this notion, noise exposure also changed the Ca2+-dependence of exocytosis from linear to supralinear. Noise exposure did not cause loss of IHCs, but did result in a small reduction in the number of IHC-SGN synapses at 1-d.a.e. which recovered by 14-d.a.e. In contrast, a strong reduction in auditory brainstem response wave-I amplitude (representing synchronous firing of SGNs) and distortion product otoacoustic emissions (reflecting outer hair cell function) indicated a profound hearing loss at 1- and 14-d.a.e. To determine the role of glutamate release in the noise-induced potentiation of exocytosis, we evaluated vesicular glutamate transporter-3 (Vglut3) knock-out (KO) mice. Unlike WT, IHCs from Vglut3 KO mice showed a noise-induced reduction in ΔC m and Ca2+ influx with no change in the Ca2+-dependence of exocytosis. Together, these results indicate that traumatic noise exposure triggers changes of IHC synaptic function including a Vglut3-dependent potentiation of exocytosis.

Project description:The molecular mechanisms underlying the great differences in susceptibility to noise-induced hearing loss (NIHL) exhibited by both humans and laboratory animals are unknown. Using microarray technology, the present study demonstrates that the effects of noise overexposure on the expression of molecules likely to be important to the development of NIHL differ among inbred mice that have distinctive susceptibilities to NIHL including B6.CAST, 129X1/SvJ, and 129S1/SvImJ. The noise-exposure protocol produced, on average, a permanent loss of about 40 dB in sensitivity for auditory brainstem responses in susceptible B6.CAST mice, but no threshold elevations for the two resistant 129S1/SvImJ and 129X1/SvJ substrains. Measurements of noise-induced gene expression changes 6 h after the noise exposure revealed significant alterations in the expression levels of 48 genes in the resistant mice, while by these same criteria, there were seven differentially expressed genes in the susceptible B6.CAST mice. Differentially expressed genes in both groups of mice included subsets of transcription factors. However, only in the resistant mice was there a significant induction of proteins involved in cell-survival pathways such as HSP70, HSP40, p21, GADD45ï¢, Ier3, and Nfï«ï¢iïº. Moreover, increased expression of three of these factors after noise was confirmed at the protein level. Drastically enhanced HSP70, GADD45ï¢, and p21 immunostaining were detected 6 h after the noise exposure in subsets of cells of the lateral wall, spiral limbus, and organ of Corti as well as in cochlear nerve fibers. Upregulation of these proteins after noise exposure likely contributes to the prevalence of survival cellular pathways and thus to the resistance to NIHL that is characteristic of the 129X1/SvJ mice. Experiment Overall Design: Female 10-wk-old mice of the B6.CAST and 129X1/SvJ strains were divided randomly into non-noise control and noise-exposure groups. The non-noise mice served as controls in the gene-profiling experiments to control for the stress induced by experimenter handling and/or confinement of the mice in the noise-exposure chamber that was not directly related to the noise. This mice were in the noise chamber for a sham exposure. In contrast, the ânoiseâ groups were exposed to a 105-dB SPL, 10-kHz octave band of noise for 1 h and sacrificed 6 h after the exposure. Of each of these major groups, eight mice were used for each of three 129X1/SvJ control and three noise-exposed 129X1/SvJ arrays and two B6.CAST control and two noise-exposed B6.CAST arrays. Consequently within each subgroup the arrays are biological replicates.

Project description:One of the primary theories of the pathogenesis of tinnitus involves maladaptive auditory?somatosensory plasticity in the dorsal cochlear nucleus (DCN), which is assumed to be due to axonal sprouting. Although a disrupted balance between auditory and somatosensory inputs may occur following hearing damage and may induce tinnitus, examination of this phenomenon employed a model of hearing damage that does not account for the causal relationship between these changes and tinnitus. The present study aimed to investigate changes in auditory?somatosensory innervation and the role that axonal sprouting serves in this process by comparing results between animals with and without tinnitus. Rats were exposed to a noise?inducing temporary threshold shift and were subsequently divided into tinnitus and non?tinnitus groups based on the results of gap prepulse inhibition of the acoustic startle reflex. DCNs were collected from rats divided into three sub?groups according to the number of weeks (1, 2 or 3) following noise exposure, and the protein levels of vesicular glutamate transporter 1 (VGLUT1), which is associated with auditory input to the DCN, and VGLUT2, which is in turn primarily associated with somatosensory inputs, were assessed. In addition, factors related to axonal sprouting, including growth?associated protein 43 (GAP43), postsynaptic density protein 95, synaptophysin, ??thalassemia/mental retardation syndrome X?linked homolog (ATRX), growth differentiation factor 10 (GDF10), and leucine?rich repeat and immunoglobulin domain?containing 1, were measured by western blot analyses. Compared to the non?tinnitus group, the tinnitus group exhibited a significant decrease in VGLUT1 at 1 week and a significant increase in VGLUT2 at 3 weeks post?exposure. In addition, rats in the tinnitus group exhibited significant increases in GAP43 and GDF10 protein expression levels in their DCN at 3 weeks following noise exposure. Results from the present study provided further evidence that changes in the neural input distribution to the DCN may cause tinnitus and that axonal sprouting underlies these alterations.

Dataset Information

Pioglitazone Represents an Effective Therapeutic Target in Preventing Oxidative/Inflammatory Cochlear Damage Induced by Noise Exposure.

Publications

Pioglitazone Represents an Effective Therapeutic Target in Preventing Oxidative/Inflammatory Cochlear Damage Induced by Noise Exposure.

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