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

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 mechan...

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Main Authors: Fabiola Paciello, Anna Rita Fetoni, Rolando Rolesi, Matthew B. Wright, Claudio Grassi, Diana Troiani, Gaetano Paludetti
Format: Article
Language:English
Published: Frontiers Media S.A. 2018-10-01
Series:Frontiers in Pharmacology
Subjects:
Online Access:https://www.frontiersin.org/article/10.3389/fphar.2018.01103/full
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spelling doaj-cb1b940559a0459dbe3f65465cb2010e2020-11-24T21:11:59ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122018-10-01910.3389/fphar.2018.01103409521Pioglitazone Represents an Effective Therapeutic Target in Preventing Oxidative/Inflammatory Cochlear Damage Induced by Noise ExposureFabiola Paciello0Fabiola Paciello1Fabiola Paciello2Anna Rita Fetoni3Anna Rita Fetoni4Anna Rita Fetoni5Rolando Rolesi6Matthew B. Wright7Claudio Grassi8Claudio Grassi9Diana Troiani10Gaetano Paludetti11Gaetano Paludetti12Fondazione Policlinico Universitario A. Gemelli, IRCCS, Rome, ItalyInstitute of Otolaryngology, Università Cattolica del Sacro Cuore, Rome, ItalyInstitute of Cell Biology and Neurobiology, CNR, Rome, ItalyFondazione Policlinico Universitario A. Gemelli, IRCCS, Rome, ItalyInstitute of Otolaryngology, Università Cattolica del Sacro Cuore, Rome, ItalyInstitute of Cell Biology and Neurobiology, CNR, Rome, ItalyFondazione Policlinico Universitario A. Gemelli, IRCCS, Rome, ItalyStrekin AG, Basel, SwitzerlandFondazione Policlinico Universitario A. Gemelli, IRCCS, Rome, ItalyInstitute of Human Physiology, Università Cattolica del Sacro Cuore, Rome, ItalyInstitute of Human Physiology, Università Cattolica del Sacro Cuore, Rome, ItalyFondazione Policlinico Universitario A. Gemelli, IRCCS, Rome, ItalyInstitute of Otolaryngology, Università Cattolica del Sacro Cuore, Rome, ItalyRecent 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-κB and IL-1β 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.https://www.frontiersin.org/article/10.3389/fphar.2018.01103/fullPPAR agonistacoustic traumaantioxidantantinflammatoryaudiologypersonalized medicine
collection DOAJ
language English
format Article
sources DOAJ
author Fabiola Paciello
Fabiola Paciello
Fabiola Paciello
Anna Rita Fetoni
Anna Rita Fetoni
Anna Rita Fetoni
Rolando Rolesi
Matthew B. Wright
Claudio Grassi
Claudio Grassi
Diana Troiani
Gaetano Paludetti
Gaetano Paludetti
spellingShingle Fabiola Paciello
Fabiola Paciello
Fabiola Paciello
Anna Rita Fetoni
Anna Rita Fetoni
Anna Rita Fetoni
Rolando Rolesi
Matthew B. Wright
Claudio Grassi
Claudio Grassi
Diana Troiani
Gaetano Paludetti
Gaetano Paludetti
Pioglitazone Represents an Effective Therapeutic Target in Preventing Oxidative/Inflammatory Cochlear Damage Induced by Noise Exposure
Frontiers in Pharmacology
PPAR agonist
acoustic trauma
antioxidant
antinflammatory
audiology
personalized medicine
author_facet Fabiola Paciello
Fabiola Paciello
Fabiola Paciello
Anna Rita Fetoni
Anna Rita Fetoni
Anna Rita Fetoni
Rolando Rolesi
Matthew B. Wright
Claudio Grassi
Claudio Grassi
Diana Troiani
Gaetano Paludetti
Gaetano Paludetti
author_sort Fabiola Paciello
title Pioglitazone Represents an Effective Therapeutic Target in Preventing Oxidative/Inflammatory Cochlear Damage Induced by Noise Exposure
title_short Pioglitazone Represents an Effective Therapeutic Target in Preventing Oxidative/Inflammatory Cochlear Damage Induced by Noise Exposure
title_full Pioglitazone Represents an Effective Therapeutic Target in Preventing Oxidative/Inflammatory Cochlear Damage Induced by Noise Exposure
title_fullStr Pioglitazone Represents an Effective Therapeutic Target in Preventing Oxidative/Inflammatory Cochlear Damage Induced by Noise Exposure
title_full_unstemmed Pioglitazone Represents an Effective Therapeutic Target in Preventing Oxidative/Inflammatory Cochlear Damage Induced by Noise Exposure
title_sort pioglitazone represents an effective therapeutic target in preventing oxidative/inflammatory cochlear damage induced by noise exposure
publisher Frontiers Media S.A.
series Frontiers in Pharmacology
issn 1663-9812
publishDate 2018-10-01
description 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-κB and IL-1β 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.
topic PPAR agonist
acoustic trauma
antioxidant
antinflammatory
audiology
personalized medicine
url https://www.frontiersin.org/article/10.3389/fphar.2018.01103/full
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