Effects of peroxisome proliferator activated receptors (PPAR)-γ and -α agonists on cochlear protection from oxidative stress

PLoS One. 2017 Nov 28;12(11):e0188596. doi: 10.1371/journal.pone.0188596. eCollection 2017.


Various insults cause ototoxicity in mammals by increasing oxidative stress leading to apoptosis of auditory hair cells (HCs). The thiazolidinediones (TZDs; e.g., pioglitazone) and fibrate (e.g., fenofibrate) drugs are used for the treatment of diabetes and dyslipidemia. These agents target the peroxisome proliferator-activated receptors, PPARγ and PPARα, which are transcription factors that influence glucose and lipid metabolism, inflammation, and organ protection. In this study, we explored the effects of pioglitazone and other PPAR agonists to prevent gentamicin-induced oxidative stress and apoptosis in mouse organ of Corti (OC) explants. Western blots showed high levels of PPARγ and PPARα proteins in mouse OC lysates. Immunofluorescence assays indicated that PPARγ and PPARα proteins are present in auditory HCs and other cell types in the mouse cochlea. Gentamicin treatment induced production of reactive oxygen species (ROS), lipid peroxidation, caspase activation, PARP-1 cleavage, and HC apoptosis in cultured OCs. Pioglitazone mediated its anti-apoptotic effects by opposing the increase in ROS induced by gentamicin, which inhibited the subsequent formation of 4-hydroxy-2-nonenal (4-HNE) and activation of pro-apoptotic mediators. Pioglitazone mediated its effects by upregulating genes that control ROS production and detoxification pathways leading to restoration of the reduced:oxidized glutathione ratio. Structurally diverse PPAR agonists were protective of HCs. Pioglitazone (PPARγ-specific), tesaglitazar (PPARγ/α-specific), and fenofibric acid (PPARα-specific) all provided >90% protection from gentamicin toxicity by regulation of overlapping subsets of genes controlling ROS detoxification. This study revealed that PPARs play important roles in the cochlea, and that PPAR-targeting drugs possess therapeutic potential as treatment for hearing loss.

MeSH terms

  • Animals
  • Cochlea / drug effects*
  • Cochlea / metabolism
  • Hypoglycemic Agents / pharmacology*
  • Mice
  • Mice, Inbred C57BL
  • Oxidative Stress*
  • PPAR alpha / agonists*
  • PPAR gamma / agonists*
  • Pioglitazone
  • Reactive Oxygen Species / metabolism
  • Thiazolidinediones / pharmacology*


  • Hypoglycemic Agents
  • PPAR alpha
  • PPAR gamma
  • Reactive Oxygen Species
  • Thiazolidinediones
  • Pioglitazone

Grants and funding

This work was supported by a grant from the Swiss Commission for Technology Innovation (CTI) Nr. 18117.1 PFLS-LS to Prof Bodmer and Dr Petkovic with a 10% matching cash contribution from Strekin AG. The Swiss Commission for Technology Innovation (CTI) had no role in the study design; collection, analysis, and interpretation of data; writing of the paper; and/or decision to submit for publication, https://www.kti.admin.ch/kti/en/home.html. Strekin AG through Dr. Wright participated in study design; interpretation of data; writing of the paper; and decision to submit for publication.