Effects of peroxisome proliferator activated receptors -[gamma] and -[alpha] agonists on cochlear protection from oxidative stress

• Published in: PloS one 2017-11, Vol.12 (11), p.e0188596
• Main Authors: Sekulic-Jablanovic, Marijana, Petkovic, Vesna, Wright, Matthew B, Kucharava, Krystsina, Huerzeler, Nathan, Levano, Soledad, Brand, Yves, Leitmeyer, Katharina, Glutz, Andrea, Bausch, Alexander, Bodmer, Daniel
• Format: Article
• Language: English
• Subjects: Apoptosis; Complications and side effects; Genetic aspects; Hair cells (Sensory receptors); Oxidative stress; Physiological aspects
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0188596

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, PPAR[gamma] and PPAR[alpha], 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 PPAR[gamma] and PPAR[alpha] proteins in mouse OC lysates. Immunofluorescence assays indicated that PPAR[gamma] and PPAR[alpha] 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 (PPAR[gamma]-specific), tesaglitazar (PPAR[gamma]/[alpha]-specific), and fenofibric acid (PPAR[alpha]-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.