Pioglitazone Ameliorates Gentamicin Ototoxicity by Affecting the TLR and STAT Pathways in the Early Postnatal Organ of Corti

Abstract

Noise trauma, infection, and ototoxic drugs are frequent external causes of hearing loss. With no pharmacological treatments currently available, understanding the mechanisms and pathways leading to auditory hair cell (HC) damage and repair is crucial for identifying potential pharmacological targets. Prior research has implicated increased reactive oxygen species (ROS) and inflammation as general mechanisms of hearing loss common to diverse causes. Novel targets of these two key mechanisms of auditory damage may provide new paths toward the prevention and treatment of hearing loss. Pioglitazone, an oral antidiabetic drug from the class of thiazolidinediones, acts as an agonist of the peroxisome proliferator-activated receptor-gamma (PPAR-γ) and is involved in the regulation of lipid and glucose metabolism. PPAR-γ is an important player in repressing the expression of inflammatory cytokines and signaling molecules. We evaluated the effects of pioglitazone in the mouse Organ of Corti (OC) explants to characterize its influence on signaling pathways involved in auditory HC damage. The OC explants was cultured with pioglitazone, gentamicin, or a combination of both agents. Pioglitazone treatment resulted in significant repression of interferon (IFN)-α and -gamma pathways and downstream cytokines, as assessed by RNA sequencing and quantitative PCR gene expression assays. More detailed investigation at the single gene and protein level showed that pioglitazone mediated its anti-inflammatory effects through alterations of the Toll-like receptor (TLR) and STAT pathways. Together, these results indicate that pioglitazone significantly represses IFN and TLR in the cochlea, dampening the activity of gentamicin-induced pathways. These data support our previous results demonstrating significant protection of auditory HCs in the OC explants exposed to pioglitazone and other PPAR-targeted agents.

Prophylactic and Ameliorative Effects of PPAR-γ Agonist Pioglitazone in Improving Oxidative Stress, Germ Cell Apoptosis and Inflammation in Gentamycin-Induced Testicular Damage in Adult Male Albino Rats

“…In previous studies, gentamycin was found to induce multi-organ damage such as hepatic toxicity, ototoxicity, and nephrotoxicity [ 20 , 35 , 36 ]. Moreover, PIO was previously approved to inhibit nephrotoxicity induced by gentamycin [ 20 ] Therefore, this study investigated whether PIO has a protective effect against testicular toxicity.…”

Current Concepts and Future Trends in Increasing the Benefits of Cochlear Implantation: A Narrative Review

“…TZDs act by activating peroxisome proliferator-activated receptors (PPARs), a group of nuclear receptors exerting an anti-inflammatory and antiproliferative effect, as well as regulating the cellular redox balance. When used with gentamicin in in vitro studies conducted by Sekulic-Jablanovic et al, pioglitazone demonstrated a protective cochlear effect against oxidative stress and prevented gentamicin toxicity [67,68]. As PPARs are involved in noise exposure cochlear damage [69], Paciello et al used pioglitazone in a biocompatible thermogel via transtympanic injection in rats with noise-induced hearing loss [70].…”

“…Other PPAR activators, such as fenofibrate, rosiglitazone, and other antidiabetic drugs, including metformin, are mentioned in the literature as having an otoprotective effect, but none of them have been studied in conjunction with cochlear implants [67,[72][73][74][75].…”