Role of STAT1 and Oxidative Stress in Gentamicin-Induced Hair Cell Death in Organ of Corti

Abstract

Rationale Oxidative stress plays a critical role in gentamicin-induced hair cell death. Prior work has implicated the cytoplasmic transcription factor STAT1 as a potential mediator of drug-induced ototoxicity, but role in aminoglycosides is largely unknown. This study investigated aminoglycosides-induced cell death, exploring contributions of reactive oxygen species and STAT1 pathway in injury and protection. Methods Neonatal murine organ of Corti explants from 2-3 day postnatal pups (n=96) were treated with gentamicin at (4 μΜ, 50 μΜ) for 4-72 hours, with/without protectants. Effects on STAT1 pathway and gentamicin-induced hair cell death were measured with 50 μΜ Epigallocatechin Gallate (EGCG, a STAT1 inhibitor) and all-trans retinoic acid (atRA, a STAT1 activator). Hair cell morphology was evaluated and hair cell loss was quantified with cytocochleograms. Mitochondrial membrane potential was assayed and superoxide generation and suppression was measured with dihydroethidium (DHE) staining. Results Co-administration of 50 μΜ EGCG conferred protection from 4 μΜ gentamicin toxicity (p < 0.001), whereas atRA potentiated gentamicin-induced hair cell death (p<.001). On immunohistochemistry, STAT1 phosphorylation at theserine 727 (Ser727) residues was increased at 72 hours with 4 μΜ gentamicin. With administration of 50 μΜ gentamicin, there was activation of STAT1 Tyr701 at 4 hours and STAT1 Ser727 at 16 hours. Gentamicin dissipated mitochondrial membrane potentials, and EGCG attenuated gentamicin-induced oxidative stress at 72 hours. Conclusion EGCG protected outer hair cells from gentamicin toxicity in a cochlear explant model, with the underlying mechanism involving both reactive oxygen species (ROS) suppression and STAT1 inhibition.

Epidemiological, clinical and mechanistic perspectives of tuberculosis in older people

“…In DM with poor metabolic control, the hyperglycaemia and advanced glycation end‐products are strongly conducive to the development of oxidative stress and mitochondrial dysfunction, often culminating in disease complications resulting in organ or system dysfunction . Similarly, oxidative stress and mitochondrial dysfunction have also been shown to be responsible for toxicities incurred by isoniazid, pyrazinamide, aminoglycosides and fluoroquinolones in different experimental models . Due to the shared pathogenetic mechanisms in organ injury, pertaining to poorly managed DM and toxicities incurred by anti‐tuberculosis drugs, the aftermath could be seriously amplified in terms of morbidity and even mortality .…”

“…62 Similarly, oxidative stress and mitochondrial dysfunction have also been shown to be responsible for toxicities incurred by isoniazid, pyrazinamide, aminoglycosides and fluoroquinolones in different experimental models. [63][64][65][66] Due to the shared pathogenetic mechanisms in organ injury, pertaining to poorly managed DM and toxicities incurred by anti-tuberculosis drugs, the aftermath could be seriously amplified in terms of morbidity and even mortality. 67 In the geriatric population, as oxidative stress and mitochondrial dysfunction are also underscored mechanisms of the ageing process, with chronic inflammation as the pathogenetic basis in many 'degenerative' disorders, quite like DM, it would be reasonable to anticipate a similar interacting scenario resulting in antituberculosis drug toxicities among the geriatric patients.…”

Blebbistatin Inhibits Neomycin-Induced Apoptosis in Hair Cell-Like HEI-OC-1 Cells and in Cochlear Hair Cells

“…Many studies, including our previous studies, have shown that caspase-associated apoptosis plays an important role in aminoglycoside-induced ototoxicity (Guan et al, 2016;He et al, 2017). The accumulation of ROS in the lysosomes and mitochondria of HCs leads to the upregulation of caspase genes, which further induces apoptosis of HCs (Esterberg et al, 2016;Jiang et al, 2016;Guo et al, 2019). In the central nervous system, myosin contraction plays an important role in oxidative stress-related neuronal apoptosis, myosin contraction, and the formation of relevant complexes needed to activate the expression of caspase-3 through the ROCK1-related pathway, indicating positive feedback regulation between myosin contraction and the oxidative stressinduced apoptosis pathway (Wang et al, 2017).…”

Histone deacetylases in hearing loss: Current perspectives for therapy

“…Ototoxic deafness is severe and permanent hearing loss and/or vestibular dysfunction caused by ototoxic drugs, such as aminoglycoside antibiotics, loop diuretics, antimalarials and platinum chemotherapy ( Layman et al., 2015 , Landier, 2016 ; Lin et al, 2015 ). Accumulating evidence have suggested that the aminoglycoside antibiotics-induced ototoxicity is associated with the generation of reactive oxygen species (ROS) and nuclear factor-κB (Nf-κB) misregulation in outer hair cells ( Jiang et al., 2016 , Kamogashira et al., 2015 , Layman et al., 2015 ). Ototoxic functional impairment and cellular degeneration are involved in activated non-classic apoptotic and necrotic pathways ( Fernández-Cervilla et al., 2017 , Jiang et al., 2006 ).…”