Combination of antioxidants and NFAT (nuclear factor of activated T cells) inhibitor protects auditory hair cells from ototoxic insult. Issue 5 (15th December 2019)

• Record Type: Journal Article
• Authors: Sekulic‐Jablanovic, Marijana; Voronkova, Krystsina; Bodmer, Daniel; Petkovic, Vesna
• Is Part Of: Journal of neurochemistry. Volume 154:Issue 5(2020)
• Page Start: 519
• Page End: 529
• Publication Date: 2019-12-15
• Subjects: antioxidants -- cochlea -- L‐carnitine -- N‐acetylcysteine -- ototoxicity -- 11R‐VIVIT; Neurochemistry -- Periodicals; 616.8042
• DOI: 10.1111/jnc.14921
• Languages: English
• ISSNs: 0022-3042

Abstract

Abstract: Hair cell (HC) degeneration causes hearing loss in millions of people worldwide. Aminoglycoside exposure is one major cause of sensory HC damage. Aminoglycosides generate free radicals within the inner ear, permanently damaging sensory cells, and thus causing hearing loss. Hearing protection requires strategies to overcome the apparently irreversible loss of HCs in mammals. The nuclear factor of activated T cells (NFAT) inhibitor 11R‐VIVIT reportedly protects HCs from gentamicin toxicity. Here we investigated whether the combination of 11R‐VIVIT with the antioxidant L‐carnitine or N‐acetylcysteine could protect mouse cochlear HCs from gentamicin damage. Compared to single‐component treatment, combined treatment with 11R‐VIVIT plus L‐carnitine yielded significant protection from gentamicin, and 11R‐VIVIT plus N‐acetylcysteine provided almost complete protection of HCs from gentamicin. Caspase activity in organ of Corti was significantly reduced by combined treatment with 11R‐VIVIT + N‐acetylcysteine + gentamicin, compared to 11R‐VIVIT + gentamicin or gentamicin alone. Analysis of relative gene expression by qPCR revealed down‐regulation of the pro‐apoptotic genes Fasl and Casp9, and up‐regulation of the antioxidant genes Hmox1 and Nrf2 after treatment with 11R‐VIVIT + N‐acetylcysteine + gentamicin, compared to single‐compound treatment or gentamicin alone in cultures. Selective NFAT inhibition by 11R‐VIVIT may be a good strategy for preventing gentamicin‐induced HC damage. L‐carnitine and N‐acetylcysteine, with their ROS‐reducing properties, contribute to the synergistic effectiveness with 11R‐VIVIT by decreasing ROS‐induced NFAT translocation. Our data suggest that a combined approach of NFAT inhibition together with an antioxidant, like N‐acetylcysteine, could be useful for hearing loss treatment and/or prevention. Cover Image for this issue: https://doi.org/10.1111/jnc.14759 . Abstract : Combination of L‐carnitine/N‐acetylcysteine`s antioxidative properties with the nuclear factor of activated T cells (NFAT)‐inhibiting aspect of 11R‐VIVIT results in a unique protective capacity against gentamicin‐induced hair cell death. Gentamicin‐induced oxidative stress and reactive oxygen species (ROS), facilitate NFAT nuclear translocation, Fasl over‐expression, and pro‐apoptotic gene expression. L‐carnitine and N‐acetylcysteine up‐regulate protective Nrf2, leading to increased Hmox1 expression. Heme oxygenase‐1 attenuates increased ROS or inhibits calcineurin, and 11R‐VIVIT interferes with calcineurin‐NFAT activation, thus protecting hair cells from gentamicin damage. We show that an adequate combination of N‐acetylcysteine and 11R‐VIVIT protects from aminoglycoside damage. ROS‐mediated damage underlies many forms of hearing loss, and this study could give a solution to their treatment. Cover Image for this issue: https://doi.org/10.1111/jnc.14759 .