Dihydromyricetin Protects Against Gentamicin-Induced Ototoxicity via PGC-1α/SIRT3 Signaling in vitro

Abstract

Aminoglycoside-induced ototoxicity can have a major impact on patients' quality of life and social development problems. Oxidative stress affects normal physiologic functions and has been implicated in aminoglycoside-induced inner ear injury. Excessive accumulation of reactive oxygen species (ROS) damages DNA, lipids, and proteins in cells and induces their apoptosis. Dihydromyricetin (DHM) is a natural flavonol with a wide range of health benefits including anti-inflammatory, antitumor, and antioxidant effects; however, its effects and mechanism of action in auditory hair cells are not well understood. The present study investigated the antioxidant mechanism and antiototoxic potential of DHM using House Ear Institute-Organ of Corti (HEI-OC)1 auditory cells and cochlear explant cultures prepared from Kunming mice. We used gentamicin to establish aminoglycoside-induced ototoxicity models. Histological and physiological analyses were carried out to determine DHM's pharmacological effects on gentamicininduced ototoxicity. Results showed DHM contributes to protecting cells from apoptotic cell death by inhibiting ROS accumulation. Western blotting and quantitative RT-PCR analyses revealed that DHM exerted its otoprotective effects by up-regulating levels of peroxisome proliferator activated receptor γ-coactivator (PGC)-1α and Sirtuin (SIRT)3. And the role of PGC-1α and SIRT3 in the protective effects of DHM was evaluated by pharmacologic inhibition of these factors using SR-18292 and 3-(1H-1,2,3-triazol-4-yl) pyridine, respectively, which indicated DHM's protective effect was dependent on activation of the PGC-1α/SIRT3 signaling. Our study is the first report to identify DHM as a potential otoprotective drug and provides a basis for the prevention and treatment of hearing loss caused by aminoglycoside antibiotic-induced oxidative damage to auditory hair cells.

Dihydromyricetin Acts as a Potential Redox Balance Mediator in Cancer Chemoprevention

“…9 Mediators of Inflammation (RAW264.7) cells, glomerular mesangial cells (MCs), and HEI-OC1 auditory cells have been successfully used to determine the protective effects of DHM in oxidative stress, and oxidative stress is generally created in cell lines by using H 2 O 2 free radicals, LPS, methylglyoxal, and sodium nitroprusside [4,41,47,55,[61][62][63][64][65][66][67].…”

Icariin Treatment Protects Against Gentamicin-Induced Ototoxicity via Activation of the AMPK-SIRT3 Pathway

“…AMPK has been described to directly affect PGC-1α activity through phosphorylation and induce mitochondrial biogenesis ( Palikaras and Tavernarakis, 2014 ). Our previous study has confirmed that PGC-1α regulates SIRT3 activity during gentamicin-induced ototoxicity ( Han et al, 2020 ). In the present study, with an increasing concentration of icariin, PGC-1α and SIRT3 expression and activity were significantly enhanced, and the ototoxicity caused by gentamicin was also weakened.…”

“…Though not the only one cause, the ROS-dependent mitochondrial damage inducing hair cells apoptosis is a major effect of gentamicin-induced ototoxicity. ( Dong et al, 2015 ; Quan et al, 2015 ; Kim et al, 2017 ; Han et al, 2020 ). In our study, icariin pretreatment significantly improved the cell viability of HEI-OC1 cells injured by gentamicin, inhibited HEI-OC1 cell apoptosis, and reduced endogenous ROS production.…”

“…SIRT3 is mainly located in mitochondria and is closely related to oxidative stress ( Salvatori et al, 2017 ), and many studies have focused on its anti-ROS effect on inner hair cells ( Brown et al, 2014 ; Quan et al, 2015 ; Han et al, 2020 ). The current study demonstrates that both PGC-1α (SIRT3 promoter) and SIRT3 expression is upregulated in icariin-treated HEI-OC1 cells damaged by gentamicin, indicating that SIRT3 plays an important role in the protective effect of icariin against gentamicin ototoxicity.…”

“…Among them, SIRT3 is closely related to oxidative stress and has been shown to be closely related to inner ear hair cell damage. SIRT3 plays a key role during the process of ROS removal ( Brown et al, 2014 ; Han et al, 2020 ). AMPK has been confirmed to be involved in the pathophysiological process of aminoglycoside antibiotic-induced ototoxicity, and phosphorylated AMPK is downregulated in gentamicin-treated hair cells ( Ebnoether et al, 2017 ).…”