A reduced form of nicotinamide riboside protects the cochlea against aminoglycoside-induced ototoxicity by SIRT1 activation

Jia Fang; Hongmin Wu; Jianning Zhang; Song Mao; Haosong Shi; Dongzhen Yu; Zhengnong Chen; Kaiming Su; Yazhi Xing; Hongjun Dong; Haibo Shi

Biomedicine & Pharmacotherapy (Jun 2022)

A reduced form of nicotinamide riboside protects the cochlea against aminoglycoside-induced ototoxicity by SIRT1 activation

Jia Fang,
Hongmin Wu,
Jianning Zhang,
Song Mao,
Haosong Shi,
Dongzhen Yu,
Zhengnong Chen,
Kaiming Su,
Yazhi Xing,
Hongjun Dong,
Haibo Shi

Affiliations

Jia Fang: Department of Otolaryngology Head & Neck Surgery, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China; Otolaryngology Institute of Shanghai Jiao Tong University, Shanghai, China
Hongmin Wu: Department of Otolaryngology Head & Neck Surgery, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China; Otolaryngology Institute of Shanghai Jiao Tong University, Shanghai, China
Jianning Zhang: Yueyang Hospital of Integrative Chinese & Western Medicine Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
Song Mao: Department of Otolaryngology Head & Neck Surgery, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China; Otolaryngology Institute of Shanghai Jiao Tong University, Shanghai, China
Haosong Shi: Department of Otolaryngology Head & Neck Surgery, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China; Otolaryngology Institute of Shanghai Jiao Tong University, Shanghai, China
Dongzhen Yu: Department of Otolaryngology Head & Neck Surgery, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China; Otolaryngology Institute of Shanghai Jiao Tong University, Shanghai, China
Zhengnong Chen: Department of Otolaryngology Head & Neck Surgery, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China; Otolaryngology Institute of Shanghai Jiao Tong University, Shanghai, China
Kaiming Su: Department of Otolaryngology Head & Neck Surgery, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China; Otolaryngology Institute of Shanghai Jiao Tong University, Shanghai, China
Yazhi Xing: Department of Otolaryngology Head & Neck Surgery, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China; Otolaryngology Institute of Shanghai Jiao Tong University, Shanghai, China; Corresponding authors at: Department of Otolaryngology Head & Neck Surgery, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China
Hongjun Dong: Department of Otorhinolaryngology, Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Zhangjiagang, China; Corresponding author.
Haibo Shi: Department of Otolaryngology Head & Neck Surgery, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China; Otolaryngology Institute of Shanghai Jiao Tong University, Shanghai, China; Corresponding authors at: Department of Otolaryngology Head & Neck Surgery, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China

Journal volume & issue: Vol. 150
p. 113071

Abstract

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Background: Nicotinamide adenine dinucleotide (NAD+), a coenzyme that plays crucial roles in many cellular processes, is a potential therapeutic target for various diseases. Dihydronicotinamide riboside (NRH), a novel reduced form of nicotinamide riboside, has emerged as a potent NAD+ precursor. Here, we studied the protective effects and underlying mechanism of NRH on aminoglycoside-induced ototoxicity. Methods: Auditory function and hair-cell (HC) morphology were examined to assess the effects of NRH on kanamycin-induced hearing loss. The pharmacokinetic parameters of NRH were measured in plasma and the cochlea using liquid chromatography tandem mass spectrometry. NAD+ levels in organ explant cultures were assessed to compare NRH with known NAD+ precursors. Immunofluorescence analysis was performed to detect reactive oxygen species (ROS) and apoptosis. We analyzed SIRT1 and 14–3–3 protein expression. EX527 and resveratrol were used to investigate the role of SIRT1 in the protective effect of NRH against kanamycin-induced ototoxicity. Results: NRH alleviated kanamycin-induced HC damage and attenuated hearing loss in mice. NRH reduced gentamicin-induced vestibular HC loss. Compared with NAD and NR, NRH produced more NAD+ in cochlear HCs and significantly ameliorated kanamycin-induced oxidative stress and apoptosis. NRH rescued the aminoglycoside-induced decreases in SIRT1 and 14–3–3 protein expression. Moreover, EX527 antagonized the protective effect of NRH on kanamycin-induced HC loss by inhibition of SIRT1, while resveratrol alleviated HC damage caused by EX527. Conclusions: NRH ameliorates aminoglycoside-induced ototoxicity by inhibiting HC apoptosis by activating SIRT1 and decreasing ROS. NRH is an effective therapeutic option for aminoglycoside-induced ototoxicity.

Published in Biomedicine & Pharmacotherapy

ISSN: 0753-3322 (Print); 1950-6007 (Online)
Publisher: Elsevier
Country of publisher: France
LCC subjects: Medicine: Therapeutics. Pharmacology
Website: https://www.journals.elsevier.com/biomedicine-and-pharmacotherapy

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