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

  • Biomed Pharmacother. 2022 Jun:150:113071. doi: 10.1016/j.biopha.2022.113071.
Jia Fang  1 ,  Hongmin Wu  1 ,  Jianning Zhang  2 ,  Song Mao  1 ,  Haosong Shi  1 ,  Dongzhen Yu  1 ,  Zhengnong Chen  1 ,  Kaiming Su  1 ,  Yazhi Xing  3 ,  Hongjun Dong  4 ,  Haibo Shi  5
Affiliations
  • 1. 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.
  • 2. Yueyang Hospital of Integrative Chinese & Western Medicine Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China.
  • 3. 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. Electronic address: [email protected].
  • 4. Department of Otorhinolaryngology, Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Zhangjiagang, China. Electronic address: [email protected].
  • 5. 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. Electronic address: [email protected].
PMID: 35658237 DOI: 10.1016/j.biopha.2022.113071
Abstract

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.

Keywords
Aminoglycoside-induced hearing loss; NAD(+); NRH; Ototoxicity; SIRT1.
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