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.
Yueyang Hospital of Integrative Chinese & Western Medicine Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China.
Biomed Pharmacother. 2022 Jun;150:113071. doi: 10.1016/j.biopha.2022.113071. Epub 2022 May 5.
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.
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.
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.
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.
烟酰胺腺嘌呤二核苷酸（NAD）是一种在许多细胞过程中发挥关键作用的辅酶，是各种疾病的潜在治疗靶点。二氢烟酰胺核糖（NRH）是烟酰胺核糖的一种新型还原形式，已成为一种有效的 NAD 前体。在这里，我们研究了 NRH 对氨基糖苷诱导的耳毒性的保护作用及其潜在机制。
通过评估 NRH 对卡那霉素诱导的听力损失的影响，检测听觉功能和毛细胞（HC）形态。使用液质联用色谱法测定 NRH 在血浆和耳蜗中的药代动力学参数。在器官外植体培养物中评估 NAD 水平，以比较 NRH 与已知的 NAD 前体。进行免疫荧光分析以检测活性氧（ROS）和细胞凋亡。我们分析了 SIRT1 和 14-3-3 蛋白的表达。使用 EX527 和白藜芦醇来研究 SIRT1 在 NRH 对卡那霉素诱导的耳毒性的保护作用中的作用。
NRH 减轻了卡那霉素诱导的 HC 损伤，并减轻了小鼠的听力损失。NRH 减少了庆大霉素诱导的前庭 HC 损失。与 NAD 和 NR 相比，NRH 在耳蜗 HC 中产生更多的 NAD，并显著改善了卡那霉素诱导的氧化应激和细胞凋亡。NRH 挽救了氨基糖苷类药物引起的 SIRT1 和 14-3-3 蛋白表达的降低。此外，通过抑制 SIRT1，EX527 拮抗了 NRH 对卡那霉素诱导的 HC 丢失的保护作用，而白藜芦醇减轻了 EX527 引起的 HC 损伤。
NRH 通过激活 SIRT1 和减少 ROS 来抑制 HC 凋亡，从而改善氨基糖苷类诱导的耳毒性。NRH 是氨基糖苷类诱导的耳毒性的有效治疗选择。
