School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
Experimental Teaching Center, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
Biochem Pharmacol. 2023 Jun;212:115575. doi: 10.1016/j.bcp.2023.115575. Epub 2023 Apr 30.
Age-related hearing loss (ARHL) is a most widespread neurodegenerative disease affecting the elderly population, but effective pharmacological treatments remain limited. Curcumin is a bioactive compound of Curcuma longa with antioxidant properties. Herein, we looked into the effects of curcumin on the HO-induced oxidative stress in cochlear hair cells and hearing function in an ARHL animal model (C57BL/6J mice). We found that pretreatment of curcumin could attenuate HO-induced apoptosis and cell senescence in auditory hair cells and prevent mitochondrial function dysfunction. More specifically, Western blot and luciferase activity assay showed that curcumin activated the nuclear translocation of Nrf2, which in turn triggered the activation of its downstream target gene Heme Oxygenase1 (HO-1). The enhanced Nrf2 and HO-1 activity by curcumin was blocked by the AKT inhibitor LY294002, indicating the protective effect of curcumin was mainly achieved by activating Nrf2/HO-1 through the AKT pathway. Furthermore, the knockdown of Nrf2 with siRNA diminished the protective effects of Nrf2 against apoptosis and senescence, consolidating the pivotal role of Nrf2 in the protective effect of curcumin on auditory hair cells. More importantly, curcumin (10 mg/kg/d) could attenuate progressive hearing loss in C57BL/6J mice, as evident from the reduced threshold of auditory nerve brainstem response. Administration of curcumin also elevated the expression of Nrf2 and reduced the expression of cleaved-caspase-3, p21, and γ-H2AX in cochlear. This study is the first to demonstrate that curcumin can prevent oxidative stress-induced auditory hair cell degeneration through Nrf2 activation, highlighting its potential therapeutic value in preventing ARHL.
年龄相关性听力损失（ARHL）是一种最常见的影响老年人群的神经退行性疾病，但有效的药物治疗仍然有限。姜黄素是姜黄的一种生物活性化合物，具有抗氧化特性。在此，我们研究了姜黄素对 HO 诱导的耳蜗毛细胞氧化应激和 ARHL 动物模型（C57BL/6J 小鼠）听力功能的影响。我们发现，姜黄素预处理可以减轻 HO 诱导的听觉毛细胞凋亡和衰老，并防止线粒体功能障碍。更具体地说，Western blot 和荧光素酶活性测定表明，姜黄素激活了 Nrf2 的核转位，从而触发了其下游靶基因血红素加氧酶 1（HO-1）的激活。AKT 抑制剂 LY294002 阻断了姜黄素增强的 Nrf2 和 HO-1 活性，表明姜黄素的保护作用主要是通过 AKT 途径激活 Nrf2/HO-1 实现的。此外，用 siRNA 敲低 Nrf2 减弱了 Nrf2 对凋亡和衰老的保护作用，证实了 Nrf2 在姜黄素对听觉毛细胞保护作用中的关键作用。更重要的是，姜黄素（10mg/kg/d）可减轻 C57BL/6J 小鼠进行性听力损失，这从听神经脑干反应阈值降低可以看出。姜黄素的给药还提高了 Nrf2 的表达，降低了耳蜗中 cleaved-caspase-3、p21 和 γ-H2AX 的表达。这项研究首次表明，姜黄素可以通过 Nrf2 激活来预防氧化应激诱导的听觉毛细胞变性，突出了其在预防 ARHL 中的潜在治疗价值。
