Yang Sixia, Xie Zeping, Pei Tingting, Zeng Yi, Xiong Qiaowu, Wei Hui, Wang Yong, Cheng Weidong
School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510515, China.
Department of Pharmacy, Zhu Jiang Hospital, Southern Medical University, Guangzhou, 510515, China.
Chin Med. 2022 Jul 4;17(1):82. doi: 10.1186/s13020-022-00634-3.
Alzheimer's disease (AD) is a neurodegenerative disease. Ferroptosis plays a critical role in neurodegenerative diseases. Nuclear factor E2-related factor 2 (Nrf2) is considered an important factor in ferroptosis. Studies have demonstrated that salidroside has a potential therapeutic effect on AD. The intrinsic effect of salidroside on ferroptosis is unclear. The purpose of this study was to investigate the protective effects and pharmacological mechanisms of salidroside on alleviating neuronal ferroptosis in Aβ-induced AD mice and glutamate-injured HT22 cells.
HT22 cells were injured by glutamate (Glu), HT22 cells transfected with siRNA Nrf2, and Aβ-induced WT and Nrf2AD mice were treated with salidroside. The mitochondria ultrastructure, intracellular Fe, reactive oxygen species, mitochondrial membrane potential, and lipid peroxidation of HT22 cells were detected. Malondialdehyde, reduced glutathione, oxidized glutathione disulfide, and superoxide dismutase were measured. The novel object recognition test, Y-maze, and open field test were used to investigate the protective effects of salidroside on Aβ-induced WT and Nrf2AD mice. The protein expressions of PTGS2, GPX4, Nrf2, and HO1 in the hippocampus were investigated by Western blot.
Salidroside increased the cell viability and the level of MMP of Glu-injured HT22 cells, reduced the level of lipid peroxidation and ROS, and increased GPX4 and SLC7A11 protein expressions. These changes were not observed in siRNA Nrf2 transfected HT22 cells. Salidroside improved the ultrastructural changes in mitochondria of HT22 cells and Aβ-induced AD mice, but not in Aβ-induced Nrf2AD mice. Salidroside increased protein expression levels of GPX4, HO1, and NQO1 and decreased protein expression of PTGS2 in Aβ-induced AD mice but not in Aβ-induced Nrf2AD mice.
Salidroside plays a neuroprotective role by inhibiting neuronal ferroptosis in Aβ-induced AD mice and Glu-injured HT22 cells, and its mechanism is related to activation of the Nrf2/HO1 signaling pathway.
阿尔茨海默病（AD）是一种神经退行性疾病。铁死亡在神经退行性疾病中起关键作用。核因子E2相关因子2（Nrf2）被认为是铁死亡中的一个重要因素。研究表明红景天苷对AD具有潜在治疗作用。红景天苷对铁死亡的内在作用尚不清楚。本研究旨在探讨红景天苷对减轻Aβ诱导的AD小鼠和谷氨酸损伤的HT22细胞中神经元铁死亡的保护作用及其药理机制。
用谷氨酸（Glu）损伤HT22细胞，用siRNA Nrf2转染HT22细胞，并用红景天苷处理Aβ诱导的野生型（WT）和Nrf2基因敲除（Nrf2AD）小鼠。检测HT22细胞的线粒体超微结构、细胞内铁、活性氧、线粒体膜电位和脂质过氧化。测定丙二醛、还原型谷胱甘肽、氧化型谷胱甘肽二硫化物和超氧化物歧化酶。采用新物体识别试验、Y迷宫试验和旷场试验研究红景天苷对Aβ诱导的WT和Nrf2AD小鼠的保护作用。通过蛋白质免疫印迹法检测海马中PTGS2、GPX4、Nrf2和HO1的蛋白表达。
红景天苷提高了Glu损伤的HT22细胞的细胞活力和线粒体膜电位水平，降低了脂质过氧化和活性氧水平，并增加了GPX4和SLC7A11蛋白表达。在转染siRNA Nrf2的HT22细胞中未观察到这些变化。红景天苷改善了HT22细胞和Aβ诱导的AD小鼠线粒体的超微结构变化，但在Aβ诱导的Nrf2AD小鼠中未观察到。红景天苷增加了Aβ诱导的AD小鼠中GPX4、HO1和NQO1的蛋白表达水平，并降低了PTGS2的蛋白表达，但在Aβ诱导的Nrf2AD小鼠中未观察到。
红景天苷通过抑制Aβ诱导的AD小鼠和Glu损伤的HT22细胞中的神经元铁死亡发挥神经保护作用，其机制与激活Nrf2/HO1信号通路有关。
