Sirt1-Keap1/Nrf2 signaling pathway mechanism of cognitive dysfunction induced by subchronic aluminum exposure in rats / 中国病理生理杂志

ABSTRACT

AIM:To investigate the effects of subchronic aluminum exposure on the expression of silent infor-mation regulator(Sirt1),Kelch-like ECH-associated protein 1(Keap1),nuclear factor E2-related factor 2(Nrf2),and microRNA-128-3p(miR-128-3p)in the hippocampus of rats.Additionally,we aimed to explore the mechanism of miR-128-3p and the Sirt1-Keap1/Nrf2 signaling pathways in aluminum-induced cognitive impairment in rats.METHODS:Thirty-two healthy 6-week-old SPF male SD rats,weighing(190±20)g,were randomly divided into four groups based on body weightcontrol group,low-dose(10 μmol/kg)group,medium-dose(20 μmol/kg)group,and high-dose(40 μmol/kg)group,with 8 rats in each group.The rat exposure model was established by intraperitoneal injection of maltol alumi-num.The Morris water maze test was used to assess the learning and memory ability of the rats.Western blot analysis was performed to measure the protein expression of Sirt1,Keap1 and Nrf2 in the hippocampus,while RT-qPCR was used to measure the expression of miR-128-3p in the hippocampus.The level of reactive oxygen species(ROS)in the cerebral cor-tex was detected using fluorescence staining in frozen sections.RESULTS:(1)In the positioning cruise experiment,the escape latency of the aluminum exposure group was significantly higher than that of the control group on the 3rd,4th,and 5th days(P＜0.05).On day 6,the number of times the rats crossed the platform and the platform quadrant in the high-dose group was reduced compared to the control and low-dose groups(P＜0.01).(2)The expression levels of Sirt1 and Nrf2 in the hippocampal tissues of all groups decreased gradually with increasing maltol aluminum exposure dose.The ex-pression level of Keap1 increased gradually with increasing maltol aluminum exposure dose.The expression level of miR-128-3p in the high-dose group was significantly higher than that in the control group(P＜0.05).(3)The content of gluta-thione peroxidase in the hippocampus of rats decreased with increasing exposure dose,while ROS levels gradually in-creased.CONCLUSION:Subchronic aluminum exposure can increase the expression of miR-128-3p in the rat hippo-campus and suppress the Sirt1-Keap1/Nrf2 signaling pathway.This inhibition prevents the activation of the Sirt1-Keap1/Nrf2 signaling pathway,leading to a reduced antioxidant capacity.The imbalance in the antioxidant system in rats results in oxidative damage to nerve cells and a subsequent decline in cognitive function.