Salidroside alleviates cognitive impairment by inhibiting ferroptosis via activation of the Nrf2/GPX4 axis in SAMP8 mice.

BACKGROUND: Alzheimer's disease (AD) is a neurogenerative disease and remains no effective method for stopping its progress. Ferroptosis and adaptive immunity have been proven to contribute to AD pathogenesis. Salidroside exhibits neuroprotective and immunomodulatory effects. However, the underlying mechanisms linking salidroside, ferroptosis, and adaptive immunity in AD remain uncertain. PURPOSE: The objective of this study is to explore the neuroprotective effects and the potential molecular mechanisms of salidroside against neuronal ferroptosis and CD8+ T cell infiltration in senescence-accelerated mouse prone 8 (SAMP8) mice. STUDY DESIGN AND METHODS: SAMP8 mice were employed as an AD model and were treated with salidroside for 12 weeks. Behavioral tests, immunohistochemistry, HE and Nissl staining, immunofluorescence, transmission electron microscopy, quantitative proteomics, bioinformatic analysis, flow cytometry, iron staining, western blotting, and molecular docking were performed. RESULTS: Treatment with salidroside dose-dependently attenuated cognitive impairment, reduced the accumulation of Aß plaques and restored neuronal damage. Salidroside also suppressed the infiltration of CD8+T cells, oxidative stress, and inflammatory cytokines, and improved mitochondrial metabolism, iron metabolism, lipid metabolism, and redox in the SAMP8 mice brain. The administration of salidroside decreased iron deposition, reduced TFR1, and ACSL4 protein expression, upregulated SLC7A11, and GPX4 protein expression, and promoted the Nrf2/GPX4 axis activation. CONCLUSION: In conclusion, neuronal ferroptosis and CD8+T cells are involved in the process of cognitive impairment in SAMP8 mice. Salidroside alleviates cognitive impairment and inhibits neuronal ferroptosis. The underlying mechanisms may involve the Nrf2/GPX4 axis activation and reduction in CD8+T cells infiltration. This study provides some evidence for the roles of salidroside in adaptive immunity and neuronal ferroptosis in SAMP8 mice.

The Combination of Salidroside and Hedysari Radix Polysaccharide Inhibits Mitochondrial Damage and Apoptosis via the PKC/ERK Pathway.

Background: Beta-amyloid (Aß) peptide is a widely recognized pathological marker of Alzheimer's disease (AD). Salidroside and Hedysari Radix polysaccharide (HRP) were extracted from Chinese herb medicine Rhodiola rosea L and Hedysarum polybotrys Hand-Mazz, respectively. The neuroprotective effects and mechanisms of the combination of salidroside and Hedysari Radix polysaccharide (CSH) against Aß 25-35 induced neurotoxicity remain unclear. Objective: This study aims to investigate the neuroprotective effects and pharmacological mechanisms of CSH on Aß 25-35-induced HT22 cells. Materials and Methods: HT22 cells were pretreated with various concentrations of salidroside or HRP for 24 h, followed by exposed to 20 µm Aß 25-35 in the presence of salidroside or RHP for another 24 h. In a CSH protective assay, HT22 cells were pretreated with 40 µm salidroside and 20 µg/mL HRP for 24 h. The cell viability assay, cell morphology observation, determination of mitochondrial membrane potential (MMP), reactive oxygen species (ROS), and cell apoptosis rate were performed. The mRNA expression of protein kinase C-beta (PKCß), Bax, and Bcl-2 were measured by qRT-PCR. The protein expression levels of cleaved caspase-3, Cyt-C, PKCß, phospho-ERK1/2, Bax, and Bcl-2 were measured by Western blot. Results: CSH treatment increased cell viability, MMP, and decreased ROS generation in Aß 25-35-induced HT22 cells. PKCß and Bcl-2 mRNA expression were elevated by CSH while Bax was decreased. CSH increased the protein expression levels of PKCß, Bcl-2, and phospho-ERK1/2, and decreased those of Bax, Cyt-C, and cleaved caspase-3. Conclusions: CSH treatment have protective effects against Aß 25-35-induced cytotoxicity through decreasing ROS levels, increasing MMP, inhibiting early apoptosis, and regulating PKC/ERK pathway in HT22 cells. CSH may be a potential therapeutic agent for treating or preventing neurodegenerative diseases.

Salidroside attenuates neuronal ferroptosis by activating the Nrf2/HO1 signaling pathway in Aß1-42-induced Alzheimer's disease mice and glutamate-injured HT22 cells.

BACKGROUND: 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 Aß1-42-induced AD mice and glutamate-injured HT22 cells. METHODS: HT22 cells were injured by glutamate (Glu), HT22 cells transfected with siRNA Nrf2, and Aß1-42-induced WT and Nrf2-/-AD mice were treated with salidroside. The mitochondria ultrastructure, intracellular Fe2+, 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 Aß1-42-induced WT and Nrf2-/-AD mice. The protein expressions of PTGS2, GPX4, Nrf2, and HO1 in the hippocampus were investigated by Western blot. RESULTS: 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 Aß1-42-induced AD mice, but not in Aß1-42-induced Nrf2-/-AD mice. Salidroside increased protein expression levels of GPX4, HO1, and NQO1 and decreased protein expression of PTGS2 in Aß1-42-induced AD mice but not in Aß1-42-induced Nrf2-/-AD mice. CONCLUSIONS: Salidroside plays a neuroprotective role by inhibiting neuronal ferroptosis in Aß1-42-induced AD mice and Glu-injured HT22 cells, and its mechanism is related to activation of the Nrf2/HO1 signaling pathway.