Frontiers in molecular neuroscience · 2026
Glycosides of Cistanche improve cognitive dysfunction in sleep-deprived model rats by activating the SIRT1/PGC-1α/Nrf2 signaling pathway.
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Li Qiang, Zhao Shijun, Huo Jiaojiao, Wang Yingzhen, Sun Yihong, Jia Jianxin
Аннотация
OBJECTIVE: Sleep deprivation suppresses the SIRT1/PGC-1α/Nrf2 signaling pathway, leading to oxidative stress, synaptic damage, and cognitive dysfunction. Glycosides of Cistanche (GCs) possess well-documented antioxidant and neuroprotective properties and have been reported to improve cognition in sleep-deprived animals, but the molecular mechanism remains unclear. We hypothesized that GCs alleviate sleep deprivation-induced cognitive dysfunction by activating the SIRT1/PGC-1α/Nrf2 signaling pathway.
METHODS: Sixty male Sprague Dawley rats were randomly assigned to six groups (n = 10): Control, Platform, Model, GCs, Control+GCs, and Estazolam (Est) groups. A 21-day sleep deprivation model was established using the modified multiple platform water method. Assessments included cognitive function by Morris water maze (MWM) test; Wake, non-rapid eye movement (NREM), rapid eye movement (REM), and total sleep time (TST) by Electroencephalogram (EEG); the serum levels of MDA, GSH-Px and SOD by ELISA, hippocampal CA1 neuronal morphology structure by Nissl staining and transmission electron microscopy (TEM), and the SIRT1/PGC-1α/Nrf2 signaling pathway and synaptic related proteins were detected by Western blot. In an additional cohort (n = 40), the SIRT1-specific inhibitor EX527 was used to validate the causal role of the pathway.
RESULTS: Compared with the Control group, the Model group exhibited significantly prolonged escape latency, along with reduced the number of platform crossings and the percentage time in the target quadrant (p < 0.05). The proportion of Wake significantly increased, while NREM, REM, and TST all significantly decreased (all p < 0.01). The serum level of MDA elevated, while GSH-Px and SOD activities markedly reduced (all p < 0.01). Hippocampal CA1 neurons showed disorganized arrangement, decreased Nissl bodies, and mitochondrial damage. Moreover, the SIRT1/PGC-1α/Nrf2 signaling pathway and synaptic related proteins significantly downregulated (all p < 0.01). Nevertheless, GCs intervention ameliorated cognitive dysfunction, alleviated oxidative stress and neuronal damage, and upregulated the protein expression levels above mentioned (all p < 0.01). Notably, these protective effects of GCs were abrogated by the SIRT1 inhibitor EX527.
CONCLUSION: GCs inhibited oxidative stress damage and improved synaptic plasticity, and thereby alleviated sleep deprivation induced cognitive dysfunction by activating the SIRT1/PGC-1α/Nrf2 signaling pathway.
METHODS: Sixty male Sprague Dawley rats were randomly assigned to six groups (n = 10): Control, Platform, Model, GCs, Control+GCs, and Estazolam (Est) groups. A 21-day sleep deprivation model was established using the modified multiple platform water method. Assessments included cognitive function by Morris water maze (MWM) test; Wake, non-rapid eye movement (NREM), rapid eye movement (REM), and total sleep time (TST) by Electroencephalogram (EEG); the serum levels of MDA, GSH-Px and SOD by ELISA, hippocampal CA1 neuronal morphology structure by Nissl staining and transmission electron microscopy (TEM), and the SIRT1/PGC-1α/Nrf2 signaling pathway and synaptic related proteins were detected by Western blot. In an additional cohort (n = 40), the SIRT1-specific inhibitor EX527 was used to validate the causal role of the pathway.
RESULTS: Compared with the Control group, the Model group exhibited significantly prolonged escape latency, along with reduced the number of platform crossings and the percentage time in the target quadrant (p < 0.05). The proportion of Wake significantly increased, while NREM, REM, and TST all significantly decreased (all p < 0.01). The serum level of MDA elevated, while GSH-Px and SOD activities markedly reduced (all p < 0.01). Hippocampal CA1 neurons showed disorganized arrangement, decreased Nissl bodies, and mitochondrial damage. Moreover, the SIRT1/PGC-1α/Nrf2 signaling pathway and synaptic related proteins significantly downregulated (all p < 0.01). Nevertheless, GCs intervention ameliorated cognitive dysfunction, alleviated oxidative stress and neuronal damage, and upregulated the protein expression levels above mentioned (all p < 0.01). Notably, these protective effects of GCs were abrogated by the SIRT1 inhibitor EX527.
CONCLUSION: GCs inhibited oxidative stress damage and improved synaptic plasticity, and thereby alleviated sleep deprivation induced cognitive dysfunction by activating the SIRT1/PGC-1α/Nrf2 signaling pathway.