Glycosides of Cistanche improve cognitive dysfunction in sleep-deprived model rats by activating the...

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.

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.

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.

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.