Total Saponins of <i>Panax notoginseng</i> Leaves Alleviate Vascular Dementia via the Gut–Brain Axis

Vascular dementia (VD) is the second most common type of dementia after Alzheimer's disease (AD), and chronic cerebral hypoperfusion (CCH) is the main causative factor of VD. Previous reports have confirmed that there is a relationship between VD and gut microbiota, and that some plant-based foods can improve VD through the gut-brain axis (GBA). <i>Panax notoginseng</i> leaves are a specialty food in Yunnan, China, and saponin is its main bioactive component. In this study, we investigated the effects of the total saponins of <i>Panax notoginseng</i> leaves (TSPNL) on CCH-induced VD and their potential mechanisms. In this experiment, the model was replicated using bilateral common carotid artery occlusion (BCCAO) and divided into Sham, Model, TSPNL-L, TSPNL-H and Positive drug control. At the end of the treatment, behavior, brain-derived neurotrophic factor (BDNF), hypothalamic-pituitary-adrenal (HPA) axis-related indices, neuronal apoptosis-related indices, gut microbiota composition, and colon and brain pathology were tested. The results showed that TSPNL attenuated CCH-induced VD, promoted BDNF synthesis, and inhibited neuronal apoptosis. Predictions of network pharmacology and experiments demonstrated that these beneficial effects are mediated in part through BDNF-TrKB-PI3K/Akt signaling. In addition, TSPNL prevented intestinal dysbiosis by increasing the abundance of the probiotic <i>Ligilactobacillus</i> and decreasing the abundance of the deleterious bacterium <i>Clostridia_ UCG_014_unclassified</i> relative to the model group. TSPNL was also able to partially reverse intestinal barrier disruption and inhibit intestinal inflammation and the hyperactivation of the HPA axis. The results of this study support the conclusion that TSPNL has potential in the prevention of CCH-induced VD and warrants further investigation.