Objective To explore the targets and molecular mechanisms of salidroside in improving cognitive function at high altitudes using network pharmacology, molecular docking, and experimental validation.

Methods The SwissTargetPrediction platform was used to screen for salidroside-related targets, and the GeneCards database was used to search for targets associated with high-altitude cognitive function. The VENNY 2.1 platform was used to create a Venn diagram showing the intersection of salidroside and the targets of high-altitude cognitive function. The STRING11.5 database was used to construct a protein-protein interaction network diagram to screen for the key targets. The DAVID database was used to perform the Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, and a component-target-pathway network was constructed using the Cytoscape 3.7.2 software platform. Furthermore, molecular docking and experimental studies were conducted for preliminary validation. Male C57BL/6J mice were randomly assigned to three groups, a low-altitude control group (Con group) receiving sterile water via intragastric gavage, a high-altitude hypoxia group (Hyp group) receiving sterile water via intragastric gavage, and a salidroside group administered with 10 mg/kg salidroside via intragastric gavage. The Hyp group and the salidroside group were pre-treated for 3 days (once daily) before rapid ascension to an altitude of 4010 m. Then, the 2 groups were exposed to a hypoxic environment for 1 day and received an additional treatment. Hippocampal tissues were collected from all three groups, and the relevant proteins were measured by Western blot.

Results A total of 100 salidroside targets, 2212 high-altitude cognition-related gene targets, and 52 common targets were identified. The improvement in high-altitude cognitive function by salidroside could be closely associated with core targets such as VEGFA, GAPDH, MMP-9, HRAS, FGF-2, HSP90AA1, and MAPK1, involving mainly the PI3K-Akt, MAPK, and VEGF signaling pathways. According to the molecular docking results, GAPDH, MMP-9, and VEGFA showed the best binding ability with salidroside. Experimental findings showed that salidroside improved high-altitude cognitive function by regulating the levels of Bcl-2/Bax, SRC-1, NF-κB, Beclin-1, and LC3BⅡ/Ⅰ.

Conclusion Salidroside exerts its therapeutic effects in improving high-altitude cognitive function by regulating the expression levels of proteins associated with cell apoptosis, cell proliferation, and cell autophagy, inhibiting inflammation and stress response, and reducing apoptosis and excessive autophagy in hippocampal neurons.