Targets and Molecular Mechanisms of Salidroside in Improving High-Altitude Cognitive Function
Abstract
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.
Keywords: Salidroside, Network pharmacology, Molecular docking, High-altitude cognition, Core targets, Signaling pathway
Full Text:
PDFReferences
CHEN X, ZHANG J, LIN Y, et al. Mechanism, prevention and treatment of cognitive impairment caused by high altitude exposure. Front Physiol, 2023, 14: 1191058. doi: 10.3389/fphys.2023.1191058.
FAN H, MENG Y, ZHU L, et al. A review of methods for assessment of cognitive function in high-altitude hypoxic environments. Brain Behav, 2024, 14(2): e3418. doi: 10.1002/brb3.3418.
CHEN Y R, HAO S F, QIAN R Y, et al. Research progress on the role of NF-κB signaling pathway in cognitive impairment after stroke and its intervention with traditional Chinese medicine. Liaoning J Tradit Chin Med Univ, 2024, 26(7): 197-203. doi: 10.13194/j.issn.1673-842x.2024.07.036.
LIU F F, ZHONG Y, CHEN L P, et al. Research progress on improving cognitive impairment by regulating PI3K/Akt signaling pathway with traditional Chinese medicine. Chin J Exp Tradit Med Form, 2024, 30(7): 281-289. doi: 10.13422/j.cnki.syfjx.20232141.
REN W H, LUO L L, CAI L H, et al. Research progress on the anti-hypoxic injury effect of Rhodiola rosea. Chin Tradit Pat Med, 2022, 44(9): 2911-2916. doi: 10.3969/j.issn.1001-1528.2022.09.029.
QIN N N, SHEN Y K, CHENG J F, et al. Protective effect of salidroside on memory impairment in mice under high altitude hypoxia. Chin Pharmacol Bull, 2023, 39(1): 65-70. doi: 10.12360/CPB202202020.
LIAO Y N, ZHAO K L, GUO H W. Research applications and challenges of network pharmacology of traditional Chinese medicine. Chin Herb Med, 2024, 55(12): 4204-4213. doi: 10.7501/j.issn.0253-2670.2024.12.027.
SUN Y M, HAN X Y, MA J H, et al. Protective effect of areca nut polyphenols on high altitude exercise-induced fatigue in rats and network pharmacology study. Chin Pharmacol Bull, 2023, 39(10): 1966-1972. doi: 10.12360/CPB202208047.
DU H T, WANG L, DING J, et al. Application status and challenges of molecular docking in traditional Chinese medicine development. Chin J Chin Mater Med, 2024, 49(3): 671-680. doi: 10.19540/j.cnki.cjcmm. 20231013.703.
SHIN J D, TANG W, JADHAV S P. Dynamics of awake hippocampal-prefrontal replay for spatial learning and memory-guided decision making. Neuron, 2019, 104(6): 1110-1125.e1117. doi: 10.1016/j.neuron. 2019.09.012.
SHARMA D, BARHWAL K K, BISWAL S N, et al. Hypoxia-mediated alteration in cholesterol oxidation and raft dynamics regulates BDNF signalling and neurodegeneration in hippocampus. J Neurochem, 2019, 148(2): 238-251. doi: 10.1111/jnc.14609.
SU R, JIA S, ZHANG N, et al. The effects of long-term high-altitude exposure on cognition: a meta-analysis. Neurosci Biobehav Rev, 2024, 161: 105682. doi: 10.1016/j.neubiorev.2024.105682.
LAN G, WANG P, CHAN R B, et al. Astrocytic VEGFA: an essential mediator in blood-brain-barrier disruption in Parkinson's disease. Glia, 2022, 70(2): 337-353. doi: 10.1002/glia.24109.
RAMOS A, ISHIZUKA K, HAYASHIDA A, et al. Nuclear GAPDH in cortical microglia mediates cellular stress-induced cognitive inflexibility. Mol Psychiatry, 2024, 29(10): 2967-2978. doi: 10.1038/s41380-024-02553-1.
JI Y, HUANG W, CHEN Y, et al. Inhibition of MMP-2 and MMP-9 attenuates surgery-induced cognitive impairment in aged mice. Brain Res Bull, 2023, 204: 110810. doi: 10.1016/j.brainresbull.2023.110810.
LUCKETT E S, ZIELONKA M, KORDJANI A, et al. Longitudinal APOE4- and amyloid-dependent changes in the blood transcriptome in cognitively intact older adults. Alzheimers Res Ther, 2023, 15(1): 121. doi: 10.1186/s13195-023-01242-5.
RAFFAELE I, SILVESTRO S, MAZZON E. MicroRNAs and MAPKs: evidence of these molecular interactions in Alzheimer's disease. Int J Mol Sci, 2023, 24(5): 4736. doi:10.3390/ijms24054736.
CHEN Y X, YANG H, WANG D S, et al. Gastrodin relieves cognitive impairment by regulating autophagy via PI3K/AKT signaling pathway in vascular dementia. Biochem Biophys Res Commun, 2023, 671: 246-254. doi: 10.1016/j.bbrc.2023.06.011.
GUO B, ZUO Z, DI X, et al. Salidroside attenuates HALI via IL-17A-mediated ferroptosis of alveolar epithelial cells by regulating Act1-TRAF6-p38 MAPK pathway. Cell Commun Signal, 2022, 20(1): 183. doi: 10.1186/s12964-022-00994-1.
APTE R S, CHEN D S, FERRARA N. VEGF in signaling and disease: beyond discovery and development. Cell, 2019, 176(6): 1248-1264. doi: 10. 1016/j.cell.2019.01.021.
NIE L, MA D, QUINN J P, et al. Src family kinases activity is required for transmitting purinergic P2X7 receptor signaling in cortical spreading depression and neuroinflammation. J Headache Pain, 2021, 22(1): 146. doi: 10.1186/s10194-021-01359-8.
NIU X, ZHENG S, LI S, et al. Role of different doses of ketamine in postoperative neurocognitive function in aged mice undergoing partial hepatectomy by regulating the Bmal1/NMDA/NF-Κb axis. Eur Surg Res, 2022, 63(4): 182-195. doi: 10.1159/000520210.
Refbacks
- There are currently no refbacks.
