Network Pharmacology and Molecular Docking Reveal Neuroprotective Potential of Ligusticum wallichii in Alzheimer’s Disease Therapy

Chanjuan Zhou,1 Yutao Peng2 1Department of Clinical Psychology, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, People’s Republic of China; 2Department of Function, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, People’s Republic of ChinaCorrespondence: Yutao Peng, Department of Function, The First Affiliated Hospital, Hengyang Medical School, University of South China, 69 Chuan Shan Road, Hengyang, Hunan, 421001, People’s Republic of China, Tel +86 15115465507, Email [email protected]: In traditional Chinese medicine, Ligusticum wallichii is a prominent herb, acclaimed for its therapeutic roles, including anti-tumor, antioxidant, and anti-inflammatory benefits. Studies conducted recently suggest it may help reduce cognitive deficits linked to Alzheimer’s disease. However, the precise neuroprotective pathways through which Ligusticum wallichii exerts its effects on Alzheimer’s disease are not yet fully understood. Network pharmacology is utilized in this research to understand the mechanisms through which Ligusticum wallichii’s active ingredient might protect against Alzheimer’s disease.Methods: The TCMSP database was utilized to extract the bioactive compounds of Ligusticum wallichii, and their related molecular targets were identified. By querying the GeneCards and OMIM databases, targets associated with Alzheimer’s disease were identified. Using Cytoscape 3.8.2, a regulatory network mapping the interactions between active compounds and their respective targets was constructed. A protein-protein interaction network was generated by analyzing the target genes influenced by Ligusticum wallichii in Alzheimer’s disease using the String database. The DAVID database was utilized to perform functional enrichment analysis, encompassing Gene Ontology (GO) and KEGG pathway analyses, to identify possible biological pathways related to these targets. Following this, molecular docking studies were carried out to confirm the interaction strength of the active compounds to the pivotal targets. Finally, in vitro experimental validation was performed to corroborate the findings.Results: Seven bioactive compounds were identified from Ligusticum wallichii, interacting with 269 potential targets. Molecular docking revealed that Myricanone, Mandenol, and Sitosterol exhibited stable binding affinities with STAT3, HSP90AA1, and EGFR, with binding energies ranging from − 4.04 to − 5.87 kcal/mol. In vitro studies demonstrated that these compounds significantly downregulated the expression of STAT3, EGFR, and HSP90AA1 in Neuro 2A cells.Conclusion: In conclusion, the results indicate that Ligusticum wallichii significantly downregulated STAT3, EGFR, and HSP90AA1 expression in Neuro 2A cells, providing mechanistic evidence that targeting these proteins may ameliorate neurodegenerative processes in Alzheimer’s disease and highlighting Ligusticum wallichii’s promising therapeutic potential.Keywords: Ligusticum wallichii, molecular docking, network pharmacology, Alzheimer’s disease