AUTHOR=Yao Jiuxiu , Wei Wei , Wen Jiayu , Cao Yu , Li Hao 

TITLE=The efficacy and mechanism of berberine in improving aging-related cognitive dysfunction: A study based on network pharmacology

JOURNAL=Frontiers in Neuroscience

VOLUME=Volume 17 - 2023

YEAR=2023

URL=https://www.frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2023.1093180

DOI=10.3389/fnins.2023.1093180

ISSN=1662-453X

ABSTRACT=Objective
 To analyze the effects and mechanisms of berberine in the treatment of aging-related cognitive dysfunction based on network pharmacology methods, molecular docking techniques and animal experiments.
Methods 
A mouse model of cognitive dysfunction was constructed by subcutaneous injection of D-galactose for 10 weeks, and the neuroprotective effects of berberine on aging-related cognitive dysfunction mice was evaluated by the Morris water maze and immunofluorescence staining. The targets of berberine were obtained by SwissTargetPrediction, GeneCards, PharmMapper. Putative targets of cognitive dysfunction were obtained by Genecards, TTD and DrugBank database. The STRING database and Cytoscape software were applied for protein-protein interaction analysis and further screening of core targets. The DAVID database was used for KEGG and GO enrichment analysis to clarify the biological processes and pathways involved in the intersection targets, and AutoDockTools was adopted for molecular docking verification of core targets. Finally, the core genes were validated using real-time quantitative PCR.
Results 
The Morris water maze results showed that treatment with berberine significantly improved spatial learning and memory in mice with cognitive decline induced by D-galactose. Immunofluorescence staining indicated that berberine modified the levels of aging related markers in the brain. A total of 386 berberine putative targets associated with cognitive dysfunction were identified based on public database. The core targets of berberine for improving cognitive function, including Mapk1, Src, Ctnnb1, Akt1, Pik3ca, Tp53, Jun, and Hsp90aa1. GO enrichment and KEGG pathway enrichment analyses indicated that the mechanism of berberine in the treatment of aging-related cognitive dysfunction attributed to pathways such as PI3K-AKT and MAPK pathway. In vivo experiments further confirmed that Akt1, Ctnnb1, Tp53, and Jun involved in the neuroprotective actions of berberine.
Conclusion 
This study reveals a multi-target and multi-pathway effects of berberine on regulating aging-related cognitive dysfunction, which provides preclinical evidence and may promote new drug development in mitigating cognitive dysfunction.