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

Jiuxiu Yao; Wei Wei; Jiayu Wen; Yu Cao; Hao Li

doi:10.3389/fnins.2023.1093180

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

Front Neurosci. 2023 Jan 20:17:1093180. doi: 10.3389/fnins.2023.1093180. eCollection 2023.

Authors

Jiuxiu Yao¹, Wei Wei^{2

3}, Jiayu Wen⁴, Yu Cao³, Hao Li^{2

3}

Affiliations

¹ College of First Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China.
² Wangjing Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
³ Department of Geriatrics, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
⁴ Graduate College, Beijing University of Chinese Medicine, Beijing, China.

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 (D-gal) for 10 weeks, and the neuroprotective effects of berberine on aging-related cognitive dysfunction mice were evaluated by the Morris water maze (MWM) and immunofluorescence staining. The targets of berberine were obtained by SwissTargetPrediction, GeneCards, and 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 (PPI) analysis and further screening of core targets. The DAVID database was used for Kyoto Encyclopedia of Genes and Genomes (KEGG) and gene ontology (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 MWM results showed that treatment with berberine significantly improved spatial learning and memory in mice with cognitive decline induced by D-gal. 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 the public database. The core targets of berberine for improving cognitive function, include 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 is attributed to pathways such as PI3K-AKT and MAPK pathways. In vivo experiments further confirmed that Akt1, Ctnnb1, Tp53, and Jun were involved in the neuroprotective actions of berberine.

Conclusion: This study reveals the 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.

Keywords: D-galactose; RT-qPCR; berberine; cognitive dysfunction; network pharmacology.

Grants and funding

This study was funded by the Fundamental Research Funds for the Central Public Welfare Research Institutes (ZZ15-YQ-013 and ZZ15-XY-PT-02) and the Science and Technology Innovation Project of Chinese Academy of Traditional Chinese Medicine (CI2021A01401 and CI2021A04618).