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Mechanistic insights into the anti-depressant effect of curcumin based on network pharmacology and experimental validation

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Abstract

Curcumin (CUR) exhibits a definite curative effect in the treatment of depression. To identify potential antidepressant targets and mechanisms of action of CUR. This study used network pharmacology to explore the signaling pathways and CUR-related targets in depression. C57BL/6 J mice (male,12–14 weeks old) were randomly divided into four groups (n = 8): saline-treated (control mice), lipopolysaccharide (LPS, 2 mg/kg/day, intraperitoneally), LPS + CUR (50 mg/kg/day, intragastrically), and LPS + CUR + LY294002 (7.5 mg/kg/day, intraperitoneally). After 1 week, behavioral tests were performed. Then, neuronal damage in the prefrontal cortex of mice was evaluated by hematoxylin–eosin (HE) staining. We uncovered the main active mechanism of CUR against depression using Western blotting and enzyme-linked immunosorbent assay (ELISA). Gene set enrichment analysis (GSEA) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways showed that the most significantly enriched pathway in CUR against depression was the PI3K-Akt pathway. Moreover, 52 targets were significantly correlated with the PI3K-Akt signaling pathway and CUR-related targets. In addition, among the top 50 targets ranked by degree in the protein–protein interaction (PPI) network, there were 23 targets involved in the 52 intersection targets. Administration of LPS alone extended immobility time in the open field test (OFT) and tail suspension test (TST) and decreased sucrose consumption in the sucrose preference test (SPT). Pretreatment with CUR relieved LPS-induced changes in the behavioral tests, activity of the PI3K-Akt signaling pathway, neuronal damage in the prefrontal cortex (PFC), and inflammatory response. Moreover, inhibition of the PI3K-Akt signaling pathway by LY294002 blocked the therapeutic effects of CUR. Our study indicates that CUR may be an effective antidepressant agent in an LPS-induced mouse model, partly because of its anti-inflammatory action through the PI3K-Akt signaling pathway.

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Data availability

All data of this study are included in this published article.

Abbreviations

BBB:

Blood-brain barrier

BCA:

Bicinchoninic acid

BDNF:

Brain-derived neurotrophic factor

BH:

Benjamini–Hochberg

COX-2:

Cyclooxygenase 2

CUMS:

Chronic unpredictable mild stress

CUR:

Curcumin

CUR-NLCs:

Curcumin-loaded nanostructured lipid carriers

ELISA:

Sandwich enzyme-linked immunosorbent assay

GEO:

Gene Expression Omnibus

GO:

Gene Ontology

GSEA:

Gene set enrichment analysis

HE:

Hematoxylin-eosin staining

i.p.:

Intraperitoneal

IDO:

Indoleamine 2, 3-dioxygenase

IL-1:

Interleukin-1

KEGG:

Kyoto Encyclopedia of Genes and Genomes

LPS:

Lipopolysaccharide

MDD:

Major depressive disorder

NES:

Normalized enrichment score

NF-κβ:

Nuclear factor kappa beta

NLRP3:

NOD-like receptor protein 3

OFT:

Open field test

PFC:

Prefrontal cortex

PPI:

Protein-protein interaction

RO5:

Lipinski’s Rule of Five

SPT:

Sucrose preference test

TBS:

Trisbuffered saline

TNF-α:

Tumor necrosis factor-alpha

TRYCATs:

Tryptophan catabolites

TST:

Tail suspension test

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Funding

This work was supported by grants from the Research Foundation of Scientific Research Program of Jianghan University (grant no. 2021yb 131), Research Foundation of Scientific Research Program of the University of South China (grant no. 220XQD090), Research Foundation of Education Bureau of Hunan Province (grant no. 22B0416), and Provincial Natural Science Foundation of Hunan (grant no. 2023JJ40560).

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Authors and Affiliations

  1. School of Medicine, Jianghan University, Wuhan, 430056, China

    Jing Guo, Meng Fang & Zhe Xiong

  2. Department of Histology and Embryology, School of Basic Medicine, Hengyang Medical College, University of South China, Hengyang, 421001, China

    Ke Zhou & Peng Zeng

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  1. Jing Guo
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  2. Meng Fang
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  3. Zhe Xiong
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  4. Ke Zhou
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  5. Peng Zeng
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Contributions

The authors declare that all data were generated in-house and that no paper mill was used. Conceptualization: P.Z. and M.F.; investigation: P.Z.; methodology: P.Z., J.G., and Z.X.; supervision: P.Z. and J.G.; visualization: P.Z., Z.X., M.F., and K.Z.; writing—original draft: J.G.; writing—review and editing: P.Z. All authors have read and agreed to the published version of the manuscript.

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Correspondence to Peng Zeng.

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Guo, J., Fang, M., Xiong, Z. et al. Mechanistic insights into the anti-depressant effect of curcumin based on network pharmacology and experimental validation. Naunyn-Schmiedeberg's Arch Pharmacol 397, 583–598 (2024). https://doi.org/10.1007/s00210-023-02628-w

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