Integrating Network Pharmacology, Transcriptomics to Reveal Neuroprotective of Curcumin Activate PI3K / AKT Pathway in Parkinson's Disease

Abstract

Background: Parkinson's disease (PD) is the most prevalent movement disorder. Curcumin, a polyphenol with hydrophobic properties, has been proved against Parkinson. Our previous study suggested that curcumin's effectiveness in treating Parkinson's disease may be linked to the gut-brain axis, although the specific mechanism by which curcumin exerts neuroprotective effects in the brain remains unknown.

Methods: The therapeutic efficacy of curcumin was evaluated using behavioral tests, immunofluorescence of tyrosine hydroxylase (TH). Network pharmacology and transcriptomics predicted the mechanisms of curcumin in PD. Activation of the phosphatidylinositol 3-kinase PI3K/AKT pathway was confirmed by quantitative polymerase chain reaction (qPCR) and immunofluorescence.

Results: Curcumin restored the dyskinesia and dopaminergic neurons damage of MPTP-induced mice. Curcumin against Parkinson's disease by regulating inflammation, oxidative stress, and aging. The mechanisms of these were associated with activation of PI3K / AKT pathway.

Conclusion: In conclusion, the neuroprotective mechanisms of curcumin activate PI3K / AKT pathway in Parkinson's disease was revealed by our study.

Keywords: PI3K / AKT pathway; Parkinson’s disease; curcumin; network pharmacology; transcriptomics.

Figure 1

The overall process of the study. Work scheme of integrating network pharmacology, and transcriptomics to confirm neuroprotective of curcumin via PI3K / AKT pathway in Parkinson’s disease.

Figure 2

The neuroprotective of curcumin on MPTP-induced mouse model. (A) Representative traces of the open field test among control, MPTP, and MPTP + Curcumin groups (n = 10); (B) Quantification of the open field test and pole test among control, MPTP, and MPTP + Curcumin groups (n = 10); (C) Representative immunofluorescence images of TH-positive cells in the Substantia nigra and striatum of the three groups; (D) Quantification analysis of TH-positive cell number in Substantia nigra and Striatum. The analysis was performed using ImageJ (n = 5). Red staining represents immunolabeling for tyrosine hydroxylase. The significance is expressed as **p<0.01.

Figure 3

The network pharmacology analysis of curcumin in the treatment of PD. (A) The chemical structure of curcumin. (B) Venn diagram of overlapping genes associated with curcumin in PD.(C) PPI of potential targets of curcumin to treat PD. The top 15 key targets were shown as core PPI network. Nodes are potential targets for curcumin in the treatment of PD. The larger the node, the deeper the color, the greater the Degree. The line between two nodes represents the interaction. The thicker the edge, the higher the interaction between targets.

Figure 4

Enrichment analysis of network pharmacology. (A) GO functional enrichment analysis. (B) KEGG pathway enrichment analysis. The closer the color to red, the smaller the P value, the more pronounced the enrichment.

Figure 5

Transcriptome analysis. (A) The volcano map showed DEGs in MPTP vs MPTP+Curcumin groups. Red nodes represented up-regulated DEGs, and blue nodes represented down-regulated DEGs.(B) The heat map showed DEGs in MPTP vs MPTP+Curcumin groups.(C) GO functional enrichment analysis of DEGs. (D) KEGG pathway enrichment analysis of DEGs.

Figure 6

Curcumin activate PI3K/AKT pathway in the Substantia nigra. (A) Representative immunofluorescence images of pi3k-positive and akt-positive in the SN of the control, MPTP, and MPTP + Curcumin groups; (B) Quantitative analysis of mean fluorescence intensity of PI3K-positive and AKT-positive regions in the SN; (C) PI3K, and AKT mRNA levels in the SN. The significance is expressed as *p<0.05,**p<0.01. The analysis was performed using ImageJ (n = 5).

Figure 7

Curcumin activate PI3K/AKT pathway in the striatum. (A) Representative immunofluorescence images of pi3k-positive and akt-positive in the STR of the control, MPTP, and MPTP + Curcumin groups; (B) Quantitative analysis of mean fluorescence intensity of PI3K-positive and AKT-positive regions in the STR; (C) PI3K, and AKT mRNA levels in the STR. The significance is expressed as **p<0.01. The analysis was performed using ImageJ (n = 5).