The Underlying Mechanism of Paeonia lactiflora Pall. in Parkinson's Disease Based on a Network Pharmacology Approach

Abstract

Background: Parkinson's disease (PD) is the second most common neurodegenerative disease worldwide, yet as of currently, there is no disease-modifying therapy that could delay its progression. Paeonia lactiflora Pall. is the most frequently used herb in formulas for PD in Traditional Chinese Medicine and also a potential neuroprotective agent for neurodegenerative diseases, while its mechanisms remain poorly understood. In this study, we aim to explore the underlying mechanism of P. lactiflora in treating PD utilizing a network pharmacology approach. Methods: The protein targets of P. lactiflora ingredients and PD were first obtained from several databases. To clarify the key targets, a Protein-Protein-Interaction (PPI) network was constructed and analyzed on the String database, and then enrichment analysis was performed by the Metascape platform to determine the main Gene Ontology biological processes and Kyoto Encyclopedia of Genes and Genomes pathways. Finally, the Ingredient-Target-Pathway (I-T-P) network was constructed and analyzed by Cytoscape software. Results: Six active ingredients of P. lactiflora (kaempferol, ß-sitosterol, betulinic acid, palbinone, paeoniflorin and (+)-catechin) as well as six core targets strongly related to PD treatment [AKT1, interleukin-6, CAT, Tumor necrosis factor (TNF), CASP3, and PTGS2] were identified. The main pathways were shown to involve neuroactive ligand-receptor interaction, Calcium signaling pathway, PI3-Akt signaling pathway, TNF signaling pathway, and apoptosis signaling pathway. The main biological process included the regulation of neurotransmitter levels. Conclusion: P. lactiflora may retard neurodegeneration by reducing neuroinflammation, inhibiting intrinsic and extrinsic apoptosis, and may improve motor and non-motor symptoms by regulating the levels of neurotransmitters. Our study has revealed the mechanism of P. lactiflora in the treatment of PD and may contribute to novel drug development for PD.

Keywords: Paeonia lactiflora Pall.; Parkinson’s disease; Traditional Chinese Medicine; apoptosis; multi-target; network pharmacology.

FIGURE 1

(A) Common targets of Paeonia lactiflora Pall. and Parkinson’s disease. (B) Protein-Protein-Interaction (PPI) network of putative targets. (C) PPI core network. The size and color of the node represent its Degree. Degree equals the number of nodes connected by a node. The larger and brighter the node is, the more important it is in the network.

FIGURE 2

Enrichment analysis of putative targets of Paeonia lactiflora P. for Parkinson’s disease. (A) Top 20 Gene Ontology biological processes. (B) Top 20 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways and Parkinson’s disease Pathway. Size of the bubble stands for the number of targets in the pathway and the color stands for p value. The red bubble represents a smaller p value. (p < 0.01).

FIGURE 3

Ingredient-Target-Pathway (I-T-P) network of Paeonia lactiflora P. for Parkinson’s disease. The purple inverted triangles represent the ingredients of Paeonia lactiflora P., the green diamonds represent the common targets, and the yellow circles represent the main pathways. Node size is proportional to its degree. The larger the area is, the more important it is in the network. The nodes of ingredients and pathways are arranged clockwise by size. PLP1, paeoniflorin; PLP2, palbinone; PLP3, kaempferol; PLP4, (+)-catechin; PLP5, betulinic acid; PLP6, beta-sitosterol.

FIGURE 4

Schematic diagram of the underlying mechanism of Paeonia lactiflora P. in Parkinson’s disease. The diagram of a nigro-striatal synapse shows three possible approaches that can be used as therapeutic targets. Parkinson’s disease is caused by the early death of dopaminergic neurons in midbrain substantia nigra leading to the reduction of dopamine neurotransmitters released to the striatum, so treatment could be either targeting the degeneration process as disease-modifying therapy (presynaptic, right side of the diagram), or synaptic transmission as symptomatic treatment (postsynaptic, left side of the diagram). The putative targets of Paeonia lactiflora P. are located on three pathways: the green arrows from TNF, IL-6, to CASP8, CASP3 are part of the extrinsic apoptosis pathway induced by neuroinflammation, the yellow arrows from CASP9 to CASP3 with the involvement of AKT1, BCL2, and PTGS2, belong to the intrinsic apoptosis pathway, and blue receptors DRD1, DRD2, ADORA2A, SLC6A3 and AKT1 are related to the regulation of neurotransmitters level. TNF, Tumor Necrosis Factor; IL-6, Interleukin 6; CASP8, Caspase-8; CASP9, Caspase-9; CASP3, Caspase-3; PTGS2, cyclooxygenase 2 (COX2); BCL2, Apoptosis regulator Bcl-2; AKT1, RAC-alpha serine/threonine-protein kinase (PKB); ADORA2A, Adenosine receptor A2a; DRD1, Dopamine D1 receptor; DRD2, Dopamine D2 receptor; SLC6A3, Sodium-dependent dopamine transporter.