Pharmacological study of the effects of cistanche on the treatment of Parkinson's disease

For more information:ali.ma@wecistanche.com

Yu Yingchun, Zhao Yang, Liang Suping, Zheng Jinghui*

(Ruikang Hospital Affiliated to Guangxi University of Traditional Chinese Medicine, Nanning, Guangxi 530001)

Keywords: Cistanche; Parkinson's disease; network pharmacology; mechanism

Parkinson's disease is a progressive, multifocal neurodegenerative disease that affects about 1% of people over 60 years of age (1), and its incidence gradually increases with age. At present, the etiology of PD is unknown, and its specific pathogenesis is not clear. It is mainly believed to be related to neuroinflammation, oxidative stress, gene mutation, immunological abnormality, cell apoptosis, mitochondrial damage, etc. [2 sentences. The most commonly used treatment for Parkinson's disease in clinical practice is dopamine replacement therapy, but only controlling clinical motor symptoms cannot prevent the progression of the disease, and long-term drug treatment may lead to serious and irreversible motor complications. Other treatment methods mainly include surgical treatment, such as destructive surgery, deep brain stimulation, etc., stem cell therapy, TCM acupuncture, exercise therapy, music therapy, and other adjuvant therapies to treat Parkinson's disease, but none of them can be completely cured.

Cistanche extract is derived from Rehmannia glutinosa Yinzi, from "Huangdi Neijing-Suwen-Xuanming Lunfang". It is a famous prescription for invigorating the kidney and resolving phlegm. It is a master drug, and the two drugs work together to exert their effects. Among them, Cistanche has the effects of nourishing liver and kidney, replenishing astringency and solidifying, etc. Modern pharmacological studies have shown that it has obvious effects of anti-oxidation, anti-inflammatory and sterilization, and lowering blood sugar. Cistanche has the effects of nourishing kidney yang, nourishing essence and blood, and moistening the bowel. Modern pharmacological research shows that Cistanche has the functions of neuroprotection, anti-oxidation, anti-aging, and immune regulation. At present, the Cornus-Russian medicine pair is widely used in the clinical treatment of Parkinson's disease, but the exact mechanism of its treatment of Parkinson's disease is still unclear. And the target of action is screened, and its target is matched with the target of Parkinson's disease, the key action target related to Cistanche treatment of PD is screened, and the material basis and mechanism of action for the treatment of PD are further analyzed.

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1 Material and methods

1.1 Cistanche composition information acquisition and sorting

Use the traditional Chinese medicine systems pharmacology database and analysis platform (traditional Chinese medicine systems pharmacology database and analysis platform, TCMSP) to collect the compounds of the traditional Chinese medicine Cistanche and Cistanche, and use the oral bioavailability (OB) N 30%, drug-likeness (drug-likeness, DL) NO. 18, because studies have found that the blood-brain barrier of patients with Parkinson's disease is damaged ⑹, the blood-brain barrier permeability (BBB) N-0.85 is set as the limiting condition Screen the collected compounds, and establish an effective compound database for the finally screened compounds.

1.2 The use of Cistanche to predict the target of action

Uses a bioinformatics analysis tool for the molecular mechanism of traditional Chinese medicine (BATMAN-TCM) to predict the target of the effective compound of Cornus-Cistanche medicine screened by TCMSP.

1.3 Regarding Parkinson's disease-related gene screening

"Parkinson's disease" is used as the search term, and Parkinson's disease-related targets are searched through the GeneCards database (https://www.genecards, org/). The Gene Cards database uses the Gifts algorithm, It can accurately calculate the correlation between the target and the disease, and rank it according to the correlation. In this study, the top 237 targets with the lowest score of more than 20 points were selected for research, and the highest score was 146.47, and the corresponding target scores were extracted. Standard gene name.

1.4 Cistanche prediction of Parkinson's disease targets and the construction of PPI network

Firstly, the predicted Cistanche's target and the selected Parkinson-related disease targets were imported into VENNY2.1, the common target of the two is derived, that is, the target that may act on Parkinson's disease. Then the obtained common target is corresponding to its compound, and the compound target map is made using Cytoscape 3.6.1 software. Upload Cistanche’s target for Parkinson’s disease to the STRING 10.5 database (https://string-db. org), select the research species as "Homo- sapiens", set the lowest point between the targets The connection score is 0.4. The unrelated targets are hidden, and the target connection network diagram is obtained. Finally, the diagram is imported into the Cytoscape 3.6.1 software to construct the PPI network diagram.

1.5 GO analysis and KEGG analysis of Cistanche targets for Parkinson's disease

Import Cistanche's targets for Parkinson's disease into the DAVID Bioinformatics Resources 6.8 database, select its Molecular function (molecular function), biological process (biological process), and cellular component (cellular component) are used to conduct GO enrichment analysis on Cistanche's targets in Parkinson's disease, and screen for biological processes with significant differences and reliable Target pathway, and use GraphPad Prism 7 software to make GO enrichment analysis results that meet P<0.05 into a visual bar graph. Select KEGG for target gene pathway annotation analysis, and use Omicshare to make a visual bubble chart with the results obtained and satisfy P<0.05 as an important pathway.

2 results

2.1 Screening of Cistanche's active ingredients

Search for all compounds of Cistanche through the TCMSP database (deadline until December 2018), and according to oral bioavailability (OB) N 30%, drug-likeness (DL) m0. 18 and blood-brain Barrier permeability (BBB) N-0.85 was used as the screening condition to screen and obtain 16 potentially active ingredients of Cistanche and 6 potential active ingredients of Cistanche.

2.2 Prediction of the target of Cistanche compound

Upload the Pubchem Cid code of the Cistanche. meat ash paste compound to the BATMAN-TCM database platform, and set the similarity model threshold to "Score cutoff = 20" to obtain the potential target corresponding to each compound, and follow the return target In order of scoring, select the first 20 targets of each compound, and all less than 20 are included, and after removing duplicate targets, 164 targets of Cistanche compound and 94 targets of Cistanche compound are finally obtained.

2.3 Screening of Parkinson’s Disease

Targets A total of 5 597 targets that may cause Parkinson’s disease were retrieved through the Gene Cards database for “Parkinson’s disease”. Among them, Synuclein Alpha targets have the highest correlation (146.47 points). ). In this study, targets with a correlation score> 20 were selected, and a total of 237 related targets were screened.

2.4 Cistanche's role in Parkinson's disease target prediction

The predicted Cistanche compound targets and screening to get Parkinson's disease-related gene targets, all imported into the VENNY2.1 software in gene name format, take the intersection of the two, get 19 compounds and disease common targets, 19 The specific target information is shown in Table 2, and the obtained Venn diagram is shown in Figure 1.

2.5 Construction of compound-target network diagram.

Cistanche medicines, 21 active ingredients, and 19 key target genes were introduced into Cytoscape.

2.6 Construction and analysis of PPI network of key targets

The 19 target genes of Cistanche for Parkinson's disease were imported into the String database to obtain protein interaction relationships, and the target interaction network diagram was obtained from the String database. The results are shown in Figure 3, where "edges" represent the interaction between the targets Associated, the node represents the target point. There are 19 nodes and 70 edges in the graph, the average node degree is 7.73, and the average local clustering coefficient is 0.661. The targets are represented by circular nodes. The thicker the connection between the targets, the more important the target is in the treatment of Parkinson's disease.

3 Results

Through GO enrichment analysis, it was found that Cistanche regulates the main biological process (BP) and dopamine secretion in the treatment of Parkinson's disease, the regulation of dopamine metabolism, chemical synaptic transmission, negative synaptic transmission, 5. serotonin receptor signaling pathway, G protein-coupled receptor signaling pathway, cell calcium homeostasis, behavior control, and other major biological processes are related. Among them, the regulation of dopamine secretion and the regulation of dopamine metabolism are closely related to the relevant mechanisms of the treatment of Parkinson's. Because Parkinson’s disease is mainly caused by a variety of reasons, dopaminergic neuron damage and apoptosis, and ultimately the concentration of dopamine in the striatum decrease, leading to The brain's feedback regulation being unbalanced and the disease occurring. Therefore, drugs that act on the dopaminergic system can effectively control Parkinson's disease by stimulating dopamine receptors and dopamine transporters. In the G protein-coupled receptor signaling pathway, studies have found that in PD mouse models, raloxifene binds to G protein-coupled estrogen receptor 30 to exert an anti-inflammatory effect, which can inhibit the inflammatory pathway and reduce the level of related inflammatory factors. , Thereby inhibiting the progression of chronic inflammation of Parkinson's disease. It shows that the G protein-coupled estrogen receptor (GPR30) is involved in the anti-inflammatory and neuroprotective effects of estrogen in PD inflammation (2). In the serotonin receptor signaling pathway, Fan Lingling et al. found that 5-HT7 receptor agonists may regulate the electrical activity of the medial prefrontal cortex (mPFC) pyramidal neurons in a variety of ways, and the substantia nigra striatum The degradation of the body pathway easily leads to dysfunction of 5-HT7 receptors on mPFC cones and interneurons. This provides a functional and cytological explanation for the involvement of 5-HT7 receptors in the symptoms of depression and anxiety in PD patients and opens up new research directions for Parkinson's disease treatment. Analysis of the GO enrichment results found that Cistanche’s biological process is mainly related to DRD2, DRD3, DRD4, SLC18A2, SLC6A3, HTR1A, and HTR2A genes, indicating that Cistanche may treat the two targets of dopamine receptors and serotonin receptors. PD. Related studies have shown that HTR2A receptor antagonists can reduce the adverse drug reactions caused by levodopa in the Parkinson’s disease model [2]; some DRD2 agonists can not only improve the motor symptoms of Parkinson's disease but also cause dyskinesias and mental diseases. The probability of side effects is low, indicating that traditional Chinese medicine has a good application prospect in the prevention and treatment of PD. The molecular function in GO enrichment analysis involves dopamine binding, dopamine neurotransmitter receptor activity, through Gi/Go coupling, dopamine neurotransmitter receptor activity, enzyme binding, acetylcholinesterase activity, cholinesterase activity, bile Alkali binding, and so on. The cellular components in GO enrichment analysis mainly involve axons, dendrites, (neuronal) synapses, postsynaptic membranes, plasma membranes, membranes, membrane rafts, etc., and mainly involve nerve signal transmission, neuron composition, and function, etc.

Enrichment analysis of gene KEGG pathway shows that Cistanche prevents PD mainly regulating dopaminergic synapses, neuroactive ligand-receptor interactions, cAMP signaling pathways, gap junctions, serotonergic synapses, and signaling pathways Nine related signal pathways such as roads and Parkinson's disease play a role, indicating that the target of Cistanche compound has multiple pathways, and the coordinated effect of each pathway can be used to treat Parkinson's disease. In the three neurotransmitter-related pathways of dopaminergic synapses, neuroactive ligand-receptor interactions, and signaling pathways, they may act on dopamine receptors [dopamine transporters, cannabinoid receptors 1, 5. serotonin Receptors to treat Parkinson's disease may also increase the number of dopamine neurons, reduce the degeneration of the substantia nigra poly-striatal dopaminergic pathway, and maintain the stability of dopamine levels.

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