A Study On The Medication Rule And Mechanism Of "General Collection For Holy Relief" Treating Primary Headache

ObjectiveAt present,headaches are very common diseases in all countries and have become a major public health problem in the world,but the level of detection,diagnosis and treatment is not ideal.As one of the three official prescriptions of the Song Dynasty,the "General Collection for Holy Relief"encompasses rich contents,and quality of prescriptions and dosage forms have significant features of the Times,which can be called the medical book of the Song Dynasty.In order to better inherit,develop and make good use of the medication experience in historical medical records,our research applied data mining technology and network pharmacology method to study the rules and mechanism of prescriptions for treating primary headache in the "General Collection for Holy Relief",with an anticipation for providing reference for clinical treatment of headache and new drug development.MethodsAll medical records related to the treatment of primary headache were collected and sorted out in the "General Collection for Holy Relief ",then medical records databases were established and standardized according to data processing principal.SPSS Statistics 23.0 software was applied to perform statistical analysis on the number of flavors,frequency,four qi,five flavors,meridian return and efficacy of TCM used in prescriptions.The potential drug combinations were analyzed by hierarchical clustering analysis method for high-frequency drugs.SPSS Modeler 15.0 software was used to analyze drug association rules and screen out common drug pairs.Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP)was conducted to obtain the active ingredients and the targets of common drug pairs with oral bioavailability(OB)≥30%as screening condition.The Therapeutic Target Database(TTD),DrugBank and GeneCards databases were integrated to obtain the targets related to primary headache,and the drug targets were mapped to disease targets to obtain the candidate targets of common drug pairs for the treatment of primary headache.The String database and Cytoscape 3.6.1 software were used to construct protein interaction network and active component-target network.The topology characteristics of the network are analyzed,and the total topology parameters greater than or equal to the average value of betweenness centrality(BC),closeness centrality(CC)and degree centrality(DC)were used to screen nodes and build a core network to mine core target proteins and active ingredients.Genetic Ontology(GO)biological function and KEGG(Kyoto Encyclopedia of Genes and Genomes)pathway enrichment analyses of common drug pairs for primary headache treatment were further performed using the Metascape database.Finally,the CBDOCK molecular docking platform was used to verify the binding ability between core active ingredients and core target proteins.ResultsA total of 258 prescriptions for the treatment of primary headache,which involving 253 kinds of Chinese herbal medicines were collected in the"General Collection for Holy Relief",with a total usage frequency of 1825 times.1.Data mining results:The number of drugs in most prescriptions was 5-10;The top 20 drugs with high frequency were glycyrrhiza,gesso,ephedra,chuanxiong,ginseng,Saposhnikovia divaricata,pinellia ternata,cinnamon,radix bupleuri,Scutellaria baicalensis,radix Peucedani,radix paeoniae alba,radix puerariae,Rhizoma Arisaematis,Atractylodes,aconite,Notopterygium incisum,asarum,Platycodon grandiflorum and Gardenia jasminoides.Most of the 253 traditional Chinese medicines were warm,cold and soothing drugs,and most of them were symplectic,sweet and bitter drugs.Most of them were distributed in the meridian of lung,stomach,liver,spleen,heart and kidney.Most of them have heat-cleansing and detoxifying,spleen-nourishing and cough-relieving effects.Five new drug combinations were obtained by high frequency drug cluster analysis.Eight pairs of potential drug combinations for the treatment of primary headache were screened out by association rule analysis,among which ephedra and glycyrrhizae had high support(22.01%)and confidence(68.42%)level.Therefore,this drug pair was selected for network pharmacology analysis.2.Network pharmacology analysis results:A total of 352 active components of ephedra and glycyrrhiza were collected.There were 144 species of licorice and 221 species of ephedra,with 13 common active components.There were 363 targets of active ingredients,392 targets related to primary headache,and 94 candidate targets for TCM treatment of primary headache.Network topological analysis showed that the key active components of ephedrin-glycyrrhiza were quercetin,β-sitosterol,stigmasterol,methyl eugenol,kaempferol,β-pinene,ephedrine,etc.Core targets are Interleukin-6(IL6),Sodium-dependent Serotonin Transporter(SLC6A4),Tumor Necrosis Factor(TNF),Sodium-dependent Transporter(SLC6A3),Glutamate Receptor Ionotropic(GRIN2A),5Hydroxytryptamine Receptor 2C(HTR2C),Estrogen Receptor(ESR1),Sodium-dependent Noradrenaline Transporter(SLC6A2),ACHE and other Acetylcholinesterase;Enrichment analysis demonstrated that 94 candidate targets were mainly involved in the regulation of signaling pathways including neuroactive ligand receptor interaction pathway,5hydroxytryptaminergic synapses,cAMP signaling pathway,CPMP-PKG signaling pathway,arachidonic acid metabolism pathway,tryptophan metabolism pathway,etc.Finally,the Vina score of all the docking results of core activity and core target protein receptor was less than-5.0,indicating good binding capability between protein receptor and ligand.Conclusions1.The "General Collection for Holy Relief " mainly uses "wind medicine" in the treatment of primary headache,and makes good use of ephedra,chuanxiong,Saposhnikovia divaricata,radix bupleuri,radix Peucedani,radix puerariae,Notopterygium incisum,Asarum sieboldii,Platycodon grandiflorum and other wind medicines to dispel the wind throughout the treatment.2.For the treatment of primary headache in the "General Collection for Holy Relief ",warm,cold and flat drugs were the main drugs,with symplectic,sweet and bitter tastes.And most of them were distributed in lung,spleen,stomach and liver ducts,followed by heart and kidney ducts.3.Through data mining,it was found that ephedra and glycyrrhiza were common drug pairs in the treatment of primary headache.It has a variety of active ingredients,thus can regulate multiple targets of disease,and participate in the activation of multiple signaling pathways to play a role in the treatment of disease,with the characteristics of multiple targets,multiple components and multiple pathways.4.The mechanism of ephedra and glycyrrhiza in the treatment of primary headache may be related to inhibiting neurogenic inflammatory response,interfering the role of neurotransmitters and synapses,and regulating the relaxation and contraction of vascular smooth muscle.