| Objective:Migraine is a recurrent primary headache.The pathogenesis is not yet fully understood.There are still many problems in the treatment and preventionof recurrent.As one of the famous 100 prescriptions recommended for the treatment of migraine,Sanpian-decoction has been widely used in clinic and has achieved good curative effect,but the appropriate dosage of Ligusticum-Chuanxiong remains controversial in clinical use.The dosage of Ligusticum-Chuanxiong used in the original prescription was 30 g.However,the current dosage of Ligusticum-Chuanxiong stipulated by Chinese medicine pharmacopoeia is 10 g.In view of the above problems,to evaluate the efficacy of and adverse events related tothe safety and effectiveness of appropriate dosage of Ligusticum-Chuanxiong used in Sanpian-decoction in this study.Methods:1.Through the TCMSP database and relevant literature,the small molecular chemical components and targets of 8 kinds of traditional Chinese medicine used in Sanpian-decoction were obtained,the active components were selected according to the ADME.Then the main targets of migraine was obtained by using the Genecards,OMIM,TTD,DRUGBANK database.The targets of drugs and disease were intersected,and the "Sanpian-decoction-migraine target" network was constructed by using Cytoscape3.7.2 software.The protein interaction network was analyzed in using the String platform to construct the PPI network.Lastly,the Metascape platform was used for GO enrichment analysis,KEGG pathway enrichment analysis and functional annotation.2.Animal experiments were conducted by inducing migraine of animal model with repeated subcutaneous injection of NO donor nitroglycerin.Details of the experiment consist of the following:① Observe the pain sensitization behavior of animals after nitroglycerin administration by mechanical pain threshold and temperature pain threshold,and study the effect of Sanpian-decoction with Chuanxiong 30 g and 10 g on pain sensitization.② By observing the effect of different doses of Ligusticum-Chuanxiong in Sanpian-decoction on blood NO,NOS,ET-1,SP,Angll,PGE2 level in migraine animal model,the mechanism of Sanpian-decoction and dose change of Ligusticum-Chuanxiong was discussed.③By observing the expression level of c-fos,c-jun,CGRP,5-HT1B receptor in trigeminal nerve vascular pathway of migraine animal model,the mechanism of Sanpian-decoction with different doses of Ligusticum-Chuanxiong was studied.3.The clinical study was a double-blind,randomized controlled trial using an opaque envelope to hide the grouping scheme.Sanpian-decoction with Chuanxiong 10 g was set up as control group and Sanpian-decoction with Chuanxiong 30 g in as treatment group.The trial conducted from September,2020,to March,2021,at Third Affiliated Hospital of Beijing University of Chinese Medicine.Participants(aged 18-65 years)with a greater than 1-year history ofmigraine and migraine on 2 to 15 days per month in the 3 monthsprior to screening were Included.Changes of blood routine,liver and kidney function,urine routine and cerebral blood flow in migraine patients were observed after 28 days of administration.The headache pain before and after treatment were compared according to the self-rating scale of headache diary,HIT-6 score,MSQ scale and clinical symptoms.Details of the study can be divided into the following parts:① Observe the clinical effect of Sanpian-decoction with different doses of Ligusticum-Chuanxiong on headache attack in migraine patients.② Use TCD to observe the effect of Sanpian-decoction with different doses of Ligusticum-Chuanxiong on intracranial vascular hemodynamics in migraine patients.③ Blood PGE2,6-Keto-PGF1α,TXB2,AngⅡ levels were observed in two groups of migraine patients before and after treatment.④ Blood routine,liver and kidney function of migraine patients were observed before and after treatment,to record and analyze the adverse reactions during the trial.⑤Investigate the safety and effectiveness of an appropriate dose of Ligusticum-Chuanxiong in the treatment of migraine.Results:1.262 related target genes,2324 migraine related genes and 171 Sanpian-decoction-common migraine targets were obtained through the database.The Sanpian-decoction component-migraine target interaction network was constructed according to the above common targets,and 31 key targets were extracted from them.The TNF signal pathway,MAPK signaling pathway,fluid shear stress and atherosclerosis,IL-17 signal pathway and other signal pathways were obtained by signal pathway analysis.2.Compared with migraine model group,Zomitriptan and Sanpian-decoction with Chuanxiong 30 g and 10 g could effectively reduce the number of head scratching and cage-climbing in rats.The Sanpian-decoction with Chuanxiong 30 g group reduced the number of cage-climbing of rats more significantly than the Sanpian-decoction with Chuanxiong 10 g group.Zomitriptan group and both Sanpian-decoction with Chuanxiong 30 g and 10 g group could increase the mechanical pain threshold of rats.Zomitriptan and Sanpian-decoction with Chuanxiong 10 g could effectively increase the temperature pain threshold of rats.3.The levels of serum NOS and PGE2 in migraine model rats were significantly down-regulated by Zomitriptan and both Sanpian-decoction groups.Down-regulations of NO,ET-1,SP were observed.Zomitriptan and Sanpian-decoction with Chuanxiong 10 g could down-regulate the level of Ang II in serum.Sanpian-decoction with Chuanxiong 30 g upregulated the level of serum Ang II in rats.4.Compared with migraine model group,Zomitriptan and both Sanpian-decoction with Chuanxiong 30 g and 10 g group could effectively reduce the number of c-fos,c-jun and CGRP positive cells in the spinal nucleus of the trigeminal nerve,and increase the number of 5-HT1B receptor positive cells in the spinal nucleus of the trigeminal nerve.The Sanpian-decoction with Chuanxiong 30 g group significantly down-regulated c-fos and up-regulated 5-HT1B receptor expression.Zolmitriptan significantly down-regulated c-jun and up-regulated 5-HT1B receptor expression..At the same time,the down-regulation of c-fos in the Sanpian-decoction with Chuanxiong 30 g was significantly different than that of the Zomitriptan group and Sanpian-decoction with Chuanxiong 10 g.5.The halving rate of headache in Sanpian-decoction with Chuanxiong 10 g group and Sanpian-decoction with Chuanxiong 30 g group was 58.33%and 66.67%respectively.The VAS score of migraine patients was significantly reduced after 28 days of drug therapy in Sanpian-decoction with Chuanxiong 30 g.This drug therapy also reduced the number of painkillers used,the impact of headaches on life,HIT-6,MSQ,TCM syndrome scores of wind,and syndrome of deficiency of blood.The VAS score of migraine patients was significantly reduced and shortened time to headache after 28 days of drug therapy in Sanpian-decoction with Chuanxiong 10 g The score of HIT-6,MSQ,TCM syndrome scores of wind,blood deficiency,blood stagnation,and Qi deficiency was also significantly reduced in Sanpian-decoction with Chuanxiong 10 g.6.The two groups have the tendency to down-regulate the PGE2,6-Keto-PGF1α and up-regulation of TXB2 in of migraine patients after treatment.On the Ang Ⅱ,Sanpian-decoction with Chuanxiong 10 g was down-regulated,while Sanpian-decoction with Chuanxiong 30 g was up-regulated.7.28 days of treatment Sanpian-decoction with Chuanxiong 30 g can reduce the differences of average blood flow velocity,systolic peak value and end-diastolic blood flow velocity between the main and contralateral MCA,ACA of in migraine patients with.The difference between average blood flow velocity,systolic peak systolic peak and end-diastolic blood flow velocity of the main and contralateral MCA of headache can be improved with 28 days of treatment in Sanpian-decoction with Chuanxiong 10 g group,while groupcould also increase blood flow velocity in the contralateral PCA of headache and decrease BA pulsation index and resistance index.The pulsation index and resistance index of the Sanpian-decoction with Chuanxiong 10 g group was more likely to be reduced compared to Sanpian-decoction with Chuanxiong 30 g group.8.No treatment-emergent serious adverse events occurred.There was no significant difference in liver and kidney function between the two groups in the treatment of Sanpian-decoction.Conclusion1.Sanpian-decoction,possibly by means of quercetin,kaempferol and luteolin,can influence PTGS2,ESR1,NOS2 on TNF signaling pathway,MAPK signaling pathway,fluid shear stress and atherosclerosis pathway,IL-17 signaling pathway,and play a multi-target,multi-pathway role in treatment of migraine.2.Sanpian-decoction may down-regulate NO,NOS,ET-1,SP,PEG2 in serum,and improve the mechanical pain threshold and temperature pain to relieving clinical symptoms of migraine model rats.Sanpian-decoction may inhibit the expression of c-fos,c-jun,CGRP in the nucleus of the spinal trigeminal nerve,and increase the expression of 5-HT1B receptors.The increase of Ligusticum-Chuanxiong dose may enhance the above effect to a certain extent.3.Compared with the Sanpian-decoction with Chuanxiong 10 g group,the Sanpian-decoction with Chuanxiong 30 g group could significantly reduce the number of cage-climbing,and down-regulate the number of c-fos-expressing positive cells in the trigeminal spinal tract nucleus of migraine model rats.4.Both groups of Sanpian-decoction with Chuanxiong 10 g and 30 g group can obviously relieve the migraine attack,correct the hemodynamic imbalance between the headache side and the normal side,reduce the VAS,HIT-6,and MSQ scores,and improve the quality of life for migraine patients.Sanpian-decoction with Chuanxiong 30 g group could do better in reducing migraine attacks and the used rescue medication.However,due to the insufficient number of samples,the statistically significantly difference and mechanism between high dose and low dose Ligusticum chuanxiong need further study.5.Compared with the Sanpian-decoction with Chuanxiong 30 g group,the decrease in PI and RI of the basilar artery was statistically significant in the Sanpian-decoction with Chuanxiong 10 g group,suggesting that low-dose Ligusticum chuanxiong has its advantages in clinical application.6.Large dose of Ligusticum-Chuanxiong of Sanpian-decoctionis safe and effective in treating migraine,being particularly effective at wind syndrome and depression syndrome of migraine patients,at the same time it should be considered in use with other drugs. |
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