Source: Tao Peng, Hui Zhang, Yifan Yang, Zhuo Chen, Jianfu Ma, Yongmei Yan.Pharmacological research progress of Chuanxiong and its prescriptions for anti-migraine [J]. Chinese Herbal Medicine, 2024, 55(3): 1004-1013.
Migraine is a common primary headache in clinical practice, with migraine, episodic, episodic, moderate and severe, throbbing headache as the clinical manifestation, its incidence and disability rate are increasing year by year [1], and it has become the third epidemic disease in the world, the second major disabling nervous system disease [2-3], epidemiological studies have found that the prevalence of migraine is the highest in people aged 18~44 years, women are more likely to suffer from migraine than men [4], and 3% of them turn to chronic migraine every year , causing a heavy economic burden to patients and society.
As a complex neurological disease, the pathogenesis of migraine is still unclear, and its pathogenesis hypotheses include vascular theory, cortical diffusion inhibition theory, trigeminal nerve vascular reflex theory, inflammatory mediator theory, central nervous system theory, and heredity theory [5]. Among them, the theory of central nervous system has become the focus of research in recent years, and it is believed that changes in brain structure and function are the possible causes of migraine, and that the morphology and volume of the brainstem, white matter, and gray matter in migraine patients are abnormally changed, and there are abnormal nerve signaling at the time of attack, but the results of this study are only statistically high and still need to be confirmed by further studies [6].
In recent years, gut microbiome and microglia-mediated central sensitization have also been found to be involved in the pathogenesis of migraine [7-8]. Currently, migraine is treated primarily with nonspecific analgesics, such as nonsteroidal anti-inflammatory drugs, and opioids, and specific drugs, such as ergot and triptans [9]. However, migraine has a familial tendency to occur and there are large individual differences, some patients are not sensitive to treatment, and long-term use is prone to adverse reactions such as dizziness, gastrointestinal reactions, and neurological symptoms, so the safety is worth considering [10]. A large number of clinical practices and studies have shown that TCM has definite efficacy in the treatment of migraine, and has the characteristics of multi-target and multi-pathway, and network meta-analysis has shown that the combination of massage and acupuncture with TCM has significant advantages in reducing the frequency and number of headache attacks [11].
Chuanxiong Rhizoma is the dried rhizome of Ligusticum chuanxiong Hort. [12], and modern pharmacological studies have found that its main chemical components are volatile oils, alkaloids, polysaccharides, etc. [13], and it has pharmacological effects such as anti-inflammatory, analgesic, antioxidant, anticoagulant, and antidepressant [14]. The treatment of headache and other neurological diseases by Chuanxiong has been discussed in ancient books, and is called blood medicine in blood and blood medicine in traditional Chinese medicine, which has the functions of promoting qi and invigorating blood, dispelling wind and relieving pain [13], and Chuanxiong monotherapy and its compound have significant effects in the treatment of migraine, and there are many clinical reports [15-16].
1 Chuanxiong monomer ingredient anti-migraine
The chemical components of Ligusticum Chuanxiong are abundant, among which phthalides are the main components in volatile oils, including Ligusticolides, Ligusticum ligustrum A, H, I, and Angelica lactone A, etc.; most of the alkaloids in Ligusticum Chuanxiong are small molecule compounds, mainly Ligustrazine, adenine, uracil, choline, trimethylamine, ryegrassine, adenosine, etc., which are relatively low in content [17-18], phenolic acids and organic acids are another important active ingredient of Ligusticum Chuanxiong [14], including ferulic acid, serdanic acid, vanillin, Vanillic acid, palmitic acid, linoleic acid, parabenic acid, chrysopsop, chlorogenic acid, caffeic acid, protocatechuic acid, etc., polysaccharide compounds include glucose, galactose, arabinose, galacturonic acid, mannose, and rhamnose [19], in addition, ligusticum chuanxiong also contains terpenes, glycosides and other components. Among these ingredients, ligustrazine, ferulic acid, ligolactone, and ligustolide have a wide range of applications in the treatment and research of migraine.
1.1 Kawa Yaku
Ligustrazine is an important component of Chuanxiong anti-migraine and the main index component of Ligustrazine Injection. Ma Lin et al. [20] selected 84 migraine patients to observe the therapeutic effect of acupoint injection of ligustrazine injection in the treatment of migraine, and the total effective rate was 95.24%, indicating that ligustrazine injection has a definite effect in the treatment of migraine. Zhang Guoming et al. [21] selected 626 migraine patients and randomly divided them into observation group (n=316) and control group (n=310), the control group was treated with flunarizine hydrochloride, and the observation group was treated with ligustrazine hydrochloride injection on the basis of the treatment of the control group, and the results showed that the total effective rate of the observation group was significantly higher than that of the control group, which showed that the efficacy of ligustrazine injection combined with flunarizine hydrochloride in the treatment of migraine was safe and reliable.
In addition, ligustrazine can not only act on the adenosine triphosphate receptor-ion channel complex to produce allosteric effects, regulate the N-terminal phosphorylation of the P2X3 receptor of the dorsal root ganglion involved in pain conduction [22-23], but also downregulate the transient receptor potential cation channel subfamily V member in the trigeminal neurovascular system of migraine rats 1, TRPV1) [24], which plays a role in the treatment of migraine.
1.2 Ferulic acid
Ferulic acid is a derivative of cinnamate, which mainly exists in plants in combination with oligosaccharides, polyamines, lipids and polysaccharides, namely sodium feruloate and ferulate. Sodium feruloate is an organophenolic acid compound that has anti-inflammatory, antioxidant, anti-apoptosis, anti-platelet aggregation, antithrombosis, and immunomodulatory effects [25].
It has been found that ferulic acid can improve microcirculation and vascular smooth muscle spasm, inhibit platelet overactivation by inhibiting the expression of substance P and calcitonin gene-related peptide (CGRP), and inhibit platelet overactivation by regulating peroxisome proliferator γ s factor-κB (NF-κB) and mitogen-activated protein kinases (MAPK) signaling pathways exert anti-inflammatory effects [27-28]. Clinical studies have found that ferulic acid can significantly improve the abnormal cerebral blood flow in migraine patients [29], and its effect on reducing the frequency and severity of migraine attacks is more durable than that of flunarizine [30], but more large-sample clinical studies are still needed for further validation.
1.3 洋川芎内脂和藁本内酯
Both Yangchuanxiong and Limenolide belong to the phthalide compounds, both of which have significant anti-migraine activity, but the current research on them is mostly biased towards basic and pharmacokinetic research, and there are few clinical research reports. Among them, Yangchuanxionglactone A, H, and I were the key research objects, and Yangchuanxionglactone I was confirmed to not only inhibit the NF-κB pathway to exert anti-inflammatory effects, but also exert anti-migraine effects by regulating nitric oxide and CGRP levels [31]. It has been found that Yangchuanxionglactone A can dilate the isolated aortic blood vessels in model mice, and can inhibit vasoconstriction induced by prostaglandin E2 (PGE2), phenylephrine, and 5-hydroxytryptamine (5-HT)[32].
Luo Yanyan [33] found that Yangchuanxionglactone H can inhibit the loss of matrix metalloproteinase (MMP) and the increase of reactive oxygen species levels in rat adrenal pheochromocytoma PC12 cells induced by 1-methyl-4-phenyl-pyridine ions, and down-regulate the expression of phosphorylated c-Jun N-terminal kinase and p-p38, and exert neuroprotective effects through MAPK and mitochondrial apoptosis pathways. It has the advantages of small relative molecular weight, high bioavailability, and easy passage through the blood-brain barrier [34], and can play a role in the treatment of migraine by promoting gene and protein expression of tight junction proteins, inhibiting hypoxia-inducible factor-1α (HIF-1α) vascular endothelial growth factor pathway and aquaporin4 to regulate the permeability of the blood-brain barrier [35-36]. The specific mechanism of action is shown in Figure 1.
2 Chuanxiong extract anti-migraine
Chuanxiong extract is extracted by ethanol reflux extraction, and then eluted with distilled water and ethanol respectively and then dried in vacuum.
Li Yajie [37] used the blood stasis model, mesenteric microcirculation disorder model, and migraine model to reveal the potential mechanism of Chuanxiong extract in blood circulation and analgesia and migraine treatment from different levels. The results showed that Chuanxiong could significantly reduce the hematological indexes such as whole blood viscosity and whole blood high-cut relative index, and the flow rate of arterioles and venules in each dose group of Chuanxiong extract was faster than that of the model group, and the recovery time of vasospasm was reduced compared with that of the model group, which was a full embodiment of its effect of activating blood and removing blood stasis. Compared with the model group, the number of twists in each dose group of Chuanxiong extract was reduced, and the number of twists in each dose group was significantly reduced, and the number of twists in the Chuanxiong group was significantly reduced in the 26.7 and 54.3 mg/kg groups.
3 Chuanxiong medicine and compound anti-migraine
The compatibility of traditional Chinese medicine is a combination of two or more kinds of traditional Chinese medicine under the guidance of traditional Chinese medicine theory, which achieves the effect of increasing efficiency and reducing toxicity after compatibility, and achieves the purpose of disease treatment [38].
3.1 Kawarei - Tenma Distribution
The main component of gastrodia is gastrodin, which is metabolized into gastrodione in the body after oral administration, and is also one of the high-frequency drugs for nervous system diseases. It was found that the Chuanxiong-Gastrodia alcohol extract group could protect the elasticity and diastolic function of blood vessel walls by regulating the contents of vasomotor factors and active substances such as CGRP, nitric oxide synthase (NOS), dopamine, nitric oxide, endothelin, and thromboxane B2 in serum and brain tissues [39-40], while Zhou et al. [41] found that Gastrodia-Chuanxiong had an effect on the metabolism of endogenous substances in the urine of migraine rats from amino acid metabolism and tricarboxylic acid cycle.
At the same time, it was found that compared with Chuanxiong alone, the compatibility of Chuanxiong-Gastrodia gastrodia has synergistic effect, which can not only improve the absorption degree of Chuanxiongzine and ferulic acid brain tissue, prolong the action time, slow down the elimination rate, and increase the accumulation, and its action intensity is dose-correlated[42], but also significantly prolong the residence time and half-life of gastrodin and gastronoside in the blood, increase the bioavailability and residence time of gastrodin in the brain, slow down the elimination rate, and exert a synergistic effect [43-44]. Further studies found that there was a significant dose-related relationship between the two effects. Chen Ying et al. [45] found that Chuanxiong-Gastrodia gastrodia 1∶4 had the best effect on the sedative and analgesic effects of migraine rats and mice. Both pharmacodynamic and pharmacokinetic studies have shown that Chuanxiong-Gastrodia 1:4 has the best effect in the treatment of a rat model of migraine with hyperactive liver yang [46-47], while Chuanxiong-Gastrodia 4:1 has the best effect when used in blood-stasis migraine rats [48-49]. Wang Qiang et al. [50] found that the optimal ratio of 4∶3 was the best ratio of Chuanxiong-Gastrodia, which was different from the above study, which may be related to the difference in dosage and research angle.
Xiongma soup originated from the Daxiong pill in the "Shengji General Record", and the "Compendium of Materia Medica" called it Tianma pill, and the pill was changed to a decoction in the "Yizong Jinjian", and it was named "Xiongma Soup". This formula is composed of Chuanxiong 1 Qian and Gastrodia 2 Qian, which is mainly used for the treatment of migraine, dizziness, dizziness, and physical fatigue [51], and has a wide range of applications in the treatment of clinical migraine. Jin Yuhua et al. [52] divided 104 migraine patients into observation group and control group, the control group was treated with conventional chemical drugs, and the observation group was treated with oral xiongma decoction.
Liu Dingding et al. [53-55] conducted extensive and in-depth research on the mechanism of action of Xiongma decoction against migraine. It was found that the CGRP-calcitonin receptor-like receptor (CRLR)/receptor activity-modifying protein 1 (RAMP1) signaling pathway was an important anti-migraine pathway in Xiongma decoction, which could be used to downregulate the trigeminal cervical myeloid complex in rat migraine model rats complex, TCC) inhibited the activation of TRPV1-CGRP/CGRP-R pathway and exerted anti-migraine effects, and ethyl acetate and n-butanol were found to be important pharmacodynamic active sites of Xiongma decoction [56], which could not only reduce the content of 5-HT and nitric oxide in tissues and peripheral blood [57-58] It can also inhibit NF-κB expression and inducible NOS and other pro-inflammatory factors [51], alleviating behavioral symptoms in migraine rats.
Endothelin is the strongest known vasoconstrictor, which can cause various vasoconstrictions and is also an important cause of migraine. Guo Qianyao et al. [59] found that the contents of endothelin and 5-HT were lower than those in the model group by using the extract of Igxiong Ma decoction in nitroglycerin-induced migraine rats, and the combination of Xiongma decoction and ibuprofen had a better effect on migraine caused by reserpine in mice [60].
Originating from the second volume of Liu Wansu's Xuanming Treatise, Dachuanxiong Fang is composed of two traditional Chinese medicines, Chuanxiong and Gastrodia, which have the effects of activating blood and removing blood stasis, calming the liver and quenching wind, and has been a classic compound for the treatment of migraine, on the basis of which a variety of Chinese patent medicines have been developed for the treatment of migraine, such as Tianshu capsules, Tianshu tablets, and Tianshu dripping pills [61]. Wang et al. [62] found that after the treatment of Tianshu capsule combined with sumatriptan, the scores of the syndrome score, Pittsburgh sleep quality index score, visual analog scale (VAS) and other scales in the treatment group of migraine patients were significantly lower than those in the control group. Yang Zhihua et al. [63] observed the therapeutic effect of Tianshu capsule combined with flunarizine hydrochloride on migraine patients and found that compared with the single use, the combination of the two treatments could not only relieve the headache symptoms of patients, but also improve the cerebral blood flow velocity with fewer adverse reactions.
Li Lixun et al. [64] systematically evaluated the efficacy and safety of Tianshu capsule in the treatment of headache, and the results showed that compared with conventional treatment with chemical drugs, Tianshu capsule combined with chemical drugs in conventional treatment of tension-type headache and vascular neurogenic headache has certain advantages.
In addition, basic studies have found that Dachuan Xiongfang can up-regulate the expression of 5-HT in brain tissue by inhibiting the activation of NOS, P substances, and CGRP in the trigeminal nucleus [65-66], reduce the levels of CGRP and endothelin in plasma, inhibit abnormal dilatation of cerebral blood vessels and platelet activation [67], and intervene in amino acid synthesis and metabolic pathways [68-69] to regulate fatty acid biosynthesis [70] Through network pharmacology, it was found that there were 16 main active ingredients and 18 protein targets, which inhibited neurogenic inflammation and the production of neurotransmitters, reduced the sensitization of nociceptive information by dural vascular receptors, and resisted the occurrence and propagation of cortical spread inhibition, which may be the specific mechanism of action of anti-migraine [71] Further studies have found that the specific anti-inflammatory effects of Dachuanxiong may be related to the inhibition of the NF-κB pathway, the reduction of NF-κBα inhibitory protein phosphorylation, the inhibition of p65 expression, and the reduction of inflammatory mediator expression [72].
3.2 川芎-白芷配伍
The combination of the two drugs can enhance the function of warming the meridians and channels, and is often used for external wind and cold, meridian stasis migraine [73]. Xing Jinhua et al. [74] used Chuanxiong-Angelica dahurica transnasal administration for the treatment of patients with intractable migraine, and the total effective rate reached 97.62%. Basic studies have found that Ligusticum Chuanxiong-Angelica Angelica extract can down-regulate the levels of cyclooxygenase-2 (COX-2), PGE2, and CGRP in brain tissue, and significantly increase the content of 5-HT, norepinephrine (NE), and endothelin in brain tissue to inhibit acute migraine attacks [75-76].
Wang et al. [77] found that the decoction of Angelica Chuanxiong-Angelica Angelica could delay the absorption of Angelica Angelica sinensis, DL-3-n-butylphthalate, and membrane lipid alcohol A in Angelica Chuanxiong, and accelerate the metabolism of these substances. Wu Hui et al. [78-80] found that the single use of Angelica dahurica, Evodia officinalis, and Chuanxiong could improve the behavioral performance of migraine rats, and the mechanism may be related to the reduction of nitric oxide and enkephalin secretion, the reduction of CGRP and c-Fos expression, and the increase of 5-HT and β β-endorphin (β-EP) content. Yu Yingchun [81] found that the combination of Chuanxiong and Angelica dahurica can act on targets and pathways related to inflammation and energy metabolism to treat migraine.
As a commonly used prescription for the clinical treatment of migraine, Chuanxiong tea has become the preferred drug recommended by guidelines [82], but its pharmacodynamic material basis, metabolic processes in vivo, and specific mechanism of action are still unclear, and current research mainly focuses on reducing the levels of nitric oxide, PGE2, and CGRP, and increasing the content of 5-HT [83]. Li Dandan et al. [84] found that the behavioral changes of the ultra-micro Chuanxiong tea adjustment group were significantly better than those of the Chuanxiong tea adjustment oral solution group, and the mechanism may be related to the reduction of CGRP content, the increase of β-EP content, and the alleviation of neurogenic inflammation in the ultramicro Chuanxiong tea adjustment group.
Other studies have found that the mechanism of migraine treatment may be related to down-regulation of CGRP and endothelin-1 gene expression, inhibition of platelet aggregation, and improvement of platelet activation and release responses and hemrheological abnormalities [85-86]. Sun Da et al. [87] used flucinazine hydrochloride capsule as a control, and found that the clinical efficacy, VAS score, serum 5-HT and β-EP expressions in the Chuanxiong tea adjustment group were better than those in the control group, and the expression of substance P was lower than that in the control group. Meta-analysis showed that the addition and subtraction of Chuanxiong tea combined with flunarizine therapy was significantly better than chemotherapy alone in slowing down the blood flow velocity of the anterior, middle, and posterior arteries and reducing the blood fibrinogen in patients with migraine [88].
Network pharmacology studies have also shown that Chuanxiong tea is divided into multiple pathways and multiple targets, quercetin, luteolin, kaempferol and other active ingredients are the main active ingredients, and Chuanxiong tea can regulate the inflammatory response, vasoconstriction, and migraine through phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt), HIF-1, endocrine resistance and other signaling pathways. biological processes such as endocrine-neurotransmitter metabolism [89].
The origin of the name Duliang Pill was first seen in the Song book Baiyi Selected Prescriptions [90], and the Duliang Pill included in the 2020 edition of the Chinese Pharmacopoeia is composed of two flavored medicines, Chuanxiong and Angelica Angelica, which have the functions of dispelling wind and cold, invigorating blood circulation, and treating headaches caused by the evil of wind and cold, the obstruction of Qingyang's qi, and the stagnation of qi and blood [91]. Modern pharmacological studies have shown that this formula has a significant analgesic effect, and previous studies have shown that its mechanism may be related to the regulation of vasoactive substance levels, the content of neurotransmitters such as 5-HT, 5-hydroxyindoleacetic acid (5-HIAA), dopamine, and NE, and the inhibition of the expression of pro-inflammatory factors [92-93]. After the improvement, Duliang pills have been developed in clinical practice, and the common ones are Duliang soft capsules and Duliang dripping pills.
A multicenter, double-blind, randomized controlled clinical study showed that Duliang soft capsules may be an effective and well-tolerated choice for prophylactic treatment in patients with chronic headache [94], and it was also reported that Duliang soft capsules combined with chemotherapy treatment could effectively regulate the expression of serum 5-HT, MMP9, and lysophosphatidic acid in migraine patients and improve prognosis [95]. Han Liyang et al. [96] found that Duliang soft capsules could improve the inhibitory state of cortical EEG in rats with cortical diffusion, reduce the high expression of c-Fos in the cortex on the stimulus side, and down-regulate the expression of central and peripheral vasoactive neuropeptides CGRP and substance P. Zhang et al. [97] observed the effect of Duliang Dripping Pill on the behavior of migraine rats and found that after 60 min of administration, compared with the model group of rats, Duliang Dripping Pill 9, 18, and 36 mg/kg could significantly reduce the number of head scratches in rats, and the mechanism may be related to reducing the levels of nitric oxide, NOS, and CGRP in plasma to alleviate migraine symptoms. In addition, pharmacodynamic experimental studies have found that Duliang soft capsules can play a role in the treatment of migraine by improving vascular permeability and hemodynamics [98].
3.3 川芎-白芍配伍
Chuanxiong-White Paeonia originated from "Seeking Truth in Materia Medica", Chuanxiong is biased towards ascending and dispersing, walking but not keeping, and White Paeonia is a common medicine pair for promoting blood circulation and removing blood stasis. It has been found that the combination of 30 g∶30 g of Chuanxiong-Paeonia alba can inhibit pain sensitization, increase the temperature pain threshold and mechanical pain threshold of migraine model rats, and can also play an anti-migraine effect by regulating the expression of c-Fos, cAMP-response element binding protein (CREB), and p-CREB [100].
At present, the clinical treatment of migraine is mostly done by adding or subtracting the original formula, or combined with chemical drugs and acupuncture, and has achieved good results [101]. Liu Wenyu et al. [102] randomly divided 136 migraine patients into observation group and control group, the control group was treated with Sanbian decoction, and the observation group was treated with acupuncture on the basis of Sanbian decoction, and the results showed that the total effective rate and serum 5-HT level in the observation group were significantly higher than those in the control group, indicating that acupuncture combined with Sanbian decoction had a good effect on migraine patients, and the mechanism may be related to the reduction of serum CGRP, NOS and other vasoactive substance levels, and the increase of serum 5-HT content. Ren Dongdong et al. [103] found that compared with the control group, Jiawei Sanbian decoction was better than the control group in reducing migraine score, VAS score, plasma endothelin level, and increasing plasma CGRP level, with significant efficacy and fewer adverse reactions.
Huang Lin et al. [104] found that 8.91, 17.82, and 35.64 g/kg of Sanbidecoction could reduce the number of head scratches and shorten the time for ear red disappearance in rats, and the effect was more significant in the medium-dose group, which may be related to the reduction of 5-HT metabolism to 5-HIAA in the hypothalamus and the increase of 5-HT content in brain tissue. In addition, it was also found that Jiawei Sanbia decoction could also inhibit the activation of the neurotransmitters NOS1 and CGRP in the nuclear nucleus of the trigeminal nerve tract by reducing the content of nitric oxide, NOS, CGRP, and interleukin-1β (IL-1β) in the plasma of migraine rat model [105], and increase the content of 5-HT in peripheral blood and the expression of foreenkephalin protein in the trigeminal ganglia [106-107] , so as to fight the abnormality of vasoactive substances and neurotransmitters, regulate the disorder of brain and blood vessel function to play a therapeutic role. Network pharmacology studies have found that the potential active ingredients of Sanbian decoction in the treatment of migraine, such as kaempferol, rotonin, and oligocin, can interact with amyloid-β precursors, CC chemokine receptor 5, IL-8 and other genes, and exert therapeutic effects on migraine by regulating signaling pathways such as MAPK, PI3K/Akt, and HIF-1 [108].
3.4 川芎-当归配伍
Angelica is sweet and spicy, not only good at replenishing blood, but also good at invigorating blood and stagnation and relieving pain, "Rihuazi Materia Medica" said: "cure all wind, all blood, make up all labor, break the evil blood, nourish new blood and the main symptom", and the spicy fragrance of the Chuanxiong is compatible, there is a supplement in the line, and it is especially suitable for blood deficiency and cold coagulation headache. Jiang Wei et al. [109] found that the prophylactic administration of Chuanxiong-Angelica sinensis could reduce the consumption of 5-HT in the brain during migraine attacks and play a vasoconstrictive effect, and the effect gradually increased with the increase of the proportion of Chuanxiong sinensis, and the network pharmacological analysis found that there were 11 core gene targets related to the anti-migraine effect in the active ingredients of Chuanxiong-Angelica, involving G protein-coupled receptor signaling pathway, chemical synaptic transmission, inflammatory response and other biological processes, and Ligustrazine, Ligusticum Chuanxiong, ferulic acid, Ligusticone A and so on were important biomarkers[110], in summary, suggests that Chuanxiong-Angelica sinensis can exert anti-migraine effects by modulating multiple targets and pathways.
Chuanxiong Qingnao granules are cut from Qingshang Pain Soup, and the formula is combined with Chuanxiong and Angelica sinensis to promote blood and invigorate blood, regulate the blood stagnation of the head, and make "blood and wind self-extinguish", which is currently widely used in clinical practice. A multicenter randomized controlled double-blind study on the treatment of migraine with Chuanxiongqing Brain Granules [111] found that the treatment group was significantly lower than the control group in terms of pain numerical score and number of headache attacks per month, indicating that Chuanxiongqing Brain Granules can effectively reduce the pain level and reduce the number of attacks in patients with mild to moderate migraine, and the safety is high.
Qin Huibing [112] divided 138 migraine patients into two groups, the control group was treated with flunarizine, and the study group was treated with Chuanxiong Qingnao Granules on the basis of the control group for 4 weeks, and found that the improvement level of endothelin-1, 5-HT, and CGRP content levels in the study group was significantly better than that of the control group, and the meta-analysis also showed that the combination of Chuanxiongqing Brain Granules and chemical drugs was better than that of chemical drugs alone in improving clinical efficacy, improving patients' biochemical detection indicators and symptom scores, and had few adverse reactions [113]. ]。 Network pharmacology studies have shown that there are 139 potential targets for the treatment of migraine, such as IL-6, IL-1β, and tumor necrosis factor-α, as well as neuroactive ligand-receptor interactions, cyclic adenosine monophosphate signaling pathway, HIF-1 signaling pathway, PI3K/Akt signaling pathway, etc., indicating that TCM compound has the characteristics of multi-component and multi-target action and regulatory advantages.
3.5 Miscellaneous
There are many studies on the compatibility of Chuanxiong with other traditional Chinese medicines in the treatment of migraine, such as the combination of Chuanxiong and Xiangfu to form Xiongfu Fang, which can not only alleviate migraine symptoms by regulating the release of monoamine neurotransmitters and vasoactive substances [115], but also slow down the distribution and metabolism of ferulic acid in the body, prolong the action time in vivo, and improve the bioavailability of ferulic acid after decoction of the two drugs [116]. Other anti-migraine prescriptions containing Chuanxiong include Buyang Huanwu Tang, Xuefu Zhuyu Tang, Chuanxiong Tianmasan, etc., but there are relatively few related research reports.
In summary, the combined use of Chuanxiong can make different active ingredients of the drug organically combine and complement each other, and will have different effects on the dissolution of active ingredients, drug absorption, metabolism and other processes, which is worthy of further exploration and research. In general, the current research on Chuanxiong monomer and related prescriptions for anti-migraine mainly focuses on the classic formula, and most of the specific mechanisms and reported experimental detection indicators are related to the common pathogenesis of migraine; Recently, some scholars have used biomics, metabolomics, network pharmacology and other methods to provide more possibilities for revealing the specific mechanism of action of Chuanxiong anti-migraine formula, but it still needs to be further confirmed in experiments and clinics.
4 Conclusion and outlook
The pathogenesis of migraine is complex, and at present, Western medicine mainly focuses on syndrome treatment, and long-term adverse drug reactions are large, which will also lead to the occurrence of drug-induced headache, while traditional Chinese medicine is guided by the overall concept and syndrome differentiation theory [117], which has obvious advantages in the prevention and treatment of migraine. Migraine caused by internal injuries and other factors has significant curative effects, and the adverse reactions are small, which is easy to be accepted by patients, and is more suitable for long-term intervention and treatment of migraine.
In this paper, we summarize the relevant literature reports on the anti-migraine effects of the active ingredients and formulas of Chuanxiong, and find that the research on the anti-migraine active ingredients of Chuanxiong mainly focuses on the monomer components such as ferulic acid, Libenolide, Yangxionglactolide, and Ligustrazine, and there is also some progress in the research of related drug pairs and formulas of Chuanxiong, but there are still the following shortcomings:
(1) The basic research mainly selects the detection and evaluation indicators according to the existing pathogenesis and theories, and the research on the intrinsic mechanism is not deep enough, and the experimental design needs to be strengthened.
(2) Although many new technologies and methods have been applied to the research of Chuanxiong anti-migraine, they are not closely related to the theory of traditional Chinese medicine, and it should be noted that traditional Chinese medicine is the product of practice under the guidance of traditional Chinese medicine theory, if the theory of traditional Chinese medicine [118] can be organically combined with pharmacokinetics and pharmacodynamics, and the targeted components of the treatment of migraine can be further studied by using network pharmacology and supramolecular chemistry methods of traditional Chinese medicine, it will be more conducive to the continuous deepening of research and the emergence of more results.
(3) The activity stability of some monomer active ingredients in Chuanxiong is poor, such as Gaobenlactone, Yangxionglactone A, etc., and the existing technical means cannot achieve effective extraction and utilization, which limits its research and further application.
(4) Whether there is a synergistic effect between different active ingredients in Chuanxiong is rarely reported at present, which is one of the key research directions that should be strengthened in the future.
In the future, we can also conduct in-depth research from the aspects of cells, protein pathways, and transcriptional regulation with the help of network pharmacology and modern omics technology, so as to provide theoretical support and reference for subsequent clinical applications and new drug development.