Research on the Mechanism of Ginger Volatile Oil in Treating Head Wind Disease Based on Network Pharmacology and Molecular Docking Technology
The term ‘Toufeng’ was first recorded in the ‘Shennong Bencao Jing’, which states’ white and fresh, bitter in taste, and cold. It is mainly used for treating Toufeng ‘. According to the “Guidelines for the Treatment of Headaches”, “There are two types of headache in medical books. Headwind is one disease, but there is a distinction between new and old symptoms. Those who are shallow and close are called headache, and the pain is sudden and easy to dissolve quickly. Those who are deep and far away are headache, and the disease does not stop often, and after recovery, it tends to recur.” Modern medicine believes that headache is a disease mainly characterized by chronic paroxysmal headache, equivalent to primary headaches such as migraine, tension headache, and cluster headache in Western medicine. During the interval between onset, the patient behaves like an ordinary person. Once stimulated by a trigger, the headache becomes severe, and the nature of each attack is similar. The course of the disease is long, and it is easy to recur. The global incidence rate of migraine alone is 8.4%~28%, and the lifetime incidence rate is about 14.0%. About 18.2% of women and 6.5% of men suffer from migraine. Migraine’s disability adjusted life years (DALYs) globally increased by 49.5% from 1990 to 2015, making it the second largest DALYs after stroke. Western medicine treatment mainly uses nonsteroidal anti-inflammatory drugs, triptans, opioids, and ergot preparations, but they have significant side effects and are prone to recurrence. Traditional oral Chinese medicine takes a long time to take and cannot immediately relieve symptoms. Acupuncture and moxibustion can dredge the meridians and improve the function of patients’ vascular endothelial cells, but it can only reduce the intensity of pain, reduce the number of attacks, and shorten the duration. It needs to be combined with drugs to achieve better results.

Ginger is the fresh rhizome of Zingiber officinale Rosc., a perennial herbaceous plant in the ginger family. Spicy taste, slightly warm in nature. It has the effects of relieving external coldness, warming the middle, and stopping nausea. Traditional Chinese medicine has long recorded the use of ginger to treat head wind disease. The “Famous Physician Case” states: “A small amount of natural ginger juice is poured into the nose, and the pain stops immediately” to treat stubborn head wind pain. Modern research has shown that ginger volatile oil has analgesic, excitatory, and sedative effects, antioxidant and protective effects against ischemic brain injury, and has a bidirectional regulatory effect of excitatory and inhibitory effects on the central nervous system. Ginger volatile oil has strong solubility and low polarity, while the nasal mucosa is a lipid membrane. Substances with low polarity and strong lipid solubility are easy to pass through. This study intends to make ginger volatile oil into a nasal drug delivery formulation, which can efficiently deliver drugs to brain regions through the “nose brain” pathway and exhibit significant brain targeting effects. Network pharmacology methods will be applied to analyze the relationship between ginger volatile oil, head wind disease, and targets, and construct a multi-level network relationship between “compound target pathway disease” to explore the mechanism of action of ginger volatile oil in treating head wind disease, providing a certain basis for later formulation research.

Traditional Chinese Medicine believes that head wind disease is caused by both internal and external factors, and it is difficult to summarize it with a single pathogenesis in clinical practice. It is caused by a combination of wind, blood stasis, cold, phlegm, and deficiency. The “Treatise on the Origins of Various Diseases” states that “those with wind on their heads and faces are weak in their bodies, and the meridians of the yang are carried by the wind. Wind pathogen is the main pathogenic factor, closely related to the onset and recurrence of head wind disease. Wu et al. compiled ancient medical treatises and literature on the treatment of headaches from the Qin and Han dynasties to the late Qing dynasty in 1911. The highest frequency of use was found in the use of topical and pungent medicines, with ginger being the fifth most commonly used among all medicines.

This study used network pharmacology to screen the main active ingredients and targets of ginger volatile oil, and intersected them with the targets of head wind disease. A chemical composition intersection target information network of ginger volatile oil was established to study the treatment of head wind disease with ginger volatile oil. Research has shown that the main active substances of ginger volatile oil in the treatment of head wind disease are ethyl acetate, synthetic dextro borneol, α – terpineol, eudesma-4,6-diene, orange blossom tertiary alcohol, citral, carbene, and β – eucalyptol. 62 key targets that may play an important role in the treatment of head wind disease with ginger volatile oil, including APP, OPRM1, ADRA2A, ADRA2C, HTR1A, DRD2, DRD4, DRD3, ADRA2B, OPRK1, were screened through PPI network analysis, as well as 642 protein interaction relationships between head wind disease targets.

To further explore the potential mechanism of ginger volatile oil in treating head wind disease, GO and KEGG enrichment analyses were conducted using the intersection targets of active ingredients in ginger volatile oil and head wind disease. A total of 1361 enrichment items were obtained from G0 enrichment analysis, including G protein coupled receptor signaling pathways coupled with cyclic nucleotide second messengers in biological processes, vascular diameter regulation, and vascular processes in the circulatory system; The postsynaptic membrane, synaptic membrane, and components of the postsynaptic membrane in cellular components; The activity of G protein coupled amine receptors, neurotransmitter receptors, G protein coupled neurotransmitter receptors, and 5-hydroxytryptamine receptors in molecular functions. KEGG enrichment analysis identified 77 enrichment items, including the neuroactive ligand receptor interaction pathway, Ca2+signaling pathway, and serotonin containing synaptic pathway. The occurrence of head wind disease is related to various neurotransmitters and receptors. It is a paroxysmal neurological disease that can exert analgesic effects by regulating the neuroactive ligand receptor interaction pathway. Literature studies have shown that migraine is closely related to the Ca2+signaling pathway, and inhibitory synapses play a key role in regulating pain signal transduction and modulation circuits in migraine production. P/Q-type Ca2+channels are typically crucial for presynaptic Ca2+entry and neurotransmitter release in many central synapses, and can inhibit or excite neurotransmission. Synapses containing serotonin, also known as the 5-HT neural pathway, are associated with controlling eating behavior, regulating body temperature, and sleep. Migraine patients experience a decrease in 5-HT receptor binding rate and an increase in 5-HT levels in the brain. Many anti migraine drugs interact with 5-HT and its receptors to exert therapeutic effects. The enrichment analysis results showed that ginger volatile oil may exert analgesic therapeutic effects by regulating key target proteins, participating in neuroactive ligand receptor interactions, Ca2+signaling pathways, and serotonin containing synaptic pathways.

To further illustrate the binding activity between the protein and its corresponding ligand compounds, based on literature reports, three core targets OPRM1, ADRA2A, and DRD2 were selected from the targets with high PPI network values in the treatment of head wind disease with ginger volatile oil. Three positive drugs related to the protein, morphine, bromomonidine, and apomorphine, were identified in Drugbank, and the ligand was the corresponding compound of the protein. Using Discovery Studio 4.0, molecular docking was performed on the protein, ligand, and positive drug. The results showed that the binding activity fraction of the protein to the ligand was higher than that to the positive drug, indicating a higher binding activity between the protein and ligand. Among the core targets, OPRM1 gene is the encoding gene for μ – opioid receptors, which play an important regulatory role in the body’s pain sensitivity and endogenous analgesia functions, especially in regulating the nervous system to produce analgesic effects. ADRA2A belongs to G protein coupled receptors and exists in noradrenergic neurons, stimulating and inhibiting postsynaptic central nervous system signaling pathways. The activation of ADRA2A receptors produces selective cerebral vasoconstriction. DRD2 is mainly located in the brain and is the main target of dopaminergic neurons in the substantia nigra striatum. During migraine attacks, there is a decrease and fluctuation in endogenous dopamine release. The polymorphism of DRD2 gene is significantly associated with the risk of migraine in Chinese Han women. Migraine patients have higher plasma DRD2 levels, and female migraine patients have significantly higher DRD2 levels than male migraine patients.

This study applied network pharmacology to confirm the effect of ginger volatile oil in treating head wind disease, predicted the potential targets of ginger volatile oil in treating head wind disease, as well as the signaling pathways and biological processes related to the treatment of head wind disease. It revealed that the treatment of head wind disease with ginger volatile oil is the result of multi-component, multi-target, and multi pathway effects. This study provides a theoretical basis and experimental verification for the mechanism of action of ginger volatile oil in treating head wind disease, in order to provide reference for later formulation research, drug development, and clinical application.