GPR84 receptor antagonist and resveratrol composition and application thereof to treatment of migraine

Abstract

The invention belongs to the field of medicines, and particularly relates to a composition of a GPR84 antagonist and resveratrol and application of the composition in the field of treatment of nervous system diseases, especially neuropathic pain or migraine.

Description

Technical Field

[0001] The present invention belongs to the field of medicine, and specifically relates to a composition of a GPR84 antagonist and resveratrol and its application in the treatment of nervous system diseases, especially neuropathic pain or migraine. Background Art

[0002] Migraine is usually manifested as self-limited, recurrent severe headaches associated with autonomic symptoms. Sensitization of the trigeminal nerve pathway is a key pathophysiological phenomenon of migraine. Neuroinflammation is considered to be an adaptive response triggered by harmful stimuli such as infection, injury, and tissue stress. It is not only a key link in the pathophysiological development of various diseases of the central nervous system, but also a key link in the pathophysiological development of migraine. Various cytokines, including tumor necrosis factor TNF, interleukin IL-1, and adiponectin, are related to inflammation, pain threshold regulation, trigeminal nerve fiber sensitization, and ultimately the precipitation of migraine ([J]. The journal of headache and pain, 2021, 22(1): 55.). The trigeminovascular theory and the cortical spreading inhibition theory believe that changes in the levels of vasoactive substances such as nitric oxide (NO), 5-hydroxytryptamine (5-HT), and endothelin-1 (ET-1) and abnormal secretion of neurotransmitters such as calcitonin gene-related peptide (CGRP) and substance P play an important role in the occurrence of migraine.

[0003] Resveratrol (structure shown below) is a non-flavonoid phenolic substance with both cis and trans structures. It is a phytoalexin belonging to the stilbene class of compounds, an antioxidant, and has vasoactive properties. Some studies have shown that migraine patients generally have poor cerebrovascular function. Resveratrol may affect cerebrovascular function by acting on estrogen receptors ERα and Erβ, and may also increase brain perfusion by increasing the production and bioavailability of nitric oxide, thereby regulating vascular function. In addition, because oxidative stress is a trigger for neurogenic inflammation, which is a key process in the pathophysiology of migraine, resveratrol as an antioxidant is believed to help prevent migraine. Although resveratrol has a certain mechanistic possibility in preventing migraine attacks, a larger-scale placebo-controlled, double-blind clinical study of resveratrol for the prevention of migraine showed that there was no significant difference between resveratrol and placebo treatment in the primary endpoints, such as the Hormone Migraine Burden Index HMBI (p=0.895) and the secondary endpoint Visual Analog Scale VAS (p=0.922) compared with the placebo group ([J]. Nutrients, 2022, 14(9):1763.).

[0004] Resveratrol mainly exists in the trans form, which is relatively stable and has strong physiological activity. Under light conditions, trans-resveratrol will be converted to cis-resveratrol, and its activity will be greatly reduced. It has been reported that strong light exposure for 1 hour can convert 80% to 90% of trans-resveratrol into cis-resveratrol. It generally needs to be stored away from light.

[0005]

[0006] GPR84 (G protein-coupled receptor 84) is a rhodopsin-like class A G protein-coupled receptor. The expression of GPR84 is significantly upregulated after acute inflammatory stimulation and in inflammatory diseases, and receptor activation plays a role in regulating proinflammatory responses and the migration of innate immune system cells (such as neutrophils, monocytes, macrophages, and microglia). In immune cells, GPR84 promotes the expression of proinflammatory mediators and stimulates chemotaxis. The expression of GPR84 is also often upregulated by acute inflammatory response stimulation, such as LPS, TLR4, and TNF-α. ([J]. British Journal of Pharmacology, 2024, 181(10): 1500-1508.). Based on this, the research on GPR84 antagonists has gradually become popular, but the research directions of GPR84 antagonists under development are mainly focused on autoimmune diseases and fibrotic diseases, such as multiple sclerosis, idiopathic pulmonary fibrosis, and liver cirrhosis. There are few studies on its mechanism of action in migraine and whether it has drug value. Summary of the invention

[0007] Based on the deficiencies in the prior art, the present invention aims to provide a pharmaceutical composition of a GPR84 antagonist and resveratrol to regulate migraine-related neuroimmune pathways, reduce the release of related inflammatory factors and oxidative stress responses, inhibit the sensitization of the trigeminal nerve pathway, and thereby provide a new drug therapy for preventing and / or treating migraine.

[0008] The present invention includes the following technical solutions:

[0009] The invention discloses a pharmaceutical composition comprising a GPR84 antagonist and resveratrol.

[0010] In a preferred embodiment of the present invention, the GPR84 antagonist is selected from any one of GLPG-2196, fezagepras, GLPG-1205, LMNL-6511, PBI-4425, BAY-3178275, BGT-004, HY-112562, HY-151100 and HY-161682.

[0011] Further, in a preferred embodiment of the present invention, the GPR84 antagonist is selected from the compounds in Table 1 below:

[0012] Table 1 GPR84 antagonists

[0013]

[0014] Furthermore, the present invention provides a use of a pharmaceutical composition of a GPR84 antagonist and resveratrol in treating and / or preventing migraine, wherein the resveratrol is one of cis-resveratrol, trans-resveratrol or a mixture of the two as shown below.

[0015]

[0016] In a preferred embodiment of the present invention, the resveratrol is preferably trans-resveratrol.

[0017] In a preferred embodiment of the present invention, the GPR84 antagonist is any one of GLPG1205, HY-112562, HY-151100 and HY-161682, preferably any one of GLPG1205, HY-151100 and HY-161682.

[0018] In a preferred embodiment of the present invention, the GPR84 antagonist is selected from any one of HY-151100 and HY-161682.

[0019] In a preferred embodiment of the present invention, the GPR84 antagonist is HY-151100.

[0020] In a preferred embodiment of the present invention, the molar ratio of the GPR84 antagonist to trans-resveratrol is in the range of 1:1-1:10, or the mass ratio of the GPR84 antagonist to trans-resveratrol is in the range of 1:5-1:15.

[0021] In another preferred embodiment of the present invention, the molar ratio of the GPR84 antagonist to trans-resveratrol is in the range of 1:3-1:10, preferably 1:4-1:7, and more preferably 1:6; the mass ratio of the GPR84 antagonist to trans-resveratrol is in the range of 1:5-1:15, preferably 1:7-1:12, and more preferably 1:10.

[0022] In a specific embodiment of the present invention, the molar ratio of the GPR84 antagonist to trans-resveratrol is 1:6; the mass ratio of the GPR84 antagonist to trans-resveratrol is 1:10.

[0023] The present invention provides a use of a pharmaceutical composition of a GPR84 antagonist and trans-resveratrol in treating and / or preventing a nervous system disease. Preferably, the nervous system disease is any one of neuropathic pain and migraine.

[0024] In one embodiment of the present invention, the neuropathic pain is selected from any one of trigeminal neuralgia, neuralgia caused by herpes zoster, diabetic peripheral neuropathy, sphenopalatine ganglion pain, occipital neuralgia, intercostal neuralgia, cervical-shoulder-brachial neuralgia, sciatica and causalgia.

[0025] In a preferred embodiment of the present invention, the neuropathic pain is preferably any one of trigeminal neuralgia, herpes zoster-induced neuralgia and diabetic peripheral neuropathy.

[0026] In one embodiment of the present invention, the migraine is selected from any one of migraine without aura, migraine with aura, chronic migraine, migraine with brainstem aura, hemiplegic migraine and retinal migraine.

[0027] In a preferred embodiment of the present invention, the migraine is preferably any one of migraine without aura, migraine with aura and chronic migraine.

[0028] The present invention provides use of a GPR84 antagonist combined with trans-resveratrol in preparing a pharmaceutical composition for treating and / or alleviating a nervous system disease, wherein the mass ratio of the GPR84 antagonist to trans-resveratrol is in the range of 1:7-1:12, and the nervous system disease is selected from neuropathic pain or migraine, preferably migraine.

[0029] In a preferred embodiment of the present invention, the mass ratio of the GPR84 antagonist to trans-resveratrol is 1:10, the GPR84 antagonist is any one of HY-151100 or HY-161682, more preferably HY-151100; the migraine is any one of migraine without aura, migraine with aura and chronic migraine.

[0030] In a specific embodiment of the present invention, the pharmaceutically acceptable salt of HY-151100 is selected from hydrochloride, hydrobromide, phosphate, sulfate, acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, benzenesulfonate, benzoate, bisulfate, preferably hydrochloride.

[0031] In one embodiment of the present invention, the pharmaceutical composition can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers. Therefore, the active compound of the present invention can be formulated into a dosage form for oral, buccal, intranasal, parenteral (e.g., intravenous, intramuscular or subcutaneous) or rectal administration, or a dosage form suitable for administration by inhalation or insufflation. The compound of the present invention or its pharmaceutically acceptable salt can also be formulated into a sustained release dosage form.

[0032] In one embodiment of the present invention, an effective dose of the compound of the present invention or a pharmaceutically acceptable salt thereof can be taken orally with an inert diluent or a carrier. According to some embodiments of the present invention, the compound of the present invention can be encapsulated in a gelatin capsule or compressed into tablets. For the purpose of oral treatment, the compound of the present invention can be used together with an excipient and in the form of tablets, lozenges, capsules, suspensions, syrups, etc. According to an embodiment of the present invention, the above-mentioned preparation should contain at least 0.5% (w / w) of the active compound of the present invention, but can be changed according to a specific dosage form, wherein 4% to about 70% of the unit weight is convenient. The amount of the active compound in such a pharmaceutical composition should reach an appropriate dose.

[0033] In one embodiment of the present invention, for oral administration, the active compound of the present invention can be formulated into tablets or capsules by conventional means with pharmaceutically acceptable excipients, such as adhesives, fillers, lubricants, disintegrants or wetting agents. Tablets can be coated by methods well known in the art. Liquid preparations for oral administration can be, for example, solutions, syrups or suspensions, or evaporated to dry products, and regenerated with water or other suitable carriers before use. Such liquid preparations can be prepared by conventional means using pharmaceutical additives, such as suspending agents, emulsifiers, non-aqueous carriers and preservatives.

[0034] In one embodiment of the present invention, when the active compound of the present invention is used for parenteral administration, the compound provided by the present invention can be combined with sterile water or organic media to form an injectable solution or suspension.

[0035] In one embodiment of the invention, the active compounds of the invention may be formulated in rectal compositions such as suppositories or retention enemas, eg, containing conventional suppository bases such as cocoa butter or other glycerides.

[0036] The present invention also provides a use of a pharmaceutical composition of a GPR84 antagonist and resveratrol in the preparation of a drug for treating and / or alleviating migraine, wherein the drug optionally contains one or more other active agents for regulating migraine in mammals, including but not limited to non-steroidal analgesics, such as acetaminophen, naproxen, ibuprofen, diclofenac, meloxicam, etc.; 5-HT1b / 1d / 1f regulators, such as sumatriptan, zolmitriptan, rizatriptan, naratriptan, fluvatriptan; anticonvulsants, such as carbamazepine, phenytoin sodium, etc.; calcium channel blockers, such as flunarizine, nimodipine, etc.; CGRP antagonists, such as remigipam, ganatriptan, and efezolizumab, etc.

[0037] Compared with the prior art, the present invention has the following outstanding beneficial effects:

[0038] The present invention provides a pharmaceutical composition of a GPR84 antagonist and trans-resveratrol for treating and / or preventing nervous system diseases, particularly migraine. Through photostability studies, it was found that GPR84 antagonists, particularly GLPG1205 and HY-151100, can significantly improve the photostability of trans-resveratrol, reduce the risk of changes in drug properties under non-harsh storage environments (non-light-proof conditions), and reduce the possibility of affecting drug efficacy, thereby ensuring the stability and reliability of drug quality.

[0039] In addition, it was found that GPR84 antagonists can help increase the serum exposure of trans-resveratrol and help improve the therapeutic effect of trans-resveratrol. In addition, in the nitroglycerin-induced migraine model of rats, it was found that the GPR84 antagonist (especially HY-151100) combined with trans-resveratrol group, compared with the single-dose groups, not only could significantly reduce the rats' head scratching behavior, but also the blood sample test results showed that the combined administration group could significantly improve the levels of NO, CGRP and ET-1. The above studies have revealed that the combination of GPR84 antagonists and trans-resveratrol has a more obvious clinical application prospect in the treatment of neurological diseases, especially migraine. DETAILED DESCRIPTION

[0040] The technical solutions in the embodiments of the present invention are described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0041] The term "comprising" is an open expression, that is, including the contents specified in the present invention, but not excluding other aspects. It should be understood that the term "comprising" can include a closed meaning, that is, "consisting of...".

[0042] The term "neurological diseases" refers to a small class of medical conditions that affect the nervous system, including central nervous system diseases and peripheral nervous system diseases. Preferred nervous system diseases of the present invention include, but are not limited to, pain (e.g., neuropathic pain, migraine, cancer pain, inflammatory pain, perioperative pain, muscle pain, etc.), psychiatric diseases (e.g., depression, schizophrenia, bipolar disorder, anxiety, etc.), neurodegenerative diseases (e.g., Parkinson's disease, Alzheimer's disease, epilepsy, amyotrophic lateral sclerosis, multiple sclerosis, etc.), preferably pain.

[0043] In addition, it should be noted that, unless explicitly stated otherwise, the description method of "respectively and independently" used in the present invention should be understood in a broad sense, which can mean that in different groups, the specific options expressed by the same symbols do not affect each other, or that in the same group, the specific options expressed by the same symbols do not affect each other.

[0044] The GPR84 antagonists GLPG1205, Fezagepras, HY-112562, HY-151100 and HY-161682 used in the present invention were purchased from Medchemexpress China, and cis- and trans-resveratrol were purchased from Shanghai Huayuan Century Trading Co., Ltd. Rat NO, CGRP, and ET-1 detection kits (Nanjing Jiancheng Bioengineering Institute, batch numbers: 20220908, 20220929, and 20220929.

[0045] Example 1

[0046] Effects of GPR84 antagonists on the photostability of trans-resveratrol.

[0047] (I) Configuration of each test product

[0048] According to the molar ratio of 1:6 between the GPR84 antagonist and trans-resveratrol in each test, the GPR84 antagonists GLPG1205, Fezagepras, HY-112562, HY-151100, HY-161682, and trans-resveratrol were accurately weighed, and ultrasonically dissolved in anhydrous methanol to prepare test sample stock solutions. The GLPG1205+trans-resveratrol group was named A-1, the Fezagepras+trans-resveratrol group was named A-2, the HY-112562+trans-resveratrol group was named A-3, the HY-151100+trans-resveratrol group was named A-4, the HY-161682+trans-resveratrol group was named A-5, and the trans-resveratrol group alone was A-0.

[0049] Accurately measure the sample stock solution of each group, convert the mass to 10 mg, and adjust the volume to a 10 mL volumetric flask, filter through a 0.45 μm filter membrane, and take the filtrate for use. Then dilute 100 times to obtain a sample solution with a mass concentration of 10 μg / mL; take the newly prepared 10 μg / mL sample solution and place it in a 100 mL volumetric flask. After irradiating with a sterilizing ultraviolet lamp for 2 hours, the sample is subjected to HPLC analysis to detect the remaining trans-resveratrol content in each sample group.

[0050] (II) Chromatographic conditions

[0051] Chromatographic column: HITACHI LaChrom C18 (5μm) 4.6mm×150mm

[0052] Mobile phase: (A) 0.1% H3PO4 (pH 2.2); (B) CH3CN

[0053] Gradient: (0 min) B 10% → (10 min) B 10% → (30 min) B 70% → (40 min) B70% → (40.1 min) B 10% → (55 min) B 10%

[0054] Flow rate: 1.0mL / min

[0055] Column temperature: 40°C

[0056] Detection wavelength: DAD 303nm

[0057] Injection volume: 10 μL

[0058] (III) Content calculation method (self-control method)

[0059] (1) The correction factor (Rf) is calculated as follows:

[0060] Rf = reference substance concentration / reference substance peak area

[0061] Wherein, the Rf is the Rf of trans-resveratrol

[0062] (2) The calculation formula for the content of the component to be tested is as follows:

[0063] Content (%) = (Rf*W*test sample dilution multiple) / test sample weighed amount*100%

[0064] W is the main peak area of ​​the component to be detected in the test solution

[0065] (IV) Test results and analysis

[0066] After the sample groups were irradiated with ultraviolet light, the remaining trans-resveratrol content was shown in Table 2 below.

[0067] Table 2 Remaining trans-resveratrol content in each sample group (%)

[0068]

[0069] As can be seen from the above table, the residual content of trans-resveratrol in group A-1 (GLPG1205+trans-resveratrol) and group A-4 (HY-151100+trans-resveratrol) was significantly higher than that in other groups A-2, A-3 and A-5, especially the residual content of trans-resveratrol in group A-4 was the highest, indicating that GLPG1205 and HY-151100, especially HY-151100, have a significant effect on improving the photostability of trans-resveratrol.

[0070] Example 2

[0071] Effects of GPR84 antagonists on increasing trans-resveratrol exposure (AUC0-inf) in mice

[0072] A standardized LC / MS assay was used to determine the effect of co-administration of a GPR84 antagonist with trans-resveratrol on increasing trans-resveratrol exposure in the serum of C57BL mice.

[0073] (I) Preparation and administration of drugs in each test group

[0074] According to the mass ratio of GPR84 antagonist to trans-resveratrol of 1:10 in each test group, the test groups were configured as B-1 group (GLPG1205 + trans-resveratrol), B-2 group (Fezagepras + trans-resveratrol), B-3 group (HY-112562 + trans-resveratrol), B-4 group (HY-151100 + trans-resveratrol), B-5 ​​group (HY-161682 + trans-resveratrol), and control group B-0 (trans-resveratrol); the dose of each combined administration group was 110 mg / kg (100 mg / kg trans-resveratrol + 10 mg / kg GPR84 antagonist), and the dose of the control group was 100 mg / kg trans-resveratrol. 48 C57BL / 6J mice were housed in plastic cages under standard conditions and given ad libitum access to standard food and water. The light intensity was maintained at 12 h / 12 ​​h.

[0075] Dark cycle, dosing according to body weight. 48 mice were randomly assigned to the control group and each test group, 8 mice in each group, and oral gavage was used for administration. Mice (non-fasting) received a single dose of trans-resveratrol (100 mg / kg); the other 40 mice were randomly assigned (non-fasting) to groups B1-B5 and received a single dose of trans-resveratrol + GPR84 antagonist (110 mg / kg).

[0076] (II) LC / MS conditions

[0077] Standards were initially dissolved in 100% ethanol at >1 mg / mL. All samples were protected from light as much as possible during preparation and handling. Preparation of calibration curves: Internal standards and standards were further diluted in 65% methanol and then added to the samples. A 7-point calibration curve was prepared for resveratrol (10, 33.3, 100.0, 333, 1000, 3333, and 10000 ng / mL) and processed simultaneously with the serum samples.

[0078] Chromatographic column: ACQUITY UPLC BEH C18, 2.1 mm × 50 mm

[0079] Mobile phase: (A) water / 1 mm ammonium bicarbonate / 2% isopropanol (pH 7.5); (B) CH3CN / 2% isopropanol

[0080] Test method: The sample (10 μL) was injected into the column equilibrated at 5% B and maintained at 35°C. After 0.5 min at 5% B, the compound was eluted with a linear gradient to 55% B in 6.5 min, and then the column was washed by increasing B to 95% in 0.5 min, maintained at 95% B for 1.5 minutes, and then the column was re-equilibrated at 5% B for 1.5 min before the next injection. After adding 0.1% ammonium hydroxide after the column, the compounds eluted from the column were analyzed in negative ion mode using an Amazon ion trap mass spectrometer. Between samples, 35% ACN was injected as a blank to ensure that sample carryover would not affect the results.

[0081] (III) Test results and analysis

[0082] By plotting the relative peak area ratio (analyte / internal standard) versus the concentration of trans-resveratrol, a calibration curve of trans-resveratrol was drawn. The R value of the calibration curve of trans-resveratrol was 0.999782.

[0083] The pharmacokinetic parameter contents of trans-resveratrol in each combined administration group and the trans-resveratrol in the control group are shown in Table 3 below.

[0084] Table 3 Pharmacokinetic parameters of trans-resveratrol in each combined drug group and control group

[0085]

[0086] The above results show that the B-4 group (HY-151100 + trans-resveratrol) and the B-5 group (HY-161682 + trans-resveratrol) can significantly increase the exposure of trans-resveratrol compared with the control group B-0 and the combined administration group, especially HY-151100. Compared with the control group B-0, the exposure of trans-resveratrol increased by 5 times, and it has the potential to significantly enhance the pharmacological effect of trans-resveratrol at the same dose.

[0087] Example 3

[0088] Therapeutic effects of GPR84 antagonist combined with trans-resveratrol on migraine rat model

[0089] (I) Animal grouping and drug administration method

[0090] 72 SD rats were randomly divided into blank group, model group, GPR84 antagonist + trans-resveratrol combined administration group, GPR84 antagonist single administration group, trans-resveratrol single administration group, each group had 6 animals. The GPR84 antagonist + trans-resveratrol combined administration groups were GLPG1205 + trans-resveratrol group (C-1), Fezagepras + trans-resveratrol group (C-2), HY-112562 + trans-resveratrol group (C-3), HY-151100 + trans-resveratrol group (C-4), HY-161682 + trans-resveratrol group (C-5), where the dosage of each GPR84 antagonist was 10 mg / kg, trans-resveratrol was 10 mg / kg, and trans-resveratrol was 10 mg / kg. The dosage of resveratrol was 100 mg / kg; the dosage of each GPR84 antagonist alone group was GLPG1205 group (C-d1), Fezagepras group (C-d2), HY-112562 group (C-d3), HY-151100 group (C-d4), HY-161682 group (C-d5), and the dosage of each group was 10 mg / kg; the dosage of trans-resveratrol alone group (C-0) was 100 mg / kg. Each GPR84 antagonist + trans-resveratrol combined administration group, each GPR84 antagonist alone administration group, and trans-resveratrol alone administration group were intragastrically administered once a day for 7 consecutive days, and the model group and the blank group were given normal saline converted by volume.

[0091] 30 minutes after the last administration of each group, the body weight of SD rats was weighed, the neck skin of the rats was disinfected with iodine disinfectant, the neck skin was pinched, and nitroglycerin injection (10 mg / kg) was slowly injected in the head to tail direction to prepare the migraine model. The blank group was injected with an equal amount of normal saline in the same way.

[0092] Behavioral observation (number of head scratching): 5 minutes after the injection of nitroglycerin injection, the rats' ears turned red and they frequently scratched their heads with their forelimbs, indicating that the model was successfully prepared. The number of head scratching with the forelimbs was recorded as an indicator, and the number of head scratching with the forelimbs was recorded in the time periods of 0-30, 30-60, 60-90, and 90-120 minutes.

[0093] Detection of vasoactive substances NO (nitric oxide), CGRP (neurotransmitter calcitonin gene-related peptide), and ET-1 (endothelin-1): 4 hours after modeling, 4% chloral hydrate was injected intraperitoneally at 1 mL / 100 g for anesthesia, and an appropriate amount of orbital blood was placed in a vacuum blood collection tube containing a coagulant, centrifuged at 3 000 r / min for 20 minutes, and the supernatant was collected and stored in a -20°C refrigerator for later use. The contents of NO, ET-1, and CGRP in rat serum were detected strictly according to the instructions of the enzyme-linked immunosorbent assay (ELISA) kit.

[0094] (II) Test results and analysis

[0095] The results of the migraine model test in the blank group, model group and each drug-treated group are shown in Table 4 below. The changes in the levels of NO, CGRP and ET-1 in the blood of the blank group, model group and each drug-treated group are shown in Table 5.

[0096] Table 4 Comparison of head scratching times in each group at different time periods (Mean±SD, n=6)

[0097]

[0098]

[0099] Table 5 Comparison of NO, CGRP, and ET-1 levels in each group (Mean±SD, n=6)

[0100]

[0101] Compared with the blank group, the P values ​​of the model group were ▼ <0.05, ▼▼ <0.01, ▼▼▼ <0.001, with statistically significant differences; compared with the model group, the P values ​​of each drug-treated group were * <0.05, ** <0.01, *** <0.001, which is a statistically significant difference.

[0102] From the results in Table 4, it can be seen that the number of head scratching of rats in the model group in the four time periods of 0-30min, 30-60min, 60-90min and 90-120min was significantly higher than that in the blank group, indicating that the migraine model was successfully established; after the last administration of each medication group, different pharmacodynamic effects on the migraine model induced by nitroglycerin were shown, among which the trans-resveratrol alone administration group had no preventive effect on migraine; and the GPR84 antagonist alone administration group also showed that the preventive effect on migraine was quite weak, and only C-d4 (HY-151100) had a preventive effect at 60-90min; indicating that whether it is trans-resveratrol or GPR84 antagonist, the preventive effect on migraine when administered alone is very weak.

[0103] For the groups of GPR84 antagonist combined with trans-resveratrol, it was found that group C-1 (GLPG1205 + trans-resveratrol), group C-3 (HY-112562 + trans-resveratrol), group C-4 (HY-151100 + trans-resveratrol) and group C-5 (HY-161682 + trans-resveratrol) all had different degrees of preventive effects on migraine; especially group C-4, compared with other combination groups, had a more significant preventive effect on nitroglycerin-induced migraine. Compared with the model group, the preventive effect in each time period reached P value <0.01 or <0.001. In summary, GPR84 antagonist combined with trans-resveratrol showed obvious clinical application prospects for the prevention or treatment of migraine.

[0104] In addition, the contents of NO, CGRP and ET-1 in the blood were tested. From the results in Table 5, it can be seen that although trans-resveratrol has a tendency to reduce and increase CGRP and ET-1, respectively, there is no significant difference. The other C-d1 group (GLPG1205) and C-d3 group (HY-112562) had no improvement effect on blood indicators; C-d4 group (HY-151100) and C-d5 group (HY-161682) only had a reducing effect on NO; the combined drug administration groups C-1, C-4 and C-5 groups had a more significant improvement effect on NO compared with their respective single drug administration groups, but only the C-4 group (HY-151100 + trans-resveratrol) had an improvement effect on NO, CGRP and ET-1, and the P values ​​compared with the model group were all <0.05 to <0.001, which were significantly different, indicating that the combination of GPR84 antagonists and trans-resveratrol (especially HY-151100 + trans-resveratrol) has a significant effect on improving migraine-related neuritis.

[0105] The above are only a few preferred embodiments of the present invention, which are described in a more specific and detailed manner, but they cannot be understood as limiting the scope of the present invention. It should be pointed out that for ordinary technicians in this field, several modifications and improvements can be made without departing from the concept of the present invention, which all belong to the protection scope of the present invention.

Claims

1. A pharmaceutical composition, characterized in that Contains a GPR84 antagonist and resveratrol.

2. The pharmaceutical composition according to claim 1, characterized in that The GPR84 antagonist is selected from any one of GLPG-2196, fezagepras, GLPG-1205, LMNL-6511, PBI-4425, BAY-3178275, BGT-004, HY-112562, HY-151100 and HY-161682; The resveratrol is selected from cis-resveratrol, trans-resveratrol or a mixture thereof.

3. The pharmaceutical composition according to claim 1, wherein the molar ratio of the GPR84 antagonist to resveratrol is in the range of 1:1-1:10, preferably 1:3-1:10, and further preferably 1:

6. 4 . The pharmaceutical composition according to claim 1 , wherein the GPR84 antagonist is HY-151100 or a pharmaceutically acceptable salt thereof, and the resveratrol is trans-resveratrol.

5. Use of GPR84 antagonists in improving the photostability of trans-resveratrol.

6. Use of a GPR84 antagonist in the preparation of a drug for increasing the serum exposure of trans-resveratrol.

7. Use of the pharmaceutical composition according to any one of claims 1 to 4 in the preparation of drugs for treating and / or preventing nervous system diseases.

8. The use according to claim 7, characterized in that The nervous system disease is any one of neuropathic pain and migraine.

9. The use according to claim 8, characterized in that The neuropathic pain is selected from any one of trigeminal neuralgia, neuralgia caused by herpes zoster and diabetic peripheral neuropathy; the migraine is selected from any one of migraine without aura, migraine with aura and chronic migraine.

10. The use according to claim 7, characterized in that The medicament is formulated for oral, buccal, intranasal, parenteral or rectal administration, or in a form suitable for administration by inhalation or insufflation, or in a sustained release form.

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