CN114699531A - Application of polyphenol compounds in preventing and treating cerebral edema - Google Patents
Application of polyphenol compounds in preventing and treating cerebral edema Download PDFInfo
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- CN114699531A CN114699531A CN202210370136.6A CN202210370136A CN114699531A CN 114699531 A CN114699531 A CN 114699531A CN 202210370136 A CN202210370136 A CN 202210370136A CN 114699531 A CN114699531 A CN 114699531A
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- China
- Prior art keywords
- procyanidin
- cerebral edema
- pharmaceutically acceptable
- catechin
- polyphenol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
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Abstract
The invention discloses an application of a polyphenol compound, in particular to an application of the polyphenol compound in preparing a medicament for preventing and treating cerebral edema. The polyphenolic compounds of the present invention are particularly those related to procyanidins, such as procyanidin B3. In the invention, procyanidine B is found in an in vitro glucose oxygen deprivation induced astrocyte damage model1Procyanidin B2Procyanidin B3And procyanidin B4Can obviously reduce the expression of aquaporin AQP4 after being administrated. Procyanidin B in a mouse acute cerebral edema model induced by hypoxia in vivo3Can be obviously taken after administrationReduce the water content of the brain of the mouse and down-regulate the expression of aquaporin AQP 4. Procyanidine B found by brain magnetic resonance imaging scanning in vivo cynomolgus monkey cerebral apoplexy model3The administration group significantly reduced the volume of cerebral edema compared to the model group.
Description
Technical Field
The invention belongs to the field of biological medicines, and particularly relates to application of polyphenol compounds in preventing and treating cerebral edema, in particular to application of the polyphenol compounds in preparing medicines for preventing and treating cerebral edema caused by high altitude low pressure hypoxia and cerebral edema caused by cerebral apoplexy.
Background
Encephaledema is a series of serious pathological changes such as brain volume increase, intracranial pressure increase, cerebral perfusion pressure and cerebral blood flow decrease and the like, even cerebral hernia is generated to endanger life, because various internal and external factors act on brain tissues to cause excessive effusion in brain cells or interstitial spaces. Common causes of cerebral edema include cerebrovascular diseases, craniocerebral trauma, cerebral apoplexy, brain tumors, and diseases affecting blood and oxygen supply to the brain, such as sudden cardiac arrest, fulminant hepatic failure, high altitude, carbon monoxide poisoning, etc. Cerebral edema is largely divided into 4 types: vasogenic cerebral edema, cytotoxic cerebral edema, interstitial cerebral edema, and osmotic cerebral edema.
Drug treatment of cerebral edema includes: 1) dehydration treatment, rapid reduction of intracranial pressure, prevention of cerebral hernia, commonly used drugs: mannitol, hypertonic saline, furosemide; 2) sedative therapy, rapid sedation and prevention of patient accidents, the common medicines: propofol, fentanyl; 3) hormone therapy, improving brain cell function and alleviating cerebral edema, commonly used drugs: dexamethasone. There is no specific medicine for high altitude cerebral edema, besides increasing oxygen uptake, dexamethasone, high glucose, acetazolamide, furosemide and the like are also given. However, no drug specifically for the treatment of cerebral edema has been marketed so far.
Disclosure of Invention
The invention aims to solve the technical problem that the prior art is lack of effective prevention and treatment of cerebral edema, and provides application of a polyphenol compound, in particular application of the polyphenol compound in preparation of medicines for preventing and treating cerebral edema caused by low-pressure hypoxia and cerebral edema caused by cerebral apoplexy, especially medicines for treating plateau cerebral edema.
At present, polyphenols, especially procyanidin B, are used in the treatment of cerebral oedema caused by hypoxia and/or stroke1-B4The effect of (A) has not been reported. The present invention has surprisingly found that procyanidin B1-B4Can inhibit the aquaporin AQP4,in mouse models, stroke or trauma can cause severe edema in the normal brain, while APQ4 aquaporin-depleted brain has very mild edema and recovers quickly. The invention discovers polyphenol compounds, in particular procyanidine B for the first time1-B4Pharmacological action and application in the aspect of cerebral edema, in particular to application in preventing and treating diseases related to high altitude cerebral edema.
The invention mainly solves the technical problems through the following technical scheme.
One of the technical schemes of the invention is as follows: the application of polyphenol compounds in preparing medicines for preventing and treating cerebral edema; the structural formula of the polyphenol compound is as follows:
wherein R is1～R6May or may not be simultaneously hydrogen, hydroxy, methoxy or fluoro.
Preferably, the polyphenol compound in the invention is procyanidin, a pharmaceutically acceptable salt thereof, a solvate of a pharmaceutically acceptable salt thereof, or a crystal form thereof.
The procyanidin is preferably selected from procyanidin B1Procyanidin B2Procyanidin B3And procyanidin B4One or more of gallocatechin- (4 α → 8) -catechin (CAS No. 78392-25-3) and catechin- (4 α → 8) -gallocatechin (CAS No. 135095-45-3).
In a preferred embodiment of the present invention, the polyphenol compound is procyanidin B1Procyanidin B2Procyanidin B3Or procyanidin B4。
In particular, the present inventors have surprisingly found that procyanidin B3(CAS number 23567-23-9) is most effective in treating cerebral edema, especially high altitude cerebral edema.
The cerebral edema described in the present invention may be conventional in the art, such as cerebral edema caused by hypoxic-hypothermia and/or stroke.
In the present invention, the cerebral edema may be acute cerebral edema; such as high altitude cerebral edema.
Procyanidin B1Procyanidin B2Procyanidin B3Procyanidin B4, a compound extracted from grape seed, and its structural formula and gallocatechin- (4 α → 8) -catechin, or catechin- (4 α → 8) -gallocatechin have the following structural formula:
in a preferred embodiment of the invention, the acute cerebral edema has one or two of the following manifestations:
(1) brain edema, increased expression of aquaporins AQP4, HIF-1 alpha;
(2) the brain barrier is destroyed, and the expression of ZO-1 and claudin-1 is reduced.
The polyphenol compound in the invention can be the only active ingredient of the medicine.
The second technical scheme of the invention is as follows: the application of polyphenol compounds in preparing medicines for recovering damage caused by astrocyte hypoxia;
the structural formula of the polyphenol compound is as follows:
wherein R is1～R6May or may not be simultaneously hydrogen, hydroxy, methoxy or fluoro.
As described in one of the technical schemes, the polyphenol compound is preferably procyanidin, a pharmaceutically acceptable salt thereof, a solvate of a pharmaceutically acceptable salt thereof, or a crystal form thereof.
As mentioned above, the procyanidin of the invention may be selected from procyanidin B1Procyanidin B2Procyanidin B3Procyanidin B4One or more of gallocatechin- (4 α → 8) -catechin and catechin- (4 α → 8) -gallocatechin; for example procyanidin B1Procyanidin B2Procyanidin B3Or procyanidin B4Preferably procyanidin B3。
In the present invention, the damage may have one or both of the following manifestations: 1) increased expression of AQP4 and HIF-1 α; 2) increased expression of inflammatory proteins; the inflammatory protein is preferably one or more of vcam-1, cox-2, iNOS, IL-6 and IL-1 beta.
As described in one of the technical solutions, the polyphenol compound may be the only active ingredient of the drug.
The third technical scheme of the invention is as follows: the application of polyphenol compounds in the preparation of AQP4 inhibitors; the structural formula of the polyphenol compound is as follows:
wherein R is1～R6May or may not be simultaneously hydrogen, hydroxy, methoxy or fluoro.
For the preferred definition of the polyphenol compounds, see the first and second technical schemes for details.
Interpretation of terms
The term "pharmaceutically acceptable" means that the salts, solvents, excipients, etc., are generally non-toxic, safe, and suitable for use by a subject. The "subject" is preferably a mammal, more preferably a human.
The term "pharmaceutically acceptable salts" refers to salts prepared from the compounds of the present invention and the drugs, pharmaceutical compositions containing them with relatively nontoxic, pharmaceutically acceptable acids or bases. When the compounds of the present invention, and the drugs and pharmaceutical compositions containing them, contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral forms of such drugs with a sufficient amount of a pharmaceutically acceptable base, either in neat solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include, but are not limited to: lithium salt, sodium salt, potassium salt, calcium salt, aluminum salt, magnesium salt, zinc salt, bismuth salt, ammonium salt, and diethanolamine salt. When the drugs of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral forms of such drugs with a sufficient amount of a pharmaceutically acceptable acid in neat solution or in a suitable inert solvent. The pharmaceutically acceptable acid includes inorganic acids including, but not limited to: hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, phosphoric acid, phosphorous acid, sulfuric acid, and the like. The pharmaceutically acceptable acids include organic acids including, but not limited to: acetic acid, propionic acid, oxalic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, salicylic acid, tartaric acid, methanesulfonic acid, isonicotinic acid, acid citric acid, oleic acid, tannic acid, pantothenic acid, hydrogen tartrate, ascorbic acid, gentisic acid, fumaric acid, gluconic acid, saccharic acid, formic acid, ethanesulfonic acid, pamoic acid (i.e. 4, 4' -methylene-bis (3-hydroxy-2-naphthoic acid)), amino acids (e.g. glutamic acid, arginine), and the like. When the drug of the present invention contains a relatively acidic and a relatively basic functional group, it can be converted into a base addition salt or an acid addition salt. See in particular Berge et al, "Pharmaceutical Salts", Journal of Pharmaceutical Science 66:1-19(1977), or, Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P.Heinrich Stahl and Camile G.Wermuth, ed., Wiley-VCH, 2002).
The "plurality" of the term "one or more" may refer to 2, 3, 4, 5, 6, 7, 8, 9, or more.
The compounds of the present invention, medicaments or pharmaceutical compositions containing them may be administered in unit dosage form, either enterally or parenterally, for example orally, topically, intravenously, intramuscularly, subcutaneously, nasally, oromucosally, ocularly, pulmonary and respiratory, dermally, vaginally, rectally, etc.
The dosage form for administration may be a liquid dosage form, a solid dosage form, or a semi-solid dosage form. The liquid dosage forms can be solution (including true solution and colloidal solution), emulsion (including o/w type, w/o type and multiple emulsion), suspension, injection (including water injection, powder injection and infusion), eye drop, nose drop, lotion, liniment, etc.; the solid dosage form can be tablet (including common tablet, enteric coated tablet, buccal tablet, dispersible tablet, chewable tablet, effervescent tablet, orally disintegrating tablet), capsule (including hard capsule, soft capsule, enteric coated capsule), granule, powder, pellet, dripping pill, suppository, pellicle, patch, aerosol (powder), spray, etc.; semisolid dosage forms can be ointments, gels, pastes, and the like.
The medicine or the medicine composition can be prepared into common preparations, sustained release preparations, controlled release preparations, targeting preparations and various particle delivery systems.
"pharmaceutical composition" refers to the combination of one or more of the compounds of the present invention or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof with another chemical ingredient, such as a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to facilitate the administration process to an animal.
"pharmaceutically acceptable carrier" refers to inactive ingredients in a pharmaceutical composition that do not cause significant irritation to an organism and do not interfere with the biological activity and properties of the administered compound, such as, but not limited to: calcium carbonate, calcium phosphate, various sugars (e.g., lactose, mannitol, etc.), starch, cyclodextrin, stearin, cellulose, carbonate, acrylic or methacrylic polymers, gelatin, water, polyethylene glycol, propylene glycol, ethylene glycol, EZ sesame oil or hydrogenated EZ or polyethoxylated hydrogenated EZ sesame oil, corn oil, peanut oil, and the like.
The aforementioned pharmaceutical compositions may contain, in addition to pharmaceutically acceptable carriers, adjuvants commonly used in pharmacology, such as: antibacterial agents, antifungal agents, antimicrobial agents, shelf-stable agents, hueing agents, solubilizing agents, thickening agents, surfactants, complexing agents, proteins, amino acids, fats, sugars, vitamins, minerals, trace elements, sweeteners, pigments, flavors or combinations thereof, and the like.
The term "treatment" refers to therapeutic therapy. Where specific conditions are involved, treatment refers to: (1) relieving one or more biological manifestations of a disease or disorder, (2) interfering with (a) one or more points in a biological cascade that causes or leads to a disorder or (b) one or more biological manifestations of a disorder, (3) ameliorating one or more symptoms, effects, or side effects associated with a disorder, or one or more symptoms, effects, or side effects associated with a disorder or treatment thereof, or (4) slowing the progression of one or more biological manifestations of a disorder or disorder.
The term "solvate" refers to a substance formed by combining a compound of the present invention with a stoichiometric or non-stoichiometric amount of a solvent. The solvent molecules in the solvate may be present in an ordered or unordered arrangement. Such solvents include, but are not limited to: water, ethanol, and the like.
The terms "pharmaceutically acceptable salt" and "solvate" of the "solvate of a pharmaceutically acceptable salt" as used herein refer to a substance formed by combining a compound of the present invention with a relatively non-toxic, pharmaceutically acceptable acid or base, with stoichiometric or non-stoichiometric amounts of a solvent, as described above. The "solvate of a pharmaceutically acceptable salt" includes, but is not limited to, the hydrochloride monohydrate of the compound of the present invention.
The terms "compound," "pharmaceutically acceptable salt," "solvate," and "solvate of a pharmaceutically acceptable salt" can exist in crystalline or amorphous form. The term "crystal form" refers to a form in which ions or molecules are arranged strictly periodically in a three-dimensional space in a defined manner and have a periodic recurring pattern at a distance; due to the above described periodic arrangement, various crystal forms, i.e. polymorphism, may exist. The term "amorphous" refers to a state in which ions or molecules are distributed in a disordered manner, i.e., the ions or molecules do not have a periodic arrangement.
In the present invention, the term "comprising, including or containing" may mean that other components exist in addition to the components listed below; it may also mean "consisting of … …", i.e. including only the ingredients listed later without the presence of other ingredients.
On the basis of the common knowledge in the field, the above preferred conditions can be combined randomly to obtain the preferred embodiments of the invention.
The reagents and starting materials used in the present invention are commercially available.
The positive progress effects of the invention are as follows:
polyphenols, such as procyanidin B, are used in the invention3After intervention of cerebral edema, leakage can be reduced, the integral lengthening of a hippocampus region caused by the cerebral edema is improved, a DG region becomes narrow, cell arrangement disorder and dispersion are found by dyeing, and a CA3 region expands outwards and is accompanied with symptoms such as dispersion and the like; can improve the expression increase of AQP4 and HIF-1 alpha and the expression decrease of ZO-1 and claudin-1 caused by cerebral edema; the expression of inflammatory proteins (vcam-1, cox-2, iNOS) was reduced.
Drawings
FIG. 1 shows the result of water content detection of procyanidin B3(MT-8) can significantly reduce the water content.
FIG. 2 shows that the barrier damage caused by acute cerebral edema is detected by EB method, and MT-8 can reduce the leakage remarkably.
FIG. 3 is a graph showing HE staining, which is an observation of the effect of acute cerebral edema on the morphology of the hippocampus, showing that acute cerebral edema causes the hippocampus to become lengthened as a whole, DG to become narrowed, and staining shows that the cells are disorganized and somewhat diffuse, and the CA3 region is enlarged outward with diffusion; the MT-8 dry prognosis is improved.
FIG. 4 shows Western blot method for detecting the expression of AQP4, HIF-1 alpha and barrier protein in hippocampal region after acute cerebral edema injury.
FIG. 5 shows the Western blot method for detecting the expression of inflammatory proteins in hippocampus after acute cerebral edema injury.
Control: control group (given corresponding volume of saline, 40mg/kg/day, ip.); HACE: plateau cerebral edema model group (given corresponding volume of saline, 40mg/kg/day, ip.); MT-8: 40mg/kg/day, ip..***p<0.001。
FIG. 6A shows the expression of AQP4 in astrocyte injured by OGD as detected by the Immunofluorescence method; FIGS. 6B and 6C show that the Western blot method detects AQP4, HIF-1 α and inflammatory protein expression after the astrocytes are injured by OGD.
Control: a control group; hypoxia: OGD lesion 6h model set; MT-8: 10 mu M;***p<0.001。
FIG. 7 is a Western blot method for detecting procyanidine B1Procyanidin B2Procyanidin B3Procyanidin B4The effect of the drug on AQP4, TRPV4, HIF-1 alpha, HIF-2 alpha and SNX13 protein expression after OGD-induced astrocyte injury.
FIG. 8 shows day8 magnetic resonance images of cynomolgus monkey administration group G2-1.
FIG. 9 shows magnetic resonance images of cynomolgus monkey administration group G2-2 at day 8.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
Procyanidin B3Abbreviated as MT-8 in the following.
Example 1 prevention and treatment of high altitude cerebral edema by MT-8
Grouping: male C57 mice weighing 22-25g (mice purchased from shanghai B & K, housed at the animal testing center of the institute of medicine, university of compound denier, SPF grade) were randomly divided into 3 groups, namely: 1) control group (corresponding volume of saline given, 40mg/kg/day, ip.n 10); 2) model group (corresponding volume of saline given, 40mg/kg/day, ip.n 10); 3) model + MT-8 group (40mg/kg/day, ip.n 10).
1) Model building
In the normal oxygen environment of the plain area, the plain contrast group mouse cage is fed conventionally without movement and pressure reduction and oxygen deficiency treatment, and the mouse cage is free to eat and drink water and naturally illuminates day and night. Before formal hypoxia exposure, plateau hypoxia mice firstly use animal experiment treadmill to perform adaptive treadmill training for 2 d. The specific training method comprises the following steps: beginning at 8:30 in the morning, setting the slope of the treadmill at 0 degree, the speed at 12m/min, the continuous exercise time at 15min, and continuing the training for 6 times after 20min of rest. The daily exercise time is 90min, and the rest time is free to drink water and illuminate naturally day and night.
The method is modified by referring to the establishment method of the plateau pulmonary edema animal model, and an acute hypoxia exposure experiment of the animal is carried out by utilizing a plateau environment simulation cabin. The specific preparation process of the disease model comprises the following steps: in a plateau environment simulation cabin with the simulated altitude of 5000m, a full-time laboratory technician in the cabin puts a mouse into an animal experiment running table to be stabilized for 30min, and then immediately leads the mouse to run the table. Animal running table setting parameters: the gradient is 10 degrees, the speed is 12m/min, and the mouse is maintained in a motion state by adopting an electric stimulation mode. After the mouse continuously moves for 4 hours, the laboratory staff in the cabin takes out the mouse from the runway, and the mouse is allowed to rest for 15-20 min, and the mouse can freely eat and drink water in the period. After the rest, the exhaustive exercise was continued 11 times in this way, with a total exercise time of 2640 min. After the exhaustion exercise of the plateau anoxic group mouse is finished, the mouse is placed into the experiment cabin, and the connecting cabin door is closed. The extravehicular technician quickly raises the altitude of the experimental chamber from 5000m to 6000 m. After 2d of exhaustion training, the altitude of the experimental cabin is increased from 6000m to 8000m, and the mouse is continuously subjected to decompression and anoxic exposure for 3d under the condition of no movement in the plateau. The temperature in the cabin is about 18 ℃, the light and dark period is 24 hours, and drinking water is freely eaten.
Finally, materials are taken in plain areas for detection.
2) Brain tissue water content detection
After anesthetizing the mice, the brains were taken out by quickly cutting the heads, the wet weight of the brain tissue was weighed, then the brain tissue was baked in an oven at 60 ℃ for 3 days, and the dry weight of the brain tissue was weighed again. The water content of each group of mice was calculated as (wet weight-dry weight)/wet weight 100%.
3) Permeability for EB leak detection
The material was obtained 1h before, 2% EB solution (4mL/kg) was injected intravenously at the tail of each mouse, and 1h later, the mice were anesthetized, and the mice were perfused with 0.9% physiological saline until the color of the heart outflow solution was transparent. The head is broken and the brain is taken, and the picture is taken roughly. After freezing at-20 ℃ for 30min, the coronal section was 6 slices and EB leakage was photographed.
4) HE staining
The materials are taken and then are sliced, HE is stained, and the morphological changes of the hippocampus and the cortex are observed.
5)Western Blot
A part of brain tissue of a mouse is taken to be homogenized, and the expression conditions of AQP4, HIF-1 alpha, inflammatory proteins (vcam-1, cox-2 and iNOS) and barrier proteins (ZO-1 and claudin-1) are detected.
Collecting cell lysate, and detecting the expression conditions of AQP4 and HIF-1 alpha.
6) The experimental results are as follows:
acute cerebral edema causes a significant increase in water content, and MT-8 can significantly reduce brain water content after drying (see table 1 and fig. 1).
TABLE 1 Water content determination
The barrier is damaged due to acute cerebral edema, and EB leakage is obvious; leakage was reduced following MT-8 intervention (FIG. 2). Acute cerebral edema causes the whole hippocampus to be lengthened, the DG to be narrowed, and the staining shows that the cell arrangement is disordered and is dispersed, and the CA3 area is expanded outwards and is accompanied with dispersion; MT-8 was improved after drying (FIG. 3). The acute cerebral edema causes the expression of AQP4 and HIF-1 alpha to be increased, and the expression of ZO-1 and claudin-1 to be decreased; all the MT-8 treatments were improved (see Table 2 and FIG. 4).
TABLE 2 Western blot assay
Acute cerebral edema caused by inflammatory protein (vcam-1, cox-2, iNOS) expression increase, MT-8 treatment can significantly reduce its expression (see Table 3 and figure 5).
TABLE 3 Western blot assay
Example 2 protection of astrocytes in hypoxic model by MT-8 and procyanidin analogs
1) Culture and purification of primary cortical astrocytes
Taking an SD rat within 24h of newborn, wiping skin with alcohol, killing the neck after cutting, placing in 75% alcohol for sterilization for a plurality of minutes, cutting the head and taking the brain, placing brain tissues in cooled PBS, removing cerebellum, meninges and blood vessels, then separating cortex, cutting cortex into pieces, collecting the cut cortex, centrifuging at 1000rpm for 8 min. Discarding the supernatant, adding 0.25% trypsin for digestion for 10min, shaking every 5min, adding DMEM/F12 medium containing 10% FBS for terminating digestion for 10min, shaking every 5min, and sieving with 200 mesh sieve. Taking the filtrate, centrifuging at 1000rpm for 5min, discarding the supernatant, adding DMEM/F12 culture medium containing 10% FBS, blowing uniformly, counting, adjusting cell density, and inoculating into a plastic bottle coated with L-polylysine in advance. Standing at 37 deg.C for 5% CO2The culture is carried out in the incubator for 30-60 min for differential separation, and then the culture solution is replaced every two days. Culturing to 7-9 days, replacing a new culture medium, covering a bottle cap, using a sterile belt to wrap, sealing, placing the culture bottle on a shaker, keeping the culture bottle horizontal, ensuring that the culture solution covers the cells, then culturing for 6h at 300rpm in an incubator at 37 ℃ to remove few colloidal cells, replacing the culture medium in the culture bottle with a fresh culture medium, further shaking for 18h at 210rpm, transferring the culture solution to a new culture bottle coated with L-polylysine, placing in the incubator for culturing, carrying out passage when the cells are fused for more than 80%, digesting for a plurality of minutes by 0.25% trypsin (containing EDTA), stopping digestion, adjusting the cell density, inoculating into the culture bottle coated with L-polylysine, and the third generation can be used for experiments.
2) Preparation of astrocyte hypoxia model
Replacing serum-free DMEM medium, and placing in 1% O2、5％CO2、94％N2And (4) carrying out anoxic model preparation in the three-gas culture box, and carrying out subsequent index detection after 6 hours of hypoxia.
3) The experimental results are as follows:
after the astrocytes are lack of oxygen, the astrocytes are marked by GFAP, the expression of AQP4 is obviously increased, and the expression of AQP4 and HIF-1 alpha can be obviously reduced after MT-8 treatment, and inflammatory responses (vcam-1, cox-2, iNOS, IL-6 and IL-1 beta) are reduced (see table 4 and figures 6A-6C).
Wherein the MT-8 treatment method comprises the steps of culturing primary astrocytes, carrying out passage and plating, performing MT-8(10 mu M) pretreatment for 4 hours when the cells grow to about 80%, replacing the cells with DMEM sugar-free medium, and placing the cells in a (1% O) culture medium2、5％CO2、94％N2) And continuously culturing for 6 hours in the three-air culture box, and collecting samples for relevant detection.
TABLE 4 Western blot assay
Detection of procyanidine B by Western blot method1Procyanidin B2Procyanidin B3And procyanidin B4The influence of the drug on the protein expression of AQP4, TRPV4, HIF-1 alpha, HIF-2 alpha and SNX13 after the injury of astrocytes induced by OGD (oxygen deprivation of sugar) is found (figure 7), and procyanidin B1Procyanidin B2Procyanidin B3And procyanidin B4After treatment, the expression of AQP4, TRPV4, HIF-1 alpha and HIF-2 alpha can be obviously reduced, and the effect of treating high altitude cerebral edema is shown.
Wherein the sugar oxygen deprivation treatment process comprises the following steps: after the primary star gum cells are cultured, passage and plating are carried out, when the cells grow to about 80 percent, DMEM sugar-free medium is replaced, and the cells are placed in (1 percent O)2、5％CO2、94％N2) And continuously culturing for 6 hours in the three-air culture box, and collecting samples for relevant detection.
The process of procyanidine treatment comprises the following steps: after primary astrocyte is cultured, passage and plating are carried out, and procyanidine B is administered when the cells grow to about 80 percent1-B4After pretreatment for 4h (10. mu.M), the medium was replaced with DMEM sugar-free medium and placed in (1% O)2、5％CO2、94％N2) And continuously culturing for 6 hours in the three-air culture box, and collecting samples for relevant detection.
Example 3 drug Effect of MT-8 on cerebral edema in cynomolgus monkey cerebral apoplexy model
1) Animals: 4 cynomolgus monkeys (Macaca Fascicularis), male, about 8 years old (cultivation method: Zhaoqing Chuangyao Biotech Co., Ltd.); the experimental procedures designed for application to animals in this protocol were performed after approval by the Pentium biological IACUC (Committee for the management and use of laboratory animals).
2) Environment: the experimental monkey was housed in a stainless monkey cage (acclimation period: 1600 mm. times.1400 mm. times.1640 mm; experimental period: 800 mm. times.700 mm. times.820 mm) in a biological animal house, and the acclimation period: two for each cage; and (3) during the experiment period: one for each cage (equipped with animal welfare appliances such as mirrors, plastic toy balls and the like). The room number where the animals were placed throughout the experiment was recorded in the experimental record. The number of filter ventilation cycles per hour was 10-20 in the room area where the experimental monkeys were placed. The temperature is maintained between 19-19 deg.C (66-84 deg.F) and the relative humidity is 35-75%. Temperature and humidity were observed and recorded every morning and afternoon. The lighting conditions were 12 hours (08:00-20:00) day of daylight lamp illumination and 12 hours of no illumination. Animal welfare measures are performed according to the standard procedures set out to reduce and help sooth the stress of the experiment.
3) Food and drinking water: experimental monkeys were fed twice daily. Each batch of animal feed received by the bentonions can be reserved for sample, if necessary, detection and analysis can be carried out, and the obtained analysis certificate is filed and stored by the bentonions. And additional vegetables and fruits were provided to the monkeys to ensure their appetite. During the whole experimental period, the experimental monkey can obtain drinking water treated by the interior of the puffed organism in an unlimited amount. The local municipal water supply is purified by a filtering system to reach the World Health Organization (WHO) human drinking water standard.
4) Establishing a cerebral apoplexy model: before the operation, the cynomolgus monkey is fasted for 10-16 hours, atropine (0.04mg/kg) is injected intramuscularly 15 minutes before anesthesia, the cynomolgus monkey is sedated by 3mg/kg of sudao, 1-3% isoflurane is inhaled to keep the anesthesia state, then the trachea cannula is started, and the monitor detects the oxygen saturation degree of blood, the heart rate and the body temperature. The trachea cannula is connected with a breathing machine, and the continuous isoflurane inhalation anesthetic concentration (0.5% -3%) is adjusted according to the heart rate and the blood oxygen saturation. Preparing the head, namely preparing the skin, namely, arranging an intersection point of a horizontal line of the upper edge of the zygomatic arch on the left side and a vertical line of the outer edge of the orbit, and an intersection point of a sagittal line of a skull and a connecting line of double external auditory canals (skull reflection line), wherein the connecting line of the two intersection points is the approximate running direction of a Middle Cerebral Artery (MCA). Opening a window on the skull: the skin and muscles were incised to expose the skull, and an approximately 20mm x 15mm skull fenestration was made with the upper side of the upper edge of the left zygomatic arch and the posterior side of the outer edge of the orbit as the boundary.
Permanent ligation of the middle cerebral artery: the dura mater is cut off crosswise, brain cotton is used for protecting along the lateral fissure of the brain to expose MCA M1 in an inward dissociative way, the blood vessel goes deep into the skull base along the blood vessel, and the emitting end of the MCA from the willis loop is searched, namely the proximal end of the MCA M1. The proximal end of MCA M1 was ligated to create a permanent cerebral ischemia model. The operation window is sutured layer by layer, the wound is disinfected, and veterinary nursing such as anti-infection and analgesia is carried out by continuously using 7 days of ceftriaxone sodium (0.1g/kg) and dolantin (2 times a day, 4mg/kg, i.m.).
5) Grouping and administration of drugs
4 cynomolgus monkeys were randomly divided into 2 groups of 2 per body weight, i.e.: 1) model group: g1-1 and G1-2 (corresponding volumes of saline given, iv. daily dosing for 7 consecutive days); 2) administration group: g2-1 and G2-2 (MT-8, 12mg/kg/day, iv. daily administration for 7 consecutive days). The first administration time point was 1 hour after the start of stroke surgery.
6) Brain magnetic resonance imaging scan
The cynomolgus monkeys were fasted for 10-16 hours before nuclear magnetic scanning, and were anesthetized with atropine (0.04mg/kg) and 3mg/kg of sutita 15 minutes before anesthesia. MRI scans were performed 3 days before surgery, Day2, Day4, Day8, with a scanning machine model of SKyra 3.0T superconducting magnetic resonance imager, siemens, and the scanning sequence included: t1WI, T2WI, T2FLAIR, DWI, scan parameters as in the table below. Comparing T1, T2 picture image information (fig. 8 and 9), edema volume percentages were obtained by manually circling the volume of left brain edema brain tissue in the T2 image against the volume of left brain in each slice thickness separately by Sante MRI Viewer software (Σ left brain edema volume per slice/∑ left brain volume per slice 100%). Opening a high B value and an ADC (analog to digital converter) image of DWI in ITK-SNAP (interactive transmission and adaptation-network application) software, marking a myocardial infarction area on the ADC image in a low signal area which presents a high signal in the high B value image of DWI, and obtaining the volume of the core infarction area.
TABLE 5 magnetic resonance imaging scan parameters
7) Results of the experiment
TABLE 6 magnetic resonance imaging scan of cerebral edema results
TABLE 7 magnetic resonance imaging scanning cerebral infarction volume results
| day2 volume (mm)3) | day4 volume (mm)3) | day8 volume (mm)3) | |
| G1-1 | 3609.37 | 4117.83 | 5965.5 |
| G1-2 | 6627.93 | 4977.21 | 5589.51 |
| G2-1 | 9624.99 | 9238.29 | 5335.29 |
| G2-2 | 1815.43 | 1195.96 | 812.83 |
The results show that the monkey brain edema of the stroke model reaches a peak value on the 4 th day, and the brain edema volume of the model group on the 8 th day is obviously higher than that of the model group on the 2 nd day (1.23 times and 2.22 times); the cerebral edema of the administration group G2-2 monkey is obviously improved, the cerebral edema volume on day8 is 66% of that on day2, and the cerebral infarction volume on day8 is 45% of that on day 2; the volume of cerebral edema on day8 of the group G2-1 monkeys was 92% of that on day2, and the volume of cerebral infarction on day8 was 55% of that on day 2. The compound MT-8 is shown to have the effect of treating cerebral edema caused by cerebral apoplexy.
Claims (10)
1. The application of polyphenol compounds in preparing medicines for preventing and treating cerebral edema; the structural formula of the polyphenol compound is as follows:
wherein R is1～R6Simultaneously or not hydrogen, hydroxyl, methoxyl or fluorine.
2. The use of claim 1, wherein the polyphenolic compound is a procyanidin, a pharmaceutically acceptable salt thereof, a solvate of a pharmaceutically acceptable salt thereof, or a crystalline form thereof.
3. The use as claimed in claim 2 wherein the procyanidin is selected from procyanidin B1Procyanidin B2Procyanidin B3Procyanidin B4One or more of gallocatechin- (4 α → 8) -catechin and catechin- (4 α → 8) -gallocatechin; for example procyanidin B1Procyanidin B2Procyanidin B3Or procyanidin B4(ii) a Preferably procyanidin B3。
4. The use of claim 1, wherein the cerebral edema is cerebral edema caused by hypoxic-hypothermia and/or stroke.
5. The use of claim 1, wherein the cerebral edema is acute cerebral edema.
6. The use of claim 5, wherein the acute cerebral edema has one or both of the following manifestations:
(1) brain edema, elevated expression of AQP4, HIF-1 α;
(2) the brain barrier is destroyed, and the expression of ZO-1 and claudin-1 is reduced.
7. The use according to any one of claims 1 to 6, wherein the polyphenol is the sole active ingredient of the medicament.
8. The application of polyphenol compounds in preparing medicines for recovering damage caused by astrocyte hypoxia;
the structural formula of the polyphenol compound is as follows:
wherein R is1～R6Simultaneously or not hydrogen, hydroxyl, methoxy or fluorine.
9. The use of claim 8, wherein the polyphenolic compound is a procyanidin, a pharmaceutically acceptable salt thereof, a solvate of a pharmaceutically acceptable salt thereof, or a crystalline form thereof; preferably:
said procyanidin is selected from procyanidin B1Procyanidin B2Procyanidin B3Procyanidin B4One or more of gallocatechin- (4 α → 8) -catechin and catechin- (4 α → 8) -gallocatechin; for example procyanidin B1Procyanidin B2Procyanidin B3Or procyanidin B4(ii) a Preferably procyanidin B3；
And/or, the injury has one or both of the following manifestations:
1) increased expression of AQP4 and HIF-1 α;
2) increased expression of inflammatory proteins; the inflammatory protein is preferably one or more of vcam-1, cox-2, iNOS, IL-6 and IL-1 beta;
and/or the polyphenol compound is the only active ingredient of the medicament.
10. The application of polyphenol compounds in the preparation of AQP4 inhibitors; the structural formula of the polyphenol compound is as follows:
wherein R is1～R6Hydrogen, hydroxyl, methoxy or fluorine at the same time or at different times;
preferably, the polyphenol compound is procyanidin, a pharmaceutically acceptable salt thereof, a solvate of a pharmaceutically acceptable salt thereof, or a crystal form thereof;
the procyanidin is preferably selected from procyanidin B1Procyanidin B2Procyanidin B3Procyanidin B4NutgallOne or more of catechin- (4 α → 8) -catechin and catechin- (4 α → 8) -gallocatechin; for example procyanidin B1Procyanidin B2Procyanidin B3Or procyanidin B4(ii) a More preferably procyanidin B3。
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Non-Patent Citations (4)
| Title |
|---|
| ALAN D等: "The Amazon rain forest plant Uncaria tomentosa (cat"s claw) and its specific proanthocyanidin constituents are potent inhibitors and reducers of both brain plaques and tangles.", 《 SCI REP》 * |
| SHUANGCHAN WU等: "Procyanidin B2 attenuates neurological deficits and blood–brain barrier disruption in a rat model of cerebral ischemia", 《MOL. NUTR. FOOD RES. 》 * |
| 李姗姗等: "低聚原花青素(OPC)对实验性大鼠局灶性脑缺血的保护作用", 《中华中医药学刊》 * |
| 石磊等: "原花青素对脑出血后脑水肿及继发性脑损伤炎症的作用研究", 《重庆医学》 * |
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