CN114392275A - Medical application of bear gall - Google Patents
Medical application of bear gall Download PDFInfo
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- CN114392275A CN114392275A CN202210208861.3A CN202210208861A CN114392275A CN 114392275 A CN114392275 A CN 114392275A CN 202210208861 A CN202210208861 A CN 202210208861A CN 114392275 A CN114392275 A CN 114392275A
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- eae
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- A—HUMAN NECESSITIES
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- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
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Abstract
The invention relates to the field of medicine, in particular to medical application of bear gall. The bear gall can be used for preventing and treating autoimmune encephalomyelitis and multiple sclerosis.
Description
Technical Field
The invention relates to the field of medical health products, in particular to medical application of bear gall.
Background
Multiple Sclerosis (MS) is an autoimmune disease that develops in early adulthood, and is characterized pathologically by leukocytic demyelination in the central nervous system, with a high disability rate in most patients manifested by recurrent neurological dysfunction, and clinically by temporal (recurrent Multiple relapses) and spatial (Multiple central nervous system lesions) Multiple signs of symptoms. The pathogenesis of the disease is not clear at present, and the main reason is that in vivo antigens cause the activation of peripheral T lymphocytes and enter the central nervous system of a patient to release a large amount of cytokines to induce the inflammatory reaction of an organism so as to damage the nervous system. Due to the unclear etiology and pathogenesis, the current treatment means of MS is extremely limited, no cure method exists, and the effect of the immunoregulation treatment is far from meeting the clinical requirement although the immunoregulation treatment is advanced. Therefore, the research on the etiology and pathogenesis of MS and the search for more therapeutic measures become the research focus of MS at present.
Autoimmune Encephalomyelitis (EAE) is a classic animal model currently used for MS studies, and induces an adaptive immune response by immunizing and sensitizing CNS-specific molecules [ Myelin oligodendrocyte expression proteins or polypeptides, such as Myelin Oligodendroglycoprotein (MOG), proteolipid Protein (PTX) ], leading to activation of T-and B-cells, migration to the CNS, production of neurotoxic cytokines, and subsequent activation of resident glial cells (microglia, astrocytes) to induce chronic inflammatory responses of the CNS, accompanied by demyelination, axonal injury, and pathologically exhibiting many similarities to MS.
Bear gall is one of four major precious animal medicines, and is a dried gall bladder of animals in the family of bear. Bear gall as a medicine is recorded in 'Xin Xiu Ben Cao' of the Tang Dynasty, and has a history of more than one thousand, three and hundred years to date; the compendium of materia Medica of Li Shizhen Ming also carries: bear gall, bitter and cold in smell, non-toxic and enters liver, gall and heart meridians. Modern pharmaceutical research proves that bear gall has the effects of clearing away heat and toxic materials, soothing liver and benefiting gallbladder, removing nebula and improving eyesight, and relieving spasm and pain. Has wide application value in the treatment of various diseases of human liver and gall system, cardiovascular and cerebrovascular system, neuropsychiatric system and the like. The dried product of the artificial drainage bear gall is taken as a substitute of natural bear gall, is approved and marketed, is named as bear gall powder (BBP), and is widely used in clinical traditional Chinese medicine.
Disclosure of Invention
The invention aims to provide a novel medical application of bear gall.
Specifically, the invention provides the application of bear gall in preparing the medicine for preventing and treating autoimmune encephalomyelitis.
In a preferred embodiment, the bear gall is used as the only active ingredient for preparing the medicine for preventing and treating the autoimmune encephalomyelitis.
The second aspect of the invention provides the application of bear gall in preparing the medicine for preventing and treating multiple sclerosis.
In a preferred embodiment, the bear gall is used as the only active ingredient for preparing the medicine for preventing and treating the multiple sclerosis.
The details of various aspects of the invention are set forth in subsequent sections. The features, objects, and advantages of the invention will be apparent from the description and from the claims.
Drawings
FIG. 1 Effect of BBP on neurological function in EAE mice (Mean + -SEM, n-8)
FIG. 2 Effect of BBP on pathological changes in spinal cord tissue in EAE mice
Detailed Description
The invention arose in part from the unexpected discovery that: the bear gall can obviously inhibit the morbidity of an EAE mouse, improve the infiltration and demyelination of spinal cord tissue inflammatory cells of the EAE mouse and prompt that the bear gall has the clinical effect of preventing and treating MS.
The bear gall can be purchased from Heilongjiang Heibao pharmaceutical industry Co., Ltd, Wan Mitang, Shanghai Kaibao pharmaceutical industry Co., Guizheng Tang, Dian bear, Yunnan Youshao pharmaceutical industry Co., Ltd and the like through commercial approaches. The purity of the product meets the pharmaceutical standard.
The bear gall can be used alone or in the form of a pharmaceutical composition. The pharmaceutical composition comprises the bear gall as an active ingredient and a pharmaceutically acceptable carrier. Preferably, the pharmaceutical composition of the present invention comprises 0.1 to 99.9% by weight of the bear gall of the present invention as an active ingredient. The medicinal carrier does not destroy the pharmaceutical activity of the bear gall, and the effective dosage of the bear gall is nontoxic to human bodies when the medicinal carrier plays a role.
Such pharmaceutically acceptable carriers include, but are not limited to: lecithin, aluminum stearate, alumina, ion exchange materials, self-emulsifying drug delivery systems, tweens or other surfactants, serum proteins, buffer substances such as phosphates, glycine, sorbic acid, water, salts, electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, magnesium silicate, mixtures of saturated fatty acid partial glycerides, and the like.
Other conventional pharmaceutical adjuvants such as binder (e.g. microcrystalline cellulose), filler (e.g. starch, glucose, anhydrous lactose and lactose beads), disintegrant (e.g. crosslinked PVP, croscarmellose sodium, low-substituted hydroxypropylcellulose), lubricant (e.g. magnesium stearate), and absorption enhancer, adsorption carrier, flavoring agent, sweetening agent, excipient, diluent, wetting agent, etc.
The bear gall and the pharmaceutical composition thereof can be prepared according to the conventional method in the field and can be administrated by an intestinal or parenteral or local route. The oral preparation comprises capsule, tablet, oral liquid, granule, pill, powder, pellet, and unguent; parenteral preparations include injections and the like; topical preparations include creams, patches, ointments, sprays, and the like. Oral formulations are preferred.
The administration route of the bear gall and the pharmaceutical composition thereof can be oral, sublingual, transdermal, intramuscular or subcutaneous, skin mucosa, vein, urethra, vagina and the like.
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out according to conventional conditions or according to conditions recommended by the manufacturers. All percentages, ratios, proportions, or parts are by weight unless otherwise specified.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred embodiments and materials described herein are intended to be exemplary only.
The features mentioned above with reference to the invention, or the features mentioned with reference to the embodiments, can be combined arbitrarily. All the features disclosed in this specification may be combined in any combination and each feature disclosed in this specification may be replaced by alternative features serving the same, equivalent or similar purpose. Thus, unless expressly stated otherwise, the features disclosed are merely generic examples of equivalent or similar features.
The method comprises the following steps:
1. experimental Material
1.1 model making medicine of experimental medicine: pertussis toxin (PTX, Cas number: 2943182, Merck, USA), incomplete Freund's adjuvant (Cas number: SLBP8465V, Sigma), inactivated Mycobacterium tuberculosis H37RA (Cas number: 7041721, Becton Dickinson), Myelin oligodendrocyte glycoprotein 35-55 (MOG)33-55Cas number: 9001 purity of 98.96% or more, Shanghai Qiangyao Biotech Co., Ltd.)
Methylprednisolone sodium succinate (MPD, Cas number: 16080508, national drug group-Capacity pharmaceutical Co., Ltd.)
Bear gall powder (BBP) is purchased from Heilongjiang Heibao pharmaceutical Co., Ltd (approved literature: Z10980057; character: irregular fragment, granule or powder), Wan Kebao pharmaceutical Co., Ltd (approved literature: Z19991013; character: powder), Shanghai Kaibao pharmaceutical Co., Ltd (bear gall pill, approved literature: Z20184064; character: pill), Guizheng Tang (approved literature: Z10980024; character: irregular fragment, granule or powder), Dian bear (approved literature: Z19991013; character: irregular fragment, granule or powder), Yunan Tian bear Co., Ltd (approved literature: Z19991016; character: irregular fragment, granule or powder), respectively.
1.2 Experimental animals
6-week-old healthy C57BL/6 mice, female, having a weight of about 18-20g, purchased from Shanghai Sepal-BiKai laboratory animals Co., Ltd (license number: SCXK 2018-.
2. Experimental methods
2.1 establishment of mouse EAE model
Preparing a molding agent: each mouse was injected with H37RA TB 400 μ g, MOG35-55300 μ g of Freund's adjuvant 100 μ L, respectively calculating H37RA TB and MOG35-55And Freund's adjuvant. Precisely weighing a certain amount of H37RA TB and MOG35-55Firstly, the MOG35-55Dissolving in sterile PBS with a certain volume, carrying out vortex dissolution, mixing uniformly, adding H37RA TB, carrying out vortex dissolution, finally adding Freund adjuvant, and carrying out vortex until the mixture is milky white emulsion to prepare the modeling agent. Each mouse was injected with 0.1mL of PTX containing 300ng, and a volume of PTX stock solution was aspirated and diluted with sterile PBS to prepare an inducer.
An EAE molding method comprises the following steps: the mice were injected subcutaneously with the molding agent 0.1mL at three points on the back (near the neck, both hind limbs), and after the injection of the molding agent, 0.1mL of the inducer PTX was injected intraperitoneally, and the same amount of PTX was administered again every other day.
2.2 mice grouping and dosing
Six-week-old female C57BL/6 mice were purchased, adaptively raised for one week, randomly divided into a blank control group, a model group, and a BBP group (Kaibao, Heibao, Wan Mich Tang, Gui Zheng Tang, Dian bear, Yunan Tian you 6 different company sources, and the dose was 100mg/kg), and 9 positive drug groups (MPD,20mg/kg) were included, and each group had 8 mice. The EAE animal model is established according to the method in 2.1, the BBP group starts to administer the drug 1d before immunization, different doses of BBP are administered by intragastric administration, the normal control group and the model group are administered with the same amount of normal saline by intragastric administration for 1 time a day, and the administration is carried out for 23d in total.
2.3 mouse neurological Scoring
Dosing was performed at the same time daily and the disease was observed and neurological scores were recorded using a double-blind method. Neurological scoring criteria: 0 point, no disease sign; 0.5 min: a tail tip point; 1 point, drooping tail or mild toddler; 1.5 minutes, the tail is completely mopped, and the gait is unstable; 2, the limbs are weak after being doubled, or one limb is paralyzed, and the limbs can recover after being turned over passively; 3 minutes, the double hind limbs are paralyzed, the double hind limbs can not recover after being passively turned over, but can be moved after being stimulated; 4 minutes, paralysis of both hind limbs, paralysis of fore limbs or weakening of muscle force with urinary and fecal incontinence; and 5, death.
2.4 animal sample Collection and histopathological staining
Taking 4 mice in each group at the 21 st day of model building, carrying out heart perfusion by using 4% paraformaldehyde, taking the spinal column in a 24-hole plate containing 4% paraformaldehyde, fixing for 2 days at 4 ℃, dehydrating by using 10% sucrose for 24 hours after the fixation is finished, dehydrating by using 30% sucrose solution for 24 hours, embedding spinal cord tissues after the dehydration is finished, continuously slicing by 20 microns, and carrying out immunofluorescence staining; after dehydration, stripping spinal cord tissue, carrying out paraffin embedding, carrying out 5-micron continuous section, carrying out HE staining and LFB staining respectively, and observing histopathological changes under a light microscope.
2.4.1 hematoxylin-eosin (HE) staining experimental method
1) Dewaxing: soaking the spinal cord tissue slices in xylene I and xylene II for 20min respectively, then soaking in absolute ethyl alcohol I, absolute ethyl alcohol II and 75% alcohol for 5min respectively, and finally washing with water;
2) and (3) hematoxylin staining: dyeing with hematoxylin dye solution for 3-5min, differentiating with hydrochloric acid water solution, bluing with ammonia water solution, and washing with water;
3) eosin staining: dehydrating spinal cord tissue slices in 85% and 95% alcohol, and staining with eosin staining solution for 5 min;
4) dewatering and sealing: sequentially placing the spinal cord tissue slices into absolute ethyl alcohol I, absolute ethyl alcohol II, absolute ethyl alcohol III, xylene I and xylene II, respectively soaking for 5min for transparency, and finally sealing the slices with neutral gum;
5) and (5) taking a picture under a microscope and analyzing the image.
2.4.2 blue fixation staining (LFB) staining experimental method
1) Dewaxing: sequentially soaking the spinal cord tissue slices in xylene I and xylene II for 20min respectively, then soaking in absolute ethyl alcohol I and absolute ethyl alcohol II for 10min respectively, soaking in 95% alcohol, 90% alcohol, 80% alcohol and 70% alcohol for 5min respectively, and finally washing with distilled water;
2) dyeing: adding 0.1% LFB dye solution into spinal cord tissue, incubating overnight at 60 ℃, and finally washing with distilled water;
3) differentiation: soaking the spinal cord tissue slices in 70% ethanol for a certain time, then placing the slices into 0.05% lithium carbonate, observing under a microscope, controlling the color separation time until the color separation is complete, and washing with distilled water;
4) eosin counterstaining: counterstaining the spinal cord tissue slices with 0.1% eosin staining solution for 1min, and washing with distilled water;
5) sealing: drying the spinal cord tissue slices by using an oven, then, carrying out transparency for several minutes by using dimethylbenzene, and finally, sealing the slices by using neutral gum;
6) and (5) taking a picture under a microscope and analyzing the image.
2.5 statistical analysis
All the experimental result data are used
Representing statistical analysis using GraphPad Prism 7 software, multiple group comparisons tested by one-way ANOVA, P<0.05 the difference was considered statistically significant.
As a result:
effect of BBP on neurological function of EAE mice
After modeling of EAE mice, neurological scores and weight changes were recorded using a random double-blind method at the same time every day. The results are shown in FIG. 1A, where the EAE model group started to develop a subsequent disease at 9d compared to the normal control group. In the experimental process, mice are listened to, the diet activity is reduced, and symptoms of nerve function damage gradually appear, which are marked by dragging of the tail tip or complete paralysis, teetering, unilateral or bilateral hind limb paralysis, forelimb paralysis and even general paralysis. The results are shown in fig. 1B, with a delay in time of onset, with clinical cumulative scores significantly lower for each of the BBP-administered groups than for the EAE group (× P <0.001) compared to the EAE model group.
Effect of BBP on EAE mouse spinal cord histopathology
The results of HE staining, LFB staining and pathology scoring are shown in fig. 2, which shows that there is a large amount of inflammatory cell infiltration and large area of demyelination in white matter region of spinal cord tissue in the EAE model group compared to the normal control group. Compared with the EAE model group, the bear gall powder group basically has no inflammatory infiltration and demyelination, is obviously improved compared with the EAE model group, and suggests that BBP administration can improve the inflammatory cell infiltration and demyelination of spinal cord tissues of EAE mice.
And (4) conclusion:
research results show that the bear gall powder can effectively relieve the disease symptoms of EAE mice, reduce inflammatory infiltration and demyelination of the central nervous system and prompt that the bear gall powder has the clinical effect of preventing and treating MS.
The various aspects of the invention are addressed above. It should be understood, however, that equivalent changes and modifications may be made thereto by those skilled in the art without departing from the spirit of the present invention, and that such changes and modifications are intended to be covered by the appended claims.
Claims (4)
1. Application of fel Ursi in preparing medicine for preventing and treating autoimmune encephalomyelitis is provided.
2. The use according to claim 1, wherein bear's gall as sole active ingredient is used for the preparation of a medicament for the prevention and treatment of autoimmune encephalomyelitis.
3. Application of fel Ursi in preparing medicine for preventing and treating multiple sclerosis is provided.
4. The use according to claim 3, wherein bear's gall as sole active ingredient is used for the preparation of a medicament for the prevention and treatment of multiple sclerosis.
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| US20170196893A1 (en) * | 2016-01-07 | 2017-07-13 | The Board Of Trustees Of The Leland Stanford Junior University | Treatment of inflammatory demyelinating disease with agonists of farnesoid x receptor |
| CN110022880A (en) * | 2016-10-31 | 2019-07-16 | 社会福祉法人三星生命公益财团 | The pharmaceutical compositions for being used to prevent or treat ischemic damage and reperfusion damage comprising bile acid |
| KR20190009174A (en) * | 2017-07-18 | 2019-01-28 | 의료법인 성광의료재단 | Composition for preventing or treating inflammatory diseases or spinal cord injury comprising ursodeoxycholic acid |
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