CN118059145A - Composition containing radix angelicae, preparation method thereof, traditional Chinese medicine preparation and application - Google Patents
Composition containing radix angelicae, preparation method thereof, traditional Chinese medicine preparation and application Download PDFInfo
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- CN118059145A CN118059145A CN202410224550.5A CN202410224550A CN118059145A CN 118059145 A CN118059145 A CN 118059145A CN 202410224550 A CN202410224550 A CN 202410224550A CN 118059145 A CN118059145 A CN 118059145A
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- radix angelicae
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- radish
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Abstract
The invention discloses a composition containing dahurian angelica root, a preparation method thereof, a traditional Chinese medicine preparation and application thereof, and belongs to the technical field of compositions; the preparation method comprises the step of mixing radix angelicae and radish extracts; the traditional Chinese medicine preparation comprises the composition and pharmaceutically acceptable auxiliary materials. The application is the application of the composition and/or the Chinese medicinal preparation in preparing medicines, wherein the medicines comprise at least one of increasing learning and memory functions, improving cognitive functions, promoting intelligence, neuroprotection, improving depression, preventing and/or treating Alzheimer disease. The composition takes medicinal and edible medicinal materials as raw materials, has good safety and has better effect of improving learning and memory disorders.
Description
Technical Field
The invention belongs to the technical field of compositions, relates to a composition containing dahurian angelica root, a preparation method thereof, a traditional Chinese medicine preparation and application thereof, and in particular relates to a composition containing dahurian angelica root, a preparation method thereof, a traditional Chinese medicine preparation and application thereof in preparing medicines for preventing and/or treating Alzheimer's disease, improving depression, increasing learning and memory functions, improving cognitive functions, promoting intelligence and protecting nerves.
Background
Learning and memory disorder is a common clinical disorder, the pathogenesis of which is very complex, not only affecting the work and life of people, but also inducing other diseases for serious people. In recent years, traditional Chinese medicine is receiving more and more attention from researchers in improving learning and memory disorders.
At present, most of drugs for improving learning and memory disorder are chemical drugs, such as cholinesterase inhibitors, drugs for regulating intestinal flora, drugs for promoting neurotransmitter function and the like, and the drugs have clear action mechanism and clear targets, but cannot meet clinical requirements. Learning and memory disorders belong to the categories of dementia, amnesia, etc. in traditional Chinese medicine, and the etiology and pathogenesis are malnutrition of brain orifices, malfilling of marrow sea, or obstruction of brain orifices by pathogenic factors, and cloudiness of marrow sea. Compared with single component, single target point and single passage of chemical medicine, which are difficult to cope with learning and memory disorder with complex pathogenesis, the Chinese medicine has the characteristics of multiple components, multiple targets, multiple passages, small toxic and side effects and the like, has more and more important, has more and more clinical application, and obtains better application effect.
Radix Angelicae Dahuricae, having warm nature, pungent taste, entering lung, spleen and stomach channels, has effects of relieving exterior syndrome, dispelling cold, dispelling pathogenic wind, relieving pain, relieving stuffy nose, eliminating dampness, stopping leukorrhagia, detumescence, expelling pus, dispelling pathogenic wind, relieving itching, and is used for treating headache, glabellar bone pain, odontalgia, nasosinusitis, cold dampness abdominal pain, intestinal wind and anal fistula, leucorrhea with reddish discharge, carbuncle, skin ulcer, skin dryness and itching, and scabies. The main ingredients include isoimperatorin (Isoimperatorin), imperatorin (Imperatorin), bergapten (Bergapten), sarcodictyins (Phellopterin), and oxydecursin (Oxypeucedanin). Imperatorin has been reported to have an inhibitory effect on acetylcholinesterase, thereby affecting the metabolism of acetylcholine, and imperatorin oxide can improve the loss of hippocampal nerves, and can be used for the preparation of a medicament for treating vascular dementia.
The angelica dahurica is a traditional medicinal and edible medicinal material, so that the research on the effect of the angelica dahurica on the aspect of treating learning and memory disorders has important practical significance on safe and effective treatment of learning and memory disorders.
Disclosure of Invention
The invention aims to provide a composition containing dahurian angelica root, a preparation method, a traditional Chinese medicine preparation and application thereof, wherein the composition takes medicinal and edible homologous medicinal materials as raw materials, has good safety and has better effect of improving learning and memory disorders.
In order to achieve the above purpose, the present invention adopts the following technical scheme:
in a first aspect, the present invention provides a composition comprising dahurian angelica root, comprising dahurian angelica root and radish extract.
The radix angelicae of the invention is radix angelicae Angelica dahurica (Fisch. Ex Hoffm.) Benth. Et hook. F. Or Hangzhou radix angelicae Angelica dahurica (Fisch. Ex Hoffm.) Benth. F. Var. Formosana (Boiss.) Shan et Yuan, umbelliferae, the use part of which is root. The radix angelicae in the invention is fresh radix angelicae or dried radix angelicae, and dried radix angelicae powder or radix angelicae decoction pieces.
The radish (Raphanus sativus L.) in the present invention is of the cruciferae family, the part used is the root. Preferably, the turnip is turnip rich in anthocyanin components, and further preferably red turnip and/or carmine turnip; still more preferably carmine radish; most preferably, the carmine radish is carmine radish with full red pericarp.
The radish extract is a dried product obtained by squeezing and filtering fresh radish. The drying is conventional in the art and suitable techniques for drying include a variety of techniques such as freeze drying, vacuum drying, spray drying, oven drying, air drying or drying in the shade.
In some specific embodiments, the composition is composed of the following raw materials, by weight, 5-15 parts of radix angelicae and 1-10 parts of radish extract.
In some specific embodiments, the amount of dahurian angelica root in the composition is 5 parts, 6 parts, 7 parts, 8 parts, 9 parts, 10 parts, 11 parts, 12 parts, 13 parts, 14 parts, 15 parts, and any one of the two ranges of values by weight.
In some specific embodiments, the amount of radish extract in the composition is 1 part, 2 parts, 3 parts, 4 parts, 5 parts, 6 parts, 7 parts, 8 parts, 9 parts, 10 parts, and any one of the two ranges of values by weight.
In some specific embodiments, the composition is composed of the following raw materials, by weight, 5-15 parts of radix angelicae and 1-5 parts of radish extract.
In some specific embodiments, the composition is composed of the following raw materials, by weight, 12 parts of dahurian angelica root, and 3 parts of radish extract.
In a second aspect, the present invention provides a process for preparing the above composition, comprising the steps of: mixing radix Angelicae Dahuricae and radix Raphani extract to obtain the composition containing radix Angelicae Dahuricae.
Preferably, the preparation method further comprises a crushing step, in particular crushing and sieving the composition.
In a third aspect, the invention provides the above Chinese medicinal preparation, comprising the composition and pharmaceutically acceptable auxiliary materials.
In some specific embodiments, the dosage form of the traditional Chinese medicine preparation is granules, tablets, capsules, powder, pills, suspension or liquid preparation.
The invention does not limit the preparation method and auxiliary materials of the traditional Chinese medicine preparation correspondingly, and a person skilled in the art can select the corresponding auxiliary materials to prepare the corresponding dosage form according to the conventional preparation method in the art.
For example:
in some specific embodiments, the Chinese medicinal preparation further comprises honey, and the person skilled in the art can prepare the Chinese medicinal preparation into honeyed pills by using the honey as an adhesive according to a conventional method.
In some specific embodiments, the Chinese medicinal preparation further comprises tea and honey, and the person skilled in the art can prepare the Chinese medicinal preparation into honeyed pills by taking honey as an adhesive and tea as a flavoring agent according to a conventional method.
In some specific embodiments, the Chinese medicinal preparation further comprises tea and honey, so that a person skilled in the art can prepare the Chinese medicinal preparation into honeyed pills by taking honey as an adhesive according to a conventional method, and the honeyed pills are taken by brewing the tea.
The honey and the tea are common products sold on the market, and the tea can be prepared into tea powder or tea extract in advance.
Specifically, the weight ratio of the composition to the honey is 1:1.0-3.0; the addition amount of the tea is 2% -20% of the weight of the composition.
In some specific embodiments, the honey is preferably a linden honey. Modern researches have shown that the linden honey has very excellent antioxidation and bacteriostasis abilities and nervous system protection effects, and the linden honey is used as a medicament, has the functions of strengthening the middle-jiao and replenishing qi, relieving cough, moistening intestines, detoxifying, aiding digestion and the like, and also has the effects of tonifying qi and tonifying kidneys, relieving pain and detoxifying, and treating and relieving various diseases such as hypertension, heart disease, constipation, insomnia and the like.
In some specific embodiments, the tea leaf is preferably shinyleaf yellowhorn leaf tea. The flavonoid compounds in the shinyleaf yellowhorn leaf in modern research are good medicines for clinically treating cardiovascular diseases, have the effects of strengthening heart, dilating coronary vessels, resisting arrhythmia, reducing blood pressure, reducing blood cholesterol, reducing capillary permeability and the like, and simultaneously have the anticancer effect because the flavonoid compounds are natural antioxidants, quercetin, derivatives thereof and the like.
The invention surprisingly discovers that the radix angelicae is taken as a main component, the radish extract is taken as an auxiliary component, and the linden honey and the shinyleaf yellowhorn tea are taken as auxiliary components, so that the mouthfeel is improved, and meanwhile, a better effect of improving the dysmnesia can be exerted.
In a fourth aspect, the present invention provides the use of the above composition and/or the Chinese medicinal preparation for the preparation of a medicament.
The medicament comprises at least one of functions of increasing learning and memory, improving cognitive functions, promoting intelligence, neuroprotection, improving depression, preventing and/or treating Alzheimer's disease.
Preferably, the composition has at least one of the following effects:
(a) Reducing aβ aggregation and/or p-Tau accumulation;
(b) Lowering TNF- α and/or IL-1β levels in hippocampal tissue;
(c) Inhibit AChE activity in brain tissue and promote Ach generation;
(d) Antioxidant stress;
(e) Repairing damage to hippocampal neurons.
The beneficial effects of the invention are as follows:
(1) The invention takes medicinal and edible medicinal materials as raw materials, has good safety and better improving effect on learning and memory disorders.
(2) Experiments prove that the composition can play roles in increasing learning and memory, improving cognitive functions, promoting intelligence, neuroprotection, improving depression, preventing and/or treating Alzheimer's disease through mechanisms of reducing Abeta aggregation and/or p-Tau accumulation, reducing TNF-alpha and/or IL-1 beta level in hippocampal tissues, inhibiting AChE activity in brain tissues, promoting Ach generation, resisting oxidative stress, repairing hippocampal neuron injury and the like.
(3) The invention surprisingly discovers that the radix angelicae is taken as a main component, the radish extract is taken as an auxiliary component, and the linden honey and the shinyleaf yellowhorn tea are taken as auxiliary components, so that the mouthfeel is improved, and meanwhile, a better effect of improving the dysmnesia can be exerted.
Drawings
FIG. 1 is a behavioral experiment timeline arrangement;
FIG. 2 is a Morris water maze apparatus diagram;
FIG. 3 is a diagram of an open field experimental set-up
Detailed Description
Other advantages and effects of the present invention will become apparent to those skilled in the art from the following disclosure, which describes the embodiments of the present invention with reference to specific examples. The invention may be practiced or carried out in other embodiments that depart from the specific details, and the details of the present description may be modified or varied from the spirit and scope of the present invention.
Before the embodiments of the invention are explained in further detail, it is to be understood that the invention is not limited in its scope to the particular embodiments described below; it is also to be understood that the terminology used in the examples of the invention is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the invention.
Where numerical ranges are provided in the examples, it is understood that unless otherwise stated herein, both endpoints of each numerical range and any number between the two endpoints are significant both in the numerical range. 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 to which this invention belongs.
The invention does not limit the sources of the adopted raw materials, and if no special description exists, the adopted raw materials are all common commercial products in the technical field.
The radix angelicae and radish extracts can be replaced by fresh radix angelicae and fresh radishes, and when the fresh radix angelicae and the fresh radishes are adopted, the dosage of the fresh radix angelicae is about 30 parts by weight, and the dosage of the fresh radishes is about 60 parts by weight.
The "pharmaceutical formulation" or "medicament" described herein, comprising the composition (hereinafter referred to as the sole active ingredient) and pharmaceutically acceptable excipients, in particular embodiments, the sole active ingredient described herein is provided in an effective amount (e.g., a therapeutically effective amount) in a pharmaceutical formulation or medicament.
The "pharmaceutically acceptable" ingredients described herein are substances suitable for use in humans and/or animals without undue adverse side effects (such as toxicity, irritation and allergic response) commensurate with a reasonable benefit/risk ratio, and include inert diluents, dispersing and/or granulating agents, surfactants and/or emulsifying agents, disintegrating agents, binders, preservatives, buffers, lubricants and/or oils. Excipients (e.g. cocoa butter and suppository waxes), colorants, coatings, sweeteners and flavoring agents may also be present in the "pharmaceutical formulation" or "medicament".
The "pharmaceutical preparation" or "drug" described in the present invention may be prepared by any method known in pharmacy. Generally, these methods of preparation involve associating the active ingredient with a carrier or excipient and/or one or more other auxiliary ingredients, and if needed and/or desired, the product may be shaped and/or packaged into the desired single or multi-dose unit.
The "pharmaceutical preparation" or "drug" of the present invention can be prepared according to a known method, for example, a method set forth in the general rules for the preparation of japanese pharmacopoeia (Japanese Pharmacopoeia) 16 th edition, united states pharmacopoeia (United States Pharmacopoeia) and european pharmacopoeia (European Pharmacopoeia) 9 th edition. The particular method of preparation depends on the dosage form.
The only active ingredient, pharmaceutically acceptable adjuvant in a "pharmaceutical formulation" or "medicament" as described herein will vary depending on the nature, size and/or condition of the subject being treated and further depending on the route of administration. A "pharmaceutical formulation" or "drug" may comprise between 0.1% and 100% (w/w) of the sole active ingredient.
The "composition", "pharmaceutical formulation" or "medicament" described herein may also optionally comprise other therapeutic ingredients for compatible use, especially those additional therapeutic ingredients as disclosed herein, such as "other nerve-protecting medicament" (i.e., a second active ingredient), wherein the other nerve-protecting medicament is a chemo-, traditional-, or chinese-patent drug formulation.
The term "treating" as used herein, unless otherwise indicated, means reversing, alleviating, inhibiting the progression of, or preventing a disorder or condition for which the term applies or one or more symptoms of such disorder or condition. The term "treatment" as used herein refers to a therapeutic action, as defined immediately above.
As used herein, an "effective amount" refers to an amount sufficient to elicit the desired biological response. The effective amount of the sole active ingredient of the present invention may vary depending on factors such as: the desired biological endpoint, the pharmacokinetics of the compound, the condition being treated, the mode of administration, and the age and health of the subject. In certain embodiments, the effective amount is a therapeutically effective amount. An effective amount is the amount of the only active ingredient set forth in the present invention in a single dose. In certain embodiments, an effective amount is the combined amount of the only active ingredients set forth in the present invention in multiple doses.
A "therapeutically effective amount" as used herein is an amount sufficient to provide a therapeutic benefit in the treatment of a disorder or to delay or minimize one or more symptoms associated with the disorder. A therapeutically effective amount of an active ingredient means an amount of the therapeutic agent alone or in combination with other therapies that provides a therapeutic benefit in the treatment of a disorder. The term "therapeutically effective amount" may encompass an amount that improves overall therapy, reduces or avoids symptoms, signs, or etiology of a disorder, and/or enhances the therapeutic efficacy of another therapeutic agent. In certain embodiments, a therapeutically effective amount is an amount sufficient to treat any of the diseases or conditions set forth.
Description of the model
Scopolamine is a non-selective competitive muscarinic cholinergic receptor antagonist, is easy to enter the center through the blood brain barrier, can reversibly block M receptors in the center, and can delay cholinergic neurotransmission, thereby interfering with the ability to acquire recent memory, and is the most widely used mode for modeling learning and memory disorders at present.
1. Safety evaluation of radix Angelicae Dahuricae pill
The SD rat is adopted as an experimental object in the experiment, and the safety of the effective dose of the administration group is judged by detecting the content of AST, ALT, BUN and CRE in serum of the angelica dahurica pill administration rat.
1. Experimental materials
1.1 Laboratory animals
Healthy SPF grade SD rats (200 g) 70, male, purchased from the medical laboratory animal center, cantonese province, using license number for the laboratory unit: SYXK (yue) 2022-0125, production license number: SYXK (Yue) 2022-0002. The animal raising environment is 18-23 deg.c, relative humidity is 45-55%, and the animal is fed with water for three days. All animal experiments were performed according to the guidelines of the experimental animal center and approved by the animal ethics committee.
1.2 Reagents and materials
Radix Angelicae Dahuricae (lot number: B5222911, chinese herbal pieces factory of Guangdong province); carmine radish (commercially available); honey (lot number: 2023072201, beijing Baihua hive scientific development Co., ltd.); xanthoceras sorbifolia leaf (lot number: 2023091801, cloisonne county forward road fort commercial limited); isoflurane (lot number: 2023071501, shenzhen Ruiword life technologies Co., ltd.); scopolamine (lot number: J2129103, aba Ding Gongsi); donepezil (lot number: 02230150, available from the plant Biotechnology Co., ltd.); 0.9% sodium chloride injection (lot number: 220818501, guangdong Daxiang pharmaceutical Co., ltd.); double distilled water (laboratory self-contained);
Glutamic pyruvic transaminase (Alanine aminotransferase, ALT) kit (batch number: 20230923, nanjing institute of biological engineering); glutamic-oxaloacetic transaminase (ASPARTATE AMINO TRANSFERASE, AST) kit (batch number: 20230922, nanjing institute of biological engineering); urea nitrogen (blood urea nitrogen, BUN) kit (lot number: 20231108, institute of bioengineering, built in tokyo); creatinine (CREATININE, CRE) kit (lot number: 20231108, nanjing's institute of biological engineering).
In particular, the method comprises the steps of,
Radix Angelicae Dahuricae pill 1 (BZ 1) comprises 50g radix Angelicae Dahuricae and 10g radix Raphani extract;
The preparation method comprises the following steps: 72g of honey is used as an adhesive, and the radix angelicae and radish extracts are prepared into radix angelicae pills.
Radix angelicae pill 2 (BZ 2): consists of 150g of angelica dahurica and 50g of radish extract;
The preparation method comprises the following steps: the radix angelicae pills are prepared from radix angelicae and radish extracts by taking 240g of honey as an adhesive.
Radix angelicae pill 3 (BZ 3): consists of 120g of angelica dahurica and 30g of radish extract;
The preparation method comprises the following steps: 180g of honey is used as an adhesive, and the radix angelicae and radish extracts are prepared into radix angelicae pills.
Wherein the radix angelicae is radix angelicae powder crushed and sieved by an 80-mesh sieve;
radix angelicae pill 4 (BZ 4): consists of 120g of angelica dahurica and 30g of radish extract;
the preparation method comprises the following steps: 180g of honey is used as an adhesive, 72g of shinyleaf yellowhorn leaf tea is used as a flavoring agent, and the radix angelicae and radish extracts are prepared into radix angelicae pills.
Wherein the radix angelicae is radix angelicae powder crushed and sieved by an 80-mesh sieve; the shinyleaf yellowhorn leaf tea is tea powder which is crushed and sieved by an 80-mesh sieve;
the radix Raphani extract is prepared by squeezing fresh radix Dauci Sativae, filtering to remove residue, freezing the filtrate to-20deg.C, and vacuum drying under 5Pa for 20 hr to obtain dried product with water content lower than 5%.
1.3 Laboratory apparatus
Multifunctional enzyme label instrument (model: spectraMax i3X, america valley molecular instrument (Shanghai) Co., ltd.)
2. Experimental method
2.1 Grouping and administration of animals
SPF-class male rats (200 g) were fed adaptively for three days, and were randomly divided into 7 groups according to body weight, namely a blank group (CON), a model group (MOD), a positive drug donepezil group (DNPQ) and a radix angelicae pill group (BZ 1-4), 10 groups each.
The CON and MOD groups were gavaged with a comparable volume of distilled water; group DNPQ rats were given donepezil at 0.52 mg/kg/d; the radix Angelicae Dahuricae pill group is administered with radix Angelicae Dahuricae pill at 2.052g/100 g/d. Dosing was performed at a fixed time daily for 30 days continuously and after 18 days dosing, a model for improving learning and memory was started. After 30min of daily administration, the MOD group and the rats of the administration group were intraperitoneally injected with scopolamine 3mg/kg/d (prepared by physiological saline), the CON group rats were injected with an equal volume of physiological saline, and the molding was continued for 12 days.
2.2 Sample collection
After 12h of the last scopolamine injection, all rats were anesthetized with isoflurane. Rat blood was collected from the abdominal aorta, blood in procoagulant blood collection tubes was centrifuged at 3500rpm for 10 minutes at 4℃and the upper serum was separated and stored in a-80℃freezer. After blood collection, the brain, heart, liver, lung, kidney, colon and fecal of the rat are dissected and collected, quenched by liquid nitrogen and then put into a refrigerator at-80 ℃ for preservation. The removed brain tissue was excised about 3mm along the transverse coronal plane and placed into an embedding cassette, which was immersed in 4% tissue cell fixative.
2.3 Biochemical serum detection
Serum was collected and tested for AST, ALT, BUN, CRE activity in rat serum, and specific procedures were performed according to the instructions of the biochemical kit of Nanjing's established biotechnology Co., ltd.
2.4 Statistical analysis
Data were analyzed using SPSS25.0 statistical software and the results are expressed as mean ± standard deviation. Drawing is carried out by adopting GraphPad prism9.0, independent sample t test is adopted for group comparison, single factor analysis of variance is adopted for multi-group mean comparison, and LSD is adopted for pairwise comparison. P <0.05 is statistically significant for differences and P <0.01 is highly statistically significant for differences.
3 Experimental results and analysis
To determine the safety of the effective dose of the administered group, the present experiment examined the content of AST, ALT, BUN and CRE in serum of rats administered with the dahurian angelica pill.
The results in Table 1 show that after 30d of administration of the radix Angelicae Dahuricae pill 1-4 groups, the differences of the biochemical indexes in serum compared with the CON group are not significant (P > 0.05), which indicates that the radix Angelicae Dahuricae pill has good safety at the dosage.
The ALT index detection result shows that compared with the CON group, the ALT level in the serum of the rats in the MOD group has a significant difference (P is less than 0.05), which indicates that after scopolamine modeling, the ALT level is increased to some extent due to damage of hepatic cell membranes.
After the radix angelicae pills are infused into the stomach, ALT level in serum of rats in BZ1-4 groups is obviously reduced (P is less than 0.05) compared with that in MOD groups, which indicates that the radix angelicae pills have a certain protection effect on liver function.
TABLE 1 influence of Dahurian Angelica pills on AST, ALT, BUN and CRE in rat serumn＝10)
Note that: # P <0.05 compared to CON group; **P<0.01,* P <0.05 compared to MOD group.
2. Radix angelicae pill for improving learning and memory
SD rats are adopted as experimental objects in the experiment, and the study and memory effects of the rats are improved by establishing a study and memory improvement model and observing the angelica dahurica pill prescription.
1. Experimental materials
1.1 Laboratory animals
Healthy SPF grade SD rats (200 g), male, purchased from the medical laboratory animal center, cantonese province, unit of experiment use license number: SYXK (yue) 2022-0125, production license number: SYXK (Yue) 2022-0002. The animal raising environment is 18-23 deg.c, relative humidity is 45-55%, and the animal is fed with water for three days. All animal experiments were performed according to the guidelines of the experimental animal center and approved by the animal ethics committee.
1.2 Reagents and materials
Radix Angelicae Dahuricae (lot number: B5222911, chinese herbal pieces factory of Guangdong province); carmine radish (commercially available); honey (lot number: 2023072201, beijing Baihua hive scientific development Co., ltd.); xanthoceras sorbifolia leaf (lot number: 2023091801, cloisonne county forward road fort commercial limited); isoflurane (lot number: 2023071501, shenzhen Ruiword life technologies Co., ltd.); scopolamine (lot number: J2129103, aba Ding Gongsi); donepezil (lot number: 02230150, available from the plant Biotechnology Co., ltd.); 0.9% sodium chloride injection (lot number: 220818501, guangdong Daxiang pharmaceutical Co., ltd.);
The composition and preparation method of the angelica dahurica pills 1-4 (BZ 1-4) are the same as the 1.2 part in the safety evaluation of the Yi and Baizhui pills, and the preparation methods of the angelica dahurica powder and the radish extract are the same as the 1.2 part in the safety evaluation of the Yi and Baizhi pills.
1.3 Laboratory apparatus
Morris water maze System (Guangzhou Bite Biotechnology Co., ltd.), open field experiment System (Anhua Zhenghua biological Equipment Co., ltd.). The data were analyzed by video tracking software (SMART 3.0).
2. Experimental method
2.1 Grouping and administration of animals
SPF-grade male rats (200 g) were fed adaptively for three days, and were randomly divided into 9 groups according to body weight, namely a blank group (CON), a model group (MOD), a positive drug donepezil group (DNPQ), 1-4 groups of radix angelicae pills (BZ 1-4), a radix angelicae group (BZ 0) and a radish group (LB 0), 7 groups each. The CON and MOD groups were gavaged with a comparable volume of distilled water; group DNPQ rats were given donepezil at 0.52 mg/kg/d; the radix angelicae pill group is administered with radix angelicae pill according to 0.228g/100 g/d. Radix Angelicae Dahuricae powder is administered according to 0.2288g/100g/d, radix Raphani extract is administered according to 0.2288g/100g/d, administration is carried out for a fixed time every day, administration is continued for 30 days, and after administration for 18 days, a learning and memory improving model is established.
After 30min of daily administration, the MOD group and the rats of the administration group were intraperitoneally injected with scopolamine 3mg/kg/d (prepared by physiological saline), the CON group rats were injected with an equal volume of physiological saline, and the molding was continued for 12 days. After 30min of modeling, a behavioural experiment is started, and whether the model is copied successfully is evaluated according to the behavioural experiment result.
2.2 Behavioural detection
The behavioural test comprises the test of learning and memory ability of rats in water maze, open field experiment and the like. Wherein the timing of each behavioural experiment is shown in figure 1.
2.2.1Morris Water maze experiments
The Morris water maze was used to evaluate the learning and memory function of mice. The Morris experimental apparatus is shown in FIG. 2 as a cylindrical pool of 150cm diameter and 50cm height, the interior of which is divided into 4 equal sized quadrants, and a platform is placed in the center of one of the quadrants, the platform position once determined will remain unchanged throughout the behavioural test. Two perpendicular intersecting lines with the center of the pool divide it into 4 quadrants: the method comprises the following steps of sequentially planning the northwest, northeast, southeast and southwest into I, II, III, IV quadrants, and adhering markers with different colors and different shapes on the inner wall of a pool in each quadrant: round, triangular, star-shaped, square, and is convenient for experimental rat memory. The water temperature was controlled at 22.+ -. 2 ℃ during the experiment. In the behavioural test, the swimming activity of the rat is recorded by a camera device above the water maze pool, and the data is processed by an image collector and behavioural software and stored in a computer.
Morris water maze experiment:
A. And (3) adaptability training: the day before the experiment starts, water is put into the water maze, but a platform is not placed, the water maze adaptability training is carried out on the rats, each rat is subjected to the adaptability training for 1-2min, and then the rats are taken out and wiped dry.
B. Positioning navigation experiment: and after molding, the molding is carried out for 30 min. The experiment is carried out at the same time point every day, when the experiment is carried out, the rat is put into water facing the pool wall, the time (latency period) of the rat for searching the platform is recorded as an index of learning and memorizing, if the rat finds the platform within 90s, the time used by the rat is recorded, and the rat stays on the platform for 5s; if the time reaches 90s and the platform is not found yet, the rat is guided to swim to the platform and stay for 5s, and the escape latency is recorded as 90s. The 2 nd training was performed after the whole group of rats had been trained. Training was continued for 5 days, 4 times per day (rats were placed from four quadrants, respectively). In the process, the position of the platform is fixed, and the water inlet point of the rat is determined in advance in a pseudo-random mode during training. The training sequence of rats on the same day is the same. The escape latency gradually shortens during the 5-day training, indicating that the learning ability of the rats is enhanced.
C. Space exploration experiment: the next day after the positioning sailing experiment is finished (namely, the sixth day of the water maze experiment), the platform is removed, the rat is put into the water from the fixed water inlet point (the diagonal position of the platform) facing the pool wall, the rat freely explores for 90s, the swimming time proportion of the rat in the quadrant where the original platform is located and the number of times of crossing the position where the original platform is located, namely, the shuttle times are measured, and the space memory capacity of the rat is reflected. The more the number of times the rat passes through the original platform position, the longer the residence time in the target quadrant, indicating that the higher the spatial memory capacity of the rat.
2.2.2 Open field experiments
Open field experimental setup as shown in figure 3. Before the test, the shooting picture is adjusted, so that the open field area can be completely displayed on a computer program. When the test starts, a camera shooting program is started, the observation time is set to be 5min, the rat is gently placed in the central area of the open field, and the free movement track of the rat in the open field, the movement distance in the central area, the total movement distance in the open field, the movement track in the open field box, the stay time in the peripheral area and the central area, the standing times, the decoration times, the total movement distance and the like are recorded. The data were analyzed by video tracking software (SMART 3.0). After the test of each rat is finished, 75% medical alcohol is sprayed into the plastic box, so that dirt in the box is thoroughly removed, and the odor of excrement in the box is reduced as much as possible, so that the residual odor or dirt can not influence the activity of the next rat.
2.3 Statistical analysis
Data were analyzed using SPSS25.0 statistical software, with the results all expressed as mean.+ -. Standard deviationAnd (3) representing. Drawing is carried out by adopting GraphPad prism9.0, independent sample t test is adopted for group comparison, single factor analysis of variance is adopted for multi-group mean comparison, and LSD is adopted for pairwise comparison. P <0.05 is statistically significant for differences and P <0.01 is highly statistically significant for differences.
3. Experimental results and analysis
3.1 Results of behavioural experiments
TABLE 2 open field experimental resultsn＝7)
Note that: **** P <0.0001, < P <0.01 compared to CON group; * P <0.05; ###P<0.001,## P <0.01 compared to MOD group.
The results in table 2 show that compared with the CON group, MOD group showed significantly reduced standing times (P < 0.0001), significantly reduced modification times (P < 0.05), significantly reduced central area residence time (P < 0.01), no significant difference in total distance and average speed (P > 0.05), indicating impaired learning and memory ability of the rats after modeling, exploration desire to be reduced, but normal exercise ability.
Compared with MOD group, BZ1-4 group has significantly increased standing times (P < 0.01) and significantly increased modification times (P < 0.05), which indicates that the administration of radix Angelicae Dahuricae pill by stomach infusion can improve learning and memory ability of rats.
Compared with the MOD group, the standing times and the modification times of the BZ0 group and the LB0 group are not significantly different (P is more than 0.05), which indicates that the radix angelicae powder or the radish extract with single gastric lavage can not improve the learning and memory ability of rats.
3.2. Results of water maze experiments
TABLE 3 spatial exploration of rats Experimental results [ ]n＝6)
Note that: **** P <0.0001, < P <0.001 compared to CON group; ####P<0.0001,###P<0.001,## P <0.01 compared to MOD group; Δp <0.05 compared to BZ1 group.
The results in Table 3 show that the MOD group has significant differences (P < 0.001) in the number of times the rats traversed the platform, the target quadrant activity distance, the target quadrant residence time, and the first time the platform was reached, compared to the CON group. The rat after scopolamine intervention has poor learning and memory ability, and the success of modeling of the experiment is proved.
Compared with the MOD group, the number of times of crossing the platform, the target quadrant activity distance and the first arrival time of rats in the BZ1-4 groups are obviously different (P is smaller than 0.01), and the number of times of crossing the platform, the target quadrant activity distance and the first arrival time of rats in the BZ0 group and the LB0 group are not obviously different (P is larger than 0.05), so that the study memory of rats can be improved by the stomach-infused angelica pills, and the study memory of rats cannot be obviously improved by single angelica powder or radish extract.
Compared with the BZ1 group, the BZ0 group and the LB0 group, the number of times of crossing the platform, the target quadrant activity distance and the first time reaching the platform of the rats are all significantly different (P is less than 0.01), which indicates that the radix angelicae pill has better effect of improving the learning ability of the rats compared with radix angelicae powder or radix angelicae extract.
3. Radix angelicae pill for treating Alzheimer disease
1. Experimental materials
1.1 Laboratory animals
Healthy SPF grade SD rats (200 g), male, purchased from the medical laboratory animal center, cantonese province, unit of experiment use license number: SYXK (yue) 2022-0125, production license number: SYXK (Yue) 2022-0002. The animal raising environment is 18-23 deg.c, relative humidity is 45-55%, and the animal is fed with water for three days. All animal experiments were performed according to the guidelines of the experimental animal center and approved by the animal ethics committee.
1.2 Reagents and materials
Radix Angelicae Dahuricae (lot number: B5222911, chinese herbal pieces factory of Guangdong province); carmine radish (commercially available); honey (lot number: 2023072201, beijing Baihua hive scientific development Co., ltd.); xanthoceras sorbifolia leaf (lot number: 2023091801, cloisonne county forward road fort commercial limited); isoflurane (lot number: 2023071501, shenzhen Ruiword life technologies Co., ltd.); scopolamine (lot number: J2129103, aba Ding Gongsi); donepezil (lot number: 02230150, available from the plant Biotechnology Co., ltd.); 0.9% sodium chloride injection (lot number: 220818501, guangdong Daxiang pharmaceutical Co., ltd.);
Rat acetylcholine (ACh) ELISA scientific kit (lot number: 20231120R219, jiangsu enzyme-free Industrial Co., ltd.); rat acetylcholinesterase (AChE) ELISA scientific kit (lot number: 20231120R205, jiangsu enzyme-free Utility Co., ltd.); rat phosphorylated Tau protein (P-Tau) ELISA scientific kit (lot number: 20231120R147, jiangsu enzyme free Industrial Co., ltd.); ELISA scientific kit for rat amyloid beta 42 (Abeta 42) (lot number: 20231120R048, jiangsu enzyme-free Utility Co., ltd.); ELISA scientific kit for rat tumor necrosis factor alpha (TNF-alpha) (lot number: 20231120R036, jiangsu enzyme-free Industrial Co., ltd.); rat interleukin 1 beta (IL-1 beta) ELISA scientific kit (lot number: 20231120R107, jiangsu enzyme-free real Co., ltd.); rat Lipopolysaccharide (LPS) ELISA scientific kit 96T (lot number: 20231120R190, jiangsu enzyme-free Industrial Co., ltd.); rat brain-derived neurotrophic factor (BDNF) ELISA scientific kit (lot number: 20231120R167, jiangsu enzyme-free Utility Co., ltd.);
ADS-W-KY011 superoxide dismutase (SOD) kit-WST-8 microplate method (lot number: ADS20231121, jiangsu enzyme free Industrial Co., ltd.); ADS-W-G003 Glutathione Peroxidase (GPX) kit-visible chromogenic microplate method (lot number: ADS20231121, jiangsu enzyme free Industrial Co., ltd.); ADS-W-YH002 Malondialdehyde (MDA) kit microplate method (lot number: ADS20231121, jiangsu enzyme free Industrial Co., ltd.);
The composition and preparation method of the angelica dahurica pills 1-4 (BZ 1-4) are the same as the 1.2 part in the safety evaluation of the Yi and Baizhui pills, and the preparation methods of the angelica dahurica powder and the radish extract are the same as the 1.2 part in the safety evaluation of the Yi and Baizhi pills.
1.3 Laboratory apparatus
Multifunctional enzyme labeling instrument (model: spectraMax i3X, america Valley molecular instruments (Shanghai Co.).
2. Experimental method
2.1 Grouping and administration of animals
SPF-grade male rats (200 g) were fed adaptively for three days, and were randomly divided into 9 groups according to body weight, namely a blank group (CON), a model group (MOD), a positive drug donepezil group (DNPQ), 1-4 groups of radix angelicae pills (BZ 1-4), a radix angelicae group (BZ 0) and a radish group (LB 0), 10 groups each. The CON and MOD groups were gavaged with a comparable volume of distilled water; group DNPQ rats were given donepezil at 0.52 mg/kg/d; the radix angelicae pill group is administered with radix angelicae pill according to 0.228g/100 g/d. Radix Angelicae Dahuricae powder is administered according to 0.2288g/100g/d, radix Raphani extract is administered according to 0.2288g/100g/d, administration is carried out for a fixed time every day, administration is continued for 30 days, and after administration for 18 days, a learning and memory improving model is established.
After 30min of daily administration, the MOD group and the rats of the administration group were intraperitoneally injected with scopolamine 3mg/kg/d (prepared by physiological saline), the CON group rats were injected with an equal volume of physiological saline, and the molding was continued for 12 days.
2.2 Sample collection
After 12h of the last scopolamine injection, all rats were anesthetized with isoflurane. Rat blood was collected from the abdominal aorta, blood in procoagulant blood collection tubes was centrifuged at 3500rpm for 10 minutes at 4℃and the upper serum was separated and stored in a-80℃freezer. After blood collection, the brain, heart, liver, lung, kidney, colon and fecal of the rat are dissected and collected, quenched by liquid nitrogen and then put into a refrigerator at-80 ℃ for preservation. The removed brain tissue was excised about 3mm along the transverse coronal plane and placed into an embedding cassette, which was immersed in 4% tissue cell fixative.
2.3Elisa assay and Biochemical index assay
Serum and brain tissues are collected, and the content of ACh, AChE, A beta 42 and the content of p-Tau in rat brain hippocampus are detected; TNF-alpha and IL-1 beta contents in cerebral cortex and LPS and BDNF contents in serum, and the specific operation is carried out according to the specification of an enzyme-linked immunoassay kit;
Brain tissues are collected, the SOD, MDA, GSH-Px content in rat brain hippocampus is detected, and the specific operation is carried out according to the instruction of an analysis kit.
2.4 Statistical analysis
Data were analyzed using GraphPad prism9.0 statistical software, and results were expressed as mean ± standard deviation, independent sample t-test was used for group-to-group comparisons, single factor analysis of variance was used for group-to-group comparisons, and LSD was used for pairwise comparisons. P <0.05 is statistically significant for differences and P <0.01 is highly statistically significant for differences.
3. Experimental results and analysis
3.1Elisa assay data analysis
(1) ACh is an important bridge for information transfer between nerve cells and the nervous system, and AChE catalyzes the hydrolysis of excess ACh after signaling. ACh and AChE play an important role in information transmission in cholinergic systems, the reduction of ACh level is an early pathological symptom of nervous systems, and the change of ACh and AChE level can evaluate that angelica dahurica pills can relieve rat memory injury caused by cholinergic system unbalance caused by scopolamine.
TABLE 4 influence of Dahurian Angelica pills on rats ACh, AChE, A beta 42, p-tau and BDNNFn＝10)/>
Note that: # # P <0.0001 compared to CON group; compared to MOD groups, P <0.0001, P <0.001, P <0.01, P <0.05; Δp <0.05 compared to BZ1 group.
As can be seen from the results in table 4, compared with the CON group, the ACh level of the brain hippocampus of the MOD group rat was significantly reduced (P < 0.0001), the AChE level was significantly increased (P < 0.0001), indicating that the cholinesterase activity of the model rat was significantly increased, resulting in a decrease in the cholinesterase content, indicating that the model of the animal model was successful, and scopolamine could significantly reduce ACh level of the brain tissue of the rat, resulting in impaired memory function of the rat.
Compared to MOD groups, BZ1-4 groups of rats had significantly elevated brain hippocampal tissue ACh levels (P < 0.0001) and significantly reduced AChE levels (P < 0.0001). AChE is an important index reflecting the function of the choline system in the brain, and the content of ACh between degradable cholinergic synapses can indirectly reflect the content of AChE in the body. The experiment shows that the ACh activity of the scopolamine induced model rat hippocampal tissue is increased and the AChE activity is reduced after the intervention of the angelica dahurica pill, which shows that the regulation of cholinergic nervous system functions is a potential cause of the angelica dahurica pill for improving the learning and memory ability disorder of the model rat.
Compared with BZ1 group, the levels of ACh of rat brain hippocampus tissues of BZ0 group and LB0 group are obviously increased (P is less than 0.05), and the levels of AChE are obviously reduced (P is less than 0.05), which shows that the radix angelicae pill has better effect than single radix angelicae powder or radix angelicae extract.
Meanwhile, compared with the COD group, the content of Abeta 42 and P-Tau in the rat brain hippocampus of the MOD group is obviously increased (P < 0.0001), which indicates that scopolamine can induce the expression of Abeta 42 and P-Tau proteins, thereby causing synaptic dysfunction and impaired memory.
Compared with the MOD group, the BZ1-4 group rat brain hippocampus has significantly reduced content of Abeta 42 and P-Tau (P < 0.0001), which indicates that the radix angelicae pill can down regulate the Abeta 42 and P-Tau level, reduce Abeta aggregation and P-Tau accumulation to a certain extent, thereby improving the memory disorder of the rat.
Compared with the MOD group, the content of Abeta 42 and P-Tau in the rat brain hippocampus of the BZ0 group and the LB0 group is not remarkably reduced (P is more than 0.05), and compared with the BZ1 group, the content of Abeta 42 and P-Tau in the rat brain hippocampus of the BZ0 group and the LB0 group is remarkably different (P is less than 0.05), which indicates that single radix angelicae powder or radish extract can not down regulate the level of Abeta 42 and P-Tau, and the effect of improving the memory disorder of rats is not achieved.
(2) Inflammatory response plays an important role in the learning and memory impairment process of scopolamine-induced mice, and increases the levels of TNF-alpha and IL-1β in patients with learning and memory impairment.
TABLE 5 influence of Dahurian Angelica pills on rat TNF-alpha, IL-1 beta and LPSn＝10)/>
Note that: # # P <0.0001 compared to CON group; compared to MOD groups, P <0.0001, P <0.001, P <0.01, P <0.05; Δp <0.05 compared to BZ1 group.
From the results in Table 5, it was found that the inflammatory reaction in rats in the MOD group was significantly increased compared to the CON group, as shown by significantly increasing the contents of the pro-inflammatory factors TNF-. Alpha.and IL-1β (P < 0.0001).
Compared with MOD group, the content of TNF-alpha and IL-1 beta in BZ1-4 group rats is obviously reduced (P < 0.05), which indicates that the radix angelicae pill can reduce the level of TNF-alpha and IL-1 beta in the hippocampal tissue of SD rat and relieve the memory dysfunction caused by scopolamine.
The reduction of TNF-alpha content in the BZ0 and LB0 rats was significant (P < 0.05) compared to MOD group, the reduction of IL-1β content was not significant (P > 0.05), while the TNF-alpha content in the BZ0 and LB0 rats was significantly different (P < 0.05) compared to BZ1 group, indicating that single radix angelicae powder or radish extract had no efficacy in alleviating scopolamine-induced memory dysfunction.
Meanwhile, the detection result of the LPS content in the rat serum can be obtained, compared with the CON group, the LPS level of the MOD group is obviously increased (P < 0.0001), and compared with the MOD group, the LPS level of the BZ1-4 group is obviously reduced (P < 0.05), which indicates that the radix angelicae pill can maintain the intestinal barrier function and prevent harmful substances such as intestinal bacteria and toxins (such as LPS) from entering blood circulation or other tissues through intestinal mucosa. Compared with MOD group, LPS level of BZ0 group and LB0 group has no significant difference (P > 0.05), which shows that single radix Angelicae Dahuricae powder or radix Raphani extract has no maintenance of intestinal barrier function, and prevents harmful substances such as intestinal bacteria and toxins (such as LPS) from entering blood circulation or other tissues through intestinal mucosa.
From the above results, it can be seen from Table 4 and Table 5 that the radix Angelicae Dahuricae pill of the invention can exert the effects of resisting dementia and improving intelligence by regulating abnormal tau protein, improving cholinergic system, resisting oxidation and other multiple ways and multiple targets.
3.2 Analysis of Biochemical index detection data
The nerve tissue structure is unique, is more easily attacked by oxygen free radicals, damages macromolecular structures such as DNA and the like, induces apoptosis and death of nerve cells, and leads to learning and memory ability disorder. Oxidative stress is an important mechanism of neuronal damage in neurodegenerative diseases, and scopolamine can induce oxidative stress. SOD is an important antioxidant enzyme in vivo, and its activity is reduced in the body of a patient with impaired learning and memory ability, and free radicals are produced in large amounts, causing impaired brain tissue function. MDA is a toxic metabolite that causes cell damage and cell death during oxidation. It can reflect the degree of influence of free radical, and has toxicity, which can lead to degeneration, apoptosis and necrosis of neuron cells of patients with learning and memory dysfunction. When SOD level is reduced and MDA content is increased, oxidative stress reaction can be initiated, so that cells are damaged and even dead, and memory is influenced. So SOD and MDA are considered as main markers reflecting the redox state of the body.
GSH is used as an important antioxidant and free radical scavenger, and can be combined with free radicals, heavy metals and the like, so that the effect of protecting cells is achieved, under normal conditions, an oxidation-antioxidation system in a machine body maintains a relatively dynamic balance state, excessive reactive oxygen species can be cleared by self antioxidant enzyme GSH-px, but when the oxidation degree exceeds self clearance capacity, the oxidation balance is broken, and the oxidative stress damage of nerve tissues finally causes impaired learning and memory and cognitive functions.
TABLE 6 influence of Dahurian Angelica pill on SOD, MDA and GPX in ratsn＝10)
Note that: #### P <0.0001 compared to CON group; compared to MOD groups, P <0.0001, P <0.001,
* P <0.01, P <0.05; Δp <0.05 compared to BZ1 group.
As shown in Table 6, the SOD level and GSH-px level were significantly reduced (P < 0.001) and MDA level was significantly increased (P < 0.0001) in the brain tissue of the mice in the MOD group, compared with the CON group, indicating that the modeling was successful.
Compared with the MOD group, the BZ1-4 groups have obviously increased brain tissue SOD level and GSH-px (P < 0.01), the MDA level is obviously reduced (P < 0.05), and compared with the MOD group, the BZ0 group and the LB0 group have obviously reduced brain tissue SOD level, GSH-px and MDA level (P > 0.05).
In conclusion, the radix angelicae pills can increase SOD activity in brain hippocampus of rats with dysmnesia, reduce MDA content, and can remarkably improve GSH-px content in brain tissues of rats with dysmnesia. Indicating that the antioxidant stress is a potential mechanism for improving the learning and memory capacity of rats with the model by pills.
The invention has been further described above in connection with specific embodiments, which are exemplary only and do not limit the scope of the invention in any way. It will be understood by those skilled in the art that various changes and substitutions of details and forms of the technical solution of the present invention may be made without departing from the spirit and scope of the present invention, but these changes and substitutions fall within the scope of the present invention.
Claims (10)
1. The composition containing the angelica dahurica is characterized by comprising the angelica dahurica and a radish extract, wherein the angelica dahurica is fresh angelica dahurica or dried angelica dahurica, and the radish extract is a dried product obtained by squeezing and filtering fresh radish.
2. The composition of claim 1, wherein the radish is red-heart radish and/or carmine radish.
3. The composition according to claim 1, which is composed of the following raw materials, by weight, 5-15 parts of dahurian angelica root and 1-10 parts of radish extract.
4. A process for the preparation of a composition as claimed in any one of claims 1 to 3, comprising the steps of: mixing radix Angelicae Dahuricae and radix Raphani extract.
5. A Chinese medicinal preparation, comprising the composition of any one of claims 1-3 and pharmaceutically acceptable excipients.
6. The traditional Chinese medicine preparation according to claim 5, wherein the dosage form of the traditional Chinese medicine preparation is granule, tablet, capsule, powder, pill, suspension or liquid preparation.
7. The traditional Chinese medicine preparation according to claim 5, comprising honey and/or tea.
8. The traditional Chinese medicine preparation according to claim 7, wherein the honey is linden honey and the tea is green tea and/or shinyleaf yellowhorn leaf tea.
9. Use of the composition of any one of claims 1-3 and/or the Chinese herbal formulation of any one of claims 5-8 for the manufacture of a medicament comprising at least one of increasing learning and memory function, improving cognitive function, promoting intelligence, neuroprotection, improving depression, preventing and/or treating alzheimer's disease.
10. The use according to claim 9, wherein the composition has at least one of the following effects:
(a) Reducing aβ aggregation and/or p-Tau accumulation;
(b) Lowering TNF- α, IL-1β levels in hippocampal tissue;
(c) Inhibit AChE activity in brain tissue, promote Ach generation;
(d) Antioxidant stress;
(e) Repairing damage to hippocampal neurons.
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