CN111569008A - A pharmaceutical composition for treating neurodegenerative diseases - Google Patents
A pharmaceutical composition for treating neurodegenerative diseases Download PDFInfo
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- CN111569008A CN111569008A CN202010385274.2A CN202010385274A CN111569008A CN 111569008 A CN111569008 A CN 111569008A CN 202010385274 A CN202010385274 A CN 202010385274A CN 111569008 A CN111569008 A CN 111569008A
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- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/105—Plant extracts, their artificial duplicates or their derivatives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/25—Araliaceae (Ginseng family), e.g. ivy, aralia, schefflera or tetrapanax
- A61K36/258—Panax (ginseng)
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/48—Fabaceae or Leguminosae (Pea or Legume family); Caesalpiniaceae; Mimosaceae; Papilionaceae
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/53—Lamiaceae or Labiatae (Mint family), e.g. thyme, rosemary or lavender
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/88—Liliopsida (monocotyledons)
- A61K36/888—Araceae (Arum family), e.g. caladium, calla lily or skunk cabbage
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
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- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
Abstract
The invention discloses a pharmaceutical composition with the effect of treating neurodegenerative diseases, which comprises the following components in parts by weight: 10-90 parts of gastrodia elata extract, 10-90 parts of pseudo-ginseng extract, 10-90 parts of rhizoma acori graminei extract, 10-90 parts of coleus forskohlii extract and 10-90 parts of peanut shell extract. The pharmaceutical composition has stronger prevention or antagonism effect on neurodegenerative diseases, and the pharmaceutical composition has better pharmacological activity compared with a single extract under the same dosage.
Description
Technical Field
The invention belongs to the field of traditional Chinese medicines, and particularly relates to a traditional Chinese medicine extract composition with a function of treating neurodegenerative diseases.
Background
Dementia is a chronic central nervous system degenerative disease characterized by memory impairment and cognitive dysfunction induced by multiple factors, which is characterized by chronic memory impairment, cognitive dysfunction and personality change, gradually progresses to severe dementia, and is a neurodegenerative disease with a high incidence rate in the elderly population. Dementia includes Alzheimer's Disease (AD), vascular dementia (VaD), brain traumatic dementia, dementia caused by poisoning, anoxia, etc., and mixed dementia. The proportion of AD is 50-75% and the proportion of VaD is 5-20% in patients with common diseases. The number of dementia patients worldwide is estimated to be 4400 ten thousand, which is expected to double every 20 years. Because the aging condition of China is intensified, the number of people suffering from dementia is also increased rapidly, so that the research and development of safe and effective prevention and treatment medicines are important subjects faced in scientific research work at home and abroad at present.
The pathogenesis of dementia is complex and not completely understood, and the general view is that dementia is caused by the deposition of cerebral cortex beta-amyloid (a β) and hyperphosphorylation of tau protein. In the process of the onset of AD, Amyloid Precursor Protein (APP) of a β and its precursor, Presenilin (PS), tau protein, apolipoprotein e (apoe), and the like play an extremely important role. VaD is mainly associated with vascular injury such as cerebral stroke and cerebral ischemia, has close relationship with the decrease of cerebral blood flow and cerebrovascular diseases, cognitive impairment caused by ischemia and hypoxic brain injury, and also associated with a β deposition and tau protein.
Currently, the relevant dementia treatment drugs on the market mainly comprise choline kinase inhibitors (polynaphthalene and galantamine); drugs that improve cerebral blood circulation and cerebral cell metabolism (e.g., neramelin, blepharam, etc.); glutamate receptor antagonists, representative of drugs such as memantine; calcium ion blockers, representing the drug nimodipine; a neuroprotective agent; non-steroidal anti-inflammatory drugs (aspirin); radical scavengers, antioxidants, and the like. However, the above drugs have limited effects and therapeutic effects, and have drug resistance and side effects after long-term use, and thus there is a clinical shortage of more drug options. Chinese medicine culture is profound and profound, and the treatment effect is obvious, so that the development of Chinese medicine medicines for treating neurodegenerative diseases has good practical value.
Gastrodia elata (Gastrodia elata) belongs to a rare traditional Chinese medicine, is mainly distributed in Sichuan, Shaanxi, Yunnan and other places, and is clinically used for treating convulsion, rheumatism, headache, dizziness, thoracic obstruction, epilepsy and the like in traditional Chinese medicine. Modern pharmacological research finds that the active ingredients in the gastrodia elata have the effects of improving intelligence and strengthening brain, have a certain curative effect on senile dementia, reduce the A beta level of an AD animal model, inhibit cholinesterase activity, improve the symptoms of the AD animal model and the like. Zhaotong is a nationally recognized genuine medicinal material production area of Gastrodia elata Blume, Zhaotong Gastrodia elata Blume is a unique biological resource of Zhaotong, and the national geographical marker product of "Zhaotong Gastrodia elata Blume" has a long history and is called "North Gastrodia elata Blume and south Notoginseng radix" together with Wensshan Notoginseng radix. The preliminary research of a subject group discovers that the rhizoma gastrodiae extract of the Showa-and-Wu-Gastrodia elata has stronger effects of benefiting intelligence and strengthening brain, and the compound preparation formed by the Showa-and-Wu-Gastrodia elata extract and other traditional Chinese medicine components has better synergistic effect on preventing and treating AD possibly.
Pseudo-ginseng, most famous for Yunnan Wenshan pseudo-ginseng, has the main clinical effects of promoting blood circulation to remove blood stasis, and relieving swelling and pain. In recent years, research shows that the pseudo-ginseng can improve the immunity. Grassleaf sweetflag rhizome, being slightly warm in nature, pungent and bitter in flavor, belongs to an resuscitative drug and is mainly used for epilepsy, amnesia, vexation in heart and chest, etc. clinically. Modern pharmacological research finds that the rhizoma acori graminei has the pharmacological effects of tranquilizing, improving memory loss, inducing resuscitation and the like. Coleus forskohlii is a plant which is required by Yunnan characteristics, has pharmacological effects of resisting inflammation and the like, and has no report on the treatment effect of dementia neurodegenerative diseases. Peanut shells, which are the woody shells of the annual herbaceous plant peanuts, are pharmaceutically acceptable. The medicinal effects of the traditional Chinese medicine are mainly cough and phlegm reduction, antibiosis and antiphlogosis, blood pressure reduction and lipid reduction and the like, but the pharmacological action for treating neurodegenerative diseases is rarely reported.
Disclosure of Invention
Aiming at the defects existing in the current dementia drug treatment, the invention provides a traditional Chinese medicine extract composition with the effect of treating neurodegenerative diseases by combining the unique advantages of traditional Chinese medicines in the aspect of dementia treatment.
In order to achieve the purpose, the invention adopts the following technical scheme:
a pharmaceutical composition comprises the following components in parts by weight: 10-90 parts of gastrodia elata or gastrodia elata extract, 1-10 parts of pseudo-ginseng or pseudo-ginseng extract, 1-10 parts of rhizoma acori graminei or rhizoma acori graminei extract, 1-10 parts of coleus forskohlii or coleus forskohlii extract and 1-50 parts of peanut shell or peanut shell extract.
The pharmaceutical composition preferably comprises the following components in parts by weight: 20-50 parts of gastrodia elata or gastrodia elata extract, 5-10 parts of pseudo-ginseng or pseudo-ginseng extract, 5-10 parts of rhizoma acori graminei or rhizoma acori graminei extract, 1-5 parts of coleus forskohlii or coleus forskohlii extract and 5-20 parts of peanut shell or peanut shell extract.
The pharmaceutical composition more preferably comprises the following components in parts by weight: 30 parts of gastrodia elata or gastrodia elata extract, 6.25 parts of pseudo-ginseng or pseudo-ginseng extract, 6 parts of grassleaf sweelflag rhizome or grassleaf sweelflag rhizome extract, 2 parts of coleus forskohlii or coleus forskohlii extract and 10 parts of peanut shell or peanut shell extract.
The medicinal composition can be directly taken after being mixed and ground according to a proportion, and can also be further processed into an extract which is mixed according to a proportion to prepare a medicament.
The gastrodia elata extract, the pseudo-ginseng extract, the grassleaf sweelflag rhizome extract, the coleus forskohlii extract and the peanut shell extract can be obtained by extracting with water, alcohol or a mixed solution thereof (such as water, ethanol and 50-70% of ethanol).
A specific example is prepared by the following method, but should not be limited by the disclosed method, and extraction solvents or combinations of solvents of similar polarity or properties and methods can be considered as equivalents of the reagents and extraction methods used in this extraction method.
Preparing a gastrodia elata extract: drying and pulverizing qualified rhizoma Gastrodiae, soaking in 50% ethanol/water, and concentrating the extractive solution. Adding the concentrate into 50% ethanol/water, and extracting under reflux at 85-90 deg.C. Concentrating the extractive solution, and drying to obtain rhizoma Gastrodiae extract.
Preparing a pseudo-ginseng extract: drying the qualified notoginseng root, adding 70% ethanol 8 times the weight of the notoginseng root, refluxing, concentrating the extract, and drying to obtain the notoginseng extract.
Preparation of the rhizoma acori graminei extract: taking qualified rhizoma Acori Graminei, drying, slicing, placing into volatile oil extraction device, soaking in distilled water, continuously extracting, extracting oil layer with petroleum acid, washing with distilled water to neutrality, dehydrating, and volatilizing petroleum ether to obtain crude oil of rhizoma Acori Graminei volatile oil.
Preparation of Coleus forskohlii extract: collecting the above-ground part of Coleus forskohlii, cold soaking with ethanol at room temperature, percolating, recovering solvent under reduced pressure to obtain extract, adding appropriate amount of water for suspension, sequentially extracting with ethyl acetate and n-butanol, and concentrating the extractive solution under reduced pressure to obtain Coleus forskohlii extract.
Preparing the peanut shell extract: drying peanut shell, pulverizing, adding 20 times of 70% ethanol, heating to 61 deg.C under stirring, extracting at the temperature, filtering, and concentrating. Adding ethanol for precipitating, filtering, evaporating filtrate, and drying to obtain peanut shell extract.
The invention also provides application of the pharmaceutical composition in preparing a medicament or a health-care product for preventing or treating neurodegenerative diseases. Neurodegenerative diseases are a group of diseases resulting from chronic, progressive degeneration of central nervous tissue, collectively including central neurodegenerative disease dementia or non-central neurodegenerative disease dementia. The central nerve degenerative disease dementia comprises Alzheimer disease, Parkinson disease and Huntington disease, and the non-central nerve degenerative disease dementia comprises one or more of vascular dementia, brain traumatic dementia or dementia caused by poisoning and anoxia factors.
The pharmaceutical composition of the present invention can be used alone, or in combination with other drugs or functional foods. Preferably, the composition can be in oral form, such as tablet or granule, and the effective amount is 10-1000mg/kg/d, and can be used for single-dose or combined-dose treatment of related diseases, which is within the scope understood by those skilled in the art.
The invention carries out formula compatibility design according to the modern pharmacological research characteristics of active ingredients of the plant medicines such as the gastrodia elata, the pseudo-ginseng and the like by referring to the theoretical basis of the traditional Chinese medicine and the clinical medication experience. Relevant pharmacological and pharmacodynamic experimental studies were performed on the following 4 disease models:
(1) animal model of cerebral ischemia induced VaD: in the experiment, cerebral ischemia injury is caused by bilateral permanent ligation of bilateral common carotid artery (2-VO), which leads to hippocampal ischemia for controlling learning and memory functions, so that neuron injury and even death in hippocampal are caused, and the change of known functions is caused. Vascular dementia accounts for approximately 20% of all demented patients at the present time, and the rate of progression and prevalence may increase 3-fold by 2050 patients with VaD, the leading cause of senile dementia in many countries in asia being VaD.
(2) APP/PS1 transgenic mouse AD animal model: AD is the major type of dementia, with about 60% of the dementias belonging to AD. The animal model can express mutant human presenilin and human and mouse amyloid proprotein fusion, thereby causing early-onset senile dementia. The APP/PS1 transgenic mice aged 6-7 months will form A beta deposition in the brain, and the A beta deposition is the main reason for the senile dementia which is recognized at present.
(3) Model of a β deposited nematodes: CL4176 nematode strain is one kind of nematode strain with expression vector and Abeta gene introduced via microinjection into nematode strain, and after temperature induction, human Abeta 1-42 protein may be expressed in muscle tissue and then paralyzed rapidly. Due to the characteristics of short growth cycle, convenient observation of polypide and high similarity between gene functions and human beings, the method is widely used for researching nervous system lesions at present.
(4) Cerebral ischemia reperfusion injury (CIR) animal model: the CIR model can cause cerebrovascular injury, leading to cerebral insufficiency, and is one of the main causes of the occurrence of clinical VaD.
Drawings
FIG. 1 shows the effect of the pharmaceutical composition of the invention on the time of the target platform for the residence of VaD rats (note: statistical test methods using one-way ANOVA Student-Newman-Keuls test, vs Model,*p<0.05)。
FIG. 2 shows the effect of the pharmaceutical composition of the present invention on the number of times the VaD rats crossed the target platform (note: statistical test methods using one-way ANOVA Student-Newman-Keuls test, vs Model,*p<0.05)。
FIG. 3 shows the effect of the pharmaceutical composition of the present invention on the residence time of transgenic AD mice on the target platform (note: statistical test method using one-way ANOVA Student-Newman-Keuls test, vs Model,*p<0.05.)。
FIG. 4 shows the effect of the pharmaceutical compositions of the present invention on the number of times transgenic AD mice cross the target platform (note: statistical test methods using one-way ANOVA Student-Newman-Keuls test, vs Model,*p<0.05)。
FIG. 5 shows the effect of the pharmaceutical composition of the present invention on the duration of paralysis due to nematodes (note: statistical test method using one-way ANOVA Student-Newman-Keuls test, vs Control,***p<0.001)。
FIG. 6 is a TTC staining of rat CIR injured brain sections with the pharmaceutical composition of the present invention.
Figure 7 effect of the pharmaceutical composition of the invention on ischemic area of brain sections of rat CIR lesions (note: statistical test method using one-way ANOVA Student-Newman-Keuls test, vs Model,**p<0.01)。
Detailed Description
The following examples illustrate specific steps of the present invention, but are not intended to limit the invention.
Terms used in the present invention generally have meanings commonly understood by those of ordinary skill in the art, unless otherwise specified.
The present invention is described in further detail below with reference to specific examples and with reference to the data. It will be understood that these examples are intended to illustrate the invention and are not intended to limit the scope of the invention in any way.
In the following examples, various procedures and methods not described in detail are conventional methods well known in the art.
The present invention is further illustrated by the following specific examples.
Example 1 preparation of Gastrodia elata extract, Panax notoginseng extract, Acorus tatarinowii extract, Coleus forskohlii extract, peanut shell extract
Preparing a gastrodia elata extract: removing impurities from qualified rhizoma Gastrodiae, cleaning, drying at low temperature of less than 60 deg.C, pulverizing, and sieving with 100 mesh sieve; the powder was soaked in 60L of 50% ethanol/water, shaken up and left to stand overnight. The next day 60L of solvent was decanted, filtered and transferred to a rotary evaporator for concentration. Adding the primary filter material of the gastrodia elata into 50% ethanol/water, transferring the mixture into a reflux extraction tank, and carrying out reflux extraction for 2 hours at 85-90 ℃. Then concentrating the extracting solution by a rotary evaporator until the extracting solution is dried to obtain the gastrodia elata extract.
Preparing a pseudo-ginseng extract: removing impurities from Notoginseng radix, cleaning, drying at low temperature of less than 60 deg.C, pulverizing, and sieving with 20 mesh sieve; adding 8 times of 70% ethanol, refluxing for 3 times, each time for 1 hr, and concentrating the extractive solution with rotary evaporator to dry to obtain Notoginseng radix extract.
Preparation of the rhizoma acori graminei extract: removing impurities from rhizoma Acori Graminei extract, cleaning, drying at low temperature of less than 60 deg.C, slicing, placing into volatile oil extraction device, soaking in distilled water, continuously extracting, extracting oil layer with petroleum acid, washing with distilled water to neutrality, dewatering, and volatilizing petroleum ether to obtain crude rhizoma Acori Graminei volatile oil.
Preparation of Coleus forskohlii extract: repeatedly cold soaking and percolating the above-ground parts of Coleus forskohlii with ethanol at room temperature, recovering solvent under reduced pressure to obtain extract, adding appropriate amount of water for suspension, sequentially extracting with ethyl acetate and n-butanol, and concentrating the extractive solution under reduced pressure to obtain Coleus forskohlii extract.
Preparing the peanut shell extract: placing peanut shell in a drying oven, drying at 50 deg.C for 4 hr, pulverizing with a pulverizer, sieving with 20 mesh sieve, adding 20 times of 70% ethanol, heating to 61 deg.C under stirring, extracting at the temperature for 1.6 hr, filtering, extracting for three times, mixing filtrates, and concentrating. Adding ethanol, precipitating with ethanol, stirring for 1 hr, standing overnight, filtering, evaporating the filtrate until ethanol smell disappears, and drying to obtain peanut shell extract.
Example 2
The medicinal extracts obtained in example 1 are combined to obtain a medicinal composition containing the following components in parts by weight: 30 parts of gastrodia elata extract, 6.25 parts of pseudo-ginseng extract and 6 parts of rhizoma acori graminei extract.
Example 3
The medicinal extracts obtained in example 1 are combined to obtain a medicinal composition containing the following components in parts by weight: 30 parts of gastrodia elata extract, 6.25 parts of pseudo-ginseng extract, 6 parts of rhizoma acori graminei extract and 2 parts of coleus forskohlii extract.
Example 4
The medicinal extracts obtained in example 1 are combined to obtain a medicinal composition containing the following components in parts by weight: 30 parts of gastrodia elata extract, 6.25 parts of pseudo-ginseng extract, 6 parts of rhizoma acori graminei extract and 10 parts of peanut shell extract.
Example 5
The medicinal extracts obtained in example 1 are combined to obtain a medicinal composition containing the following components in parts by weight: 30 parts of gastrodia elata extract, 6.25 parts of pseudo-ginseng extract, 6 parts of rhizoma acori graminei extract, 2 parts of coleus forskohlii extract and 10 parts of peanut shell extract.
Example 6 vascular dementia (VaD) assay in rats
Experimental materials: heparin sodium injection is purchased from Wanbang biochemical medicine of Jiangsu; the chloramphenicol eye drops are purchased from Sichuan Meida Kanghuakang pharmaceutical Co., Ltd; chloral hydrate is purchased from Guangdi Fine chemical research institute of Tianjin; 75% ethanol solution was purchased from Kunming Lijian disinfectant products, Inc.; the 0.9% sodium chloride injection is purchased from Zhejiang national mirror pharmaceutical Co., Ltd; phosphate Buffered Saline (PBS) was purchased from shanghai culture biotechnology limited.
Experimental animals: experimental animals: healthy SD rats, SPF grade, body weight 160-. Animals were fed with standard feed and water ad libitum and kept in controlled experimental environment (temperature: 25. + -. 2 ℃).
Experimental groups:
f2: example 2 pharmaceutical composition, F3: example 3 pharmaceutical composition, F4: example 4 pharmaceutical composition, F5: example 5 pharmaceutical composition, Col: coleus forskohlii extract group, Pea: peanut shell extract group, Col + Pea: coleus forskohlii extract + peanut shell extract group.
Administration dose: 720mg/kg, 14.5mg/kg (Col) for Coleus forskohlii extract group, 72.7mg/kg for peanut shell extract group (Pea), 7.25mg/kg for Coleus forskohlii extract group in Coleus forskohlii extract + peanut shell extract group (Col + Pea), and 36.35mg/kg for peanut shell extract group (Pea), and the administration is performed by dissolving with physiological saline and administering according to the dose of 1ml/100g for rat body weight.
The experimental method comprises the following steps: permanent ligation of bilateral common carotid arteries (2-VO) was used to establish a VaD model with a modeling time of 1 month. And 3d, performing a water maze sieve Model after modeling, and uniformly and randomly classifying the rats successfully modeled into a Sham operation group (Sham), a VaD Model group (Model), example 2,3, 4 and 5 pharmaceutical composition groups, a coleus forskohlii extract group, a peanut shell extract group, a coleus forskohlii extract + peanut shell extract group according to the mild, moderate and severe dementia. And gavage was performed daily for 1month by rat body weight, starting at 7d after the model was created. And detecting the learning and memory change condition of the rats of each treatment group by using a Morris water maze, collecting data, and analyzing and processing the data by using SigmaStat 10.0 statistical analysis software. Double/single factor variance analysis is adopted among multiple groups of indexes, and p <0.05 is taken as statistical significance.
The results of the five-day escape latency experiment of the rat localization navigation experiment are shown in table 1. Compared with the model group and other pharmaceutical compositions, after the treatment of the pharmaceutical composition (F5) in example 5, the positioning flight escape latency of the VaD model rat is significantly reduced (p is less than 0.05), and the remaining treatment groups have no significant change, which shows that the pharmaceutical composition of the invention has a good improvement effect on the learning and memory abilities of the model rat.
TABLE 1 rat localization experiment five-day escape latency (Mean + -SEM)
Note: statistical test methods used Two factors-Fisher LSD, vs Model,. about.p <0.001, and. about.p <0.05.Data analyzed by Two-way ANOVA-Fisher LSD,. about.p <0.001, and. about.p <0.05compared to Model group.
The experimental results of the influence of the pharmaceutical composition on the time of the VaD rat staying on the target platform and the times of passing through the target platform are shown in figures 1 and 2. Both the residence target platform time and the number of target platform crossings (p <0.05) were significantly increased in VaD model rats after treatment with the pharmaceutical composition of example 5 (F5) compared to the model group and other pharmaceutical compositions.
Example 7AD mouse experiments
Experimental materials: example 5 pharmaceutical compositions; chloral hydrate is purchased from Guangdi Fine chemical research institute of Tianjin; 75% ethanol solution was purchased from Kunming Lijian disinfectant products, Inc.; the 0.9% sodium chloride injection is purchased from Zhejiang national mirror pharmaceutical Co., Ltd; phosphate Buffered Saline (PBS) was purchased from shanghai culture biotechnology limited.
Experimental animals: APP (PSN) B6 strain transgenic AD mice, provided by Nanjing biomedical research institute. The experimental animals were acclimatized to standard feed and free water for 1 week (laboratory humidity 25 deg.C, relative humidity 60% -70%, day and night 12 hours each.)
Administration dose: the dosage is calculated by taking the content of the rhizoma gastrodiae extract in the pharmaceutical composition as a metering standard: 720mg/kg, dissolved in physiological saline, was administered in a dose of 1ml/100g of rat body weight.
The experimental method comprises the following steps: the effect of the pharmaceutical composition of example 5 on learning and memory of APP/PS1 transgenic mice was examined using a water maze test using commercially available AD mice transgenic for APP/PS1, fed freely for 8 months with the diet of example 5.
The experimental results of the influence of the pharmaceutical composition on the residence time of a target platform and the number of times of crossing the target platform of a transgenic AD mouse are shown in fig. 3 and 4. Compared with the model, after the treatment of the pharmaceutical composition (F5) in example 5, the time of staying at the target platform and the frequency of crossing the target platform of the AD mouse are both obviously increased (p is less than 0.05), which shows that the pharmaceutical composition of the invention has a good improving effect on the learning and memory ability of the AD mouse.
Example 8 nematode paralysis test
Experimental materials: the combination of extracts of example 5; CL4176(smg-1ts [ pAF29(myo-3/A β 1-42/letUTR) + pRF4(rol-6(sul0069)) ]) nematode strain, live nematode food bacteria OP50 were provided by Kunming plants of the Chinese academy of sciences; preparation of culture Medium reagents such as agar, peptone and cholesterol were purchased from Sigma, USA.
Administration dose: respectively weighing the gastrodia elata extract, the pseudo-ginseng extract, the grassleaf sweelflag rhizome extract, the coleus forskohlii extract and the peanut shell extract with corresponding mass according to the extract combination proportion in the embodiment 5, mixing, and diluting the mixture into working solution containing the gastrodin with the PBS according to the content of the gastrodin in the composition.
The experimental method comprises the following steps: the paralytic phenotype method of the nematode is adopted.
Recovering CL4176 nematode strain, placing the nematode in culture plate containing fresh OP50, and culturing in 16 deg.C incubator. After the nematodes lay eggs, the newly-born nematodes are synchronized to be in the L1 stage. Culturing at 16 deg.C for about 48h, allowing larva to develop to L3 stage, and immediately heating to 2Culturing at 5 deg.C. And (5) after the temperature rises for 20h, observing and recording paralysis behaviors, and observing and recording the time and the number of paralysis every 2 h. Contacting the head or the trunk of the nematode by using a worm picker, and judging that the nematode is in a paralyzed state if the nematode can only move the head but can not move the trunk; repeating the steps for more than 3 times at each drug concentration, wherein the total number of nematodes is more than 100; and counting the paralyzed nematode number and total nematode number of each plate, and performing data analysis and mapping by adopting Sigmaplot3.5. For data
Is represented by p<0.05 is statistically significant.
The results of the experiment are shown in table 2 and fig. 5. The results show that compared with the Control group, the pharmaceutical composition of the invention can obviously reduce the paralysis time of the nematodes.
TABLE 2 nematode survival Rate
Example 9 rat Cerebral Ischemia Reperfusion (CIR) experiment
Experimental materials: the pharmaceutical compositions of examples 4, 5; heparin sodium injection is purchased from Wanbang biochemical medicine of Jiangsu; the chloramphenicol eye drops are purchased from Sichuan Meida Kanghuakang pharmaceutical Co., Ltd; chloral hydrate is purchased from Guangdi Fine chemical research institute of Tianjin; 75% ethanol solution was purchased from Kunming Lijian disinfectant products, Inc.; the 0.9% sodium chloride injection is purchased from Zhejiang national mirror pharmaceutical Co., Ltd; 2,3, 5-Triphenyltetrazolium chloride (TTC) was purchased from Sigma, USA; phosphate Buffered Saline (PBS) was purchased from shanghai culture biotechnology limited.
Experimental animals: healthy SD rats, SPF grade, body weight 160-. Animals were fed with standard feed and water ad libitum and kept in controlled experimental environment (temperature: 25. + -. 2 ℃).
Administration dose: respectively weighing the gastrodia elata extract, the pseudo-ginseng extract, the grassleaf sweelflag rhizome extract, the coleus forskohlii extract and the peanut shell extract with corresponding mass according to the proportion of the pharmaceutical composition described in the embodiments 4 and 5, mixing, preparing the dosage of 720mg/kg according to the content of the gastrodia elata extract in the mixture, dissolving the mixture by using normal saline, and administering the mixture according to the dosage of 1ml/100g of the weight of a rat.
The experimental method comprises the following steps: a rat CIR injury model is established by adopting an MCAO line embolism method.
The experiments were grouped into Model groups (Model), examples 4, 5 groups, 10 rats each. The model group was given 0.9% sodium chloride, and the gavage extract was administered 1 time a day for 4 consecutive days, and immediately after gavage on day 4. A rat middle cerebral artery ischemia (MCAO)/reperfusion model is established by adopting a classical line embolism method which is simple to operate, and each animal is subjected to reperfusion for 24 hours after being subjected to ischemia for 1 hour. After the model is built, 10% chloral hydrate is used for abdominal anesthesia, the brain is taken out after head breaking, the brain is placed in a low-temperature refrigerator at the temperature of minus 20 ℃ for freezing, the brain is taken out after about 30min, the brain is evenly cut into 5 pieces from the head side to the tail side, the 5 pieces are placed in a 1% TTC solution, the 1% TTC solution is subjected to constant-temperature oscillation and dyeing in a water bath at the temperature of 37 ℃ for 10min, then the 5 pieces are fixed in a 4% paraformaldehyde solution, and the picture is taken for. The ischemic area of the brain tissue section and the corrected ischemic volume were calculated by Image-Pro Plus17.0 Image analysis software. Results of the experiment to
It shows that the data is analyzed and processed by using the statistical analysis software SigmaStat 10.0. Adopting one-way ANOVA among multiple groups of indexes, and taking p as<0.05 is statistically significant.
The TTC staining pattern of the pharmaceutical composition of the invention on rat CIR injured brain section is shown in FIG. 6. The results of the effect of the pharmaceutical composition of the present invention on the ischemic area of the brain section of CIR-injured rats are shown in fig. 7. The result shows that compared with the model group, the pharmaceutical composition provided by the invention can obviously reduce the cerebral infarction area (p <0.05) of the rats with ischemia-reperfusion injury.
Claims (7)
1. The pharmaceutical composition is characterized by comprising the following components in parts by weight: 10-90 parts of gastrodia elata or gastrodia elata extract, 1-10 parts of pseudo-ginseng or pseudo-ginseng extract, 1-10 parts of rhizoma acori graminei or rhizoma acori graminei extract, 1-10 parts of coleus forskohlii or coleus forskohlii extract and 1-50 parts of peanut shell or peanut shell extract.
2. The pharmaceutical composition according to claim 1, characterized by comprising the following parts by weight: 20-50 parts of gastrodia elata or gastrodia elata extract, 5-10 parts of pseudo-ginseng or pseudo-ginseng extract, 5-10 parts of rhizoma acori graminei or rhizoma acori graminei extract, 1-5 parts of coleus forskohlii or coleus forskohlii extract and 5-20 parts of peanut shell or peanut shell extract.
3. The pharmaceutical composition according to claim 1, characterized by comprising the following parts by weight: 30 parts of gastrodia elata or gastrodia elata extract, 6.25 parts of pseudo-ginseng or pseudo-ginseng extract, 6 parts of grassleaf sweelflag rhizome or grassleaf sweelflag rhizome extract, 2 parts of coleus forskohlii or coleus forskohlii extract and 10 parts of peanut shell or peanut shell extract.
4. Use of the pharmaceutical composition according to any one of claims 1 to 3 for the preparation of a medicament for the prevention or treatment of neurodegenerative diseases.
5. Use according to claim 4, characterized in that said neurodegenerative disease comprises central neurodegenerative dementia or non-central neurodegenerative dementia.
6. Use according to claim 5, characterized in that said neurodegenerative disease comprises dementia, Parkinson's disease or Huntington's disease.
7. The use according to claim 6, wherein the dementia comprises one or more of Alzheimer's disease, vascular dementia, brain traumatic dementia, or dementia caused by toxic or hypoxic factors.
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