CN103099911A - Application of mental treasure pills in preparation of medicine for treating senile dementia - Google Patents
Application of mental treasure pills in preparation of medicine for treating senile dementia Download PDFInfo
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Abstract
The invention discloses application of mental treasure pills in preparation of a medicine for treating senile dementia. Due to the improvement effect of the mental treasure pills on mouse reproduction memory disorder caused by scopolamine and mouse memory consolidating hinder caused by NaNO2 and mouse reproduction memory disorder caused by ethanol through a step-down test and a Morris water maze test, the mental treasure pills have a certain effect of improving the learning and memory. In addition, the Morris water maze test of APP/PSI double transgenic mice further proves that the mental treasure pills have a certain effect of improving the dysmnesia. The experimental result proves that the mental treasure pills can be used for preparing the medicine for treating senile dementia and have the characteristics of stable curative effect, medication safety, low toxic-side effect, low price and the like.
Description
Technical field
The invention belongs to field of medicaments, be specifically related to the application of mental precious ball in preparation control medicine for senile dementia.
Background technology
Alzheimer (Alazheimer ' s disease, AD) be a kind of take the cognitive disorder of carrying out property and memory impairment as main central nervous system degenerative disease, main pathological characters is senile plaque, cerebrovascular precipitate and neurofibrillary tangle in cerebral atrophy, cerebral tissue.Along with the increase of mankind's average life, senile dementia has become one of principal disease that threatens mankind quality of life in old age, and its sickness rate is ascendant trend year by year, and approximately has 70% to be AD in senile dementia.Because the cause of disease of AD is not illustrated yet fully, there is no the specific treatment medicine.
Treatment AD medicine commonly used comprises that acetylcholinesteraseinhibitors inhibitors (AChEI) is (as tacrine at present, huperzine is first-class), calcium ion antagonist (as nimodipine), brain blood circulation improving agent (as hydergine, duxil), brain energy metabolism activator (as piracetam), antioxidant (as vitamin e, vitamin C etc.), neurotrophic factor (NGF), anti-inflammatory agent etc.The western medicine effect is limited, and side effect is larger.
The traditional Chinese medical science is stressed the wholism and is controlled, and by the regulating functions of ZANG FU-organs relation, reaches the purpose for the treatment of.Simultaneously, the traditional Chinese medical science is treated for different pattern of syndrome by determination for the treatment of based on pathogenesis obtained through differentiation of symptoms and signs.For the senile dementia of pathological factor complexity, the traditional Chinese medical science has certain advantage.
Mental precious ball is comprised of the 10 flavor medicines such as Radix Rehmanniae, Fructus Schisandrae Chinensis, Semen Cuscutae, Radix Polygalae, Rhizoma Acori Graminei, Poria, Cortex Lycii, Rhizoma Chuanxiong, vitamin E, vitamin B, is to adopt the refining Chinese patent medicine that forms of the modern pharmaceutical techniques such as water extract-alcohol precipitation, percolation, steaming stripped oil, low temperature distillation, concentrating under reduced pressure, vacuum drying; In prescription, Radix Ginseng, Poria, Rhizoma Acori Graminei, Radix Polygalae are the highest four Chinese medicines of numerous prescriptions medicine frequency of occurrences used for the treatment of at present senile dementia, and that for example includes in volume 14 small intestinal internal organs sides in Prescriptions Worth Thousand Gold for Emergencies gets well the side of forgetting.Radix Rehmanniae records kidney nourishing water, packing bone marrow, sharp blood vessels, the effects such as tonification is Kidney-Yin, hearing-improing and eyesight improving according to " Bencao Congxin "; Cortex Lycii records in " book on Chinese herbal medicine is stated " and cures mainly the effects such as deficient fever, alternate attacks of chills and fever, apoplexy, dizzy, convulsion epilepsy, fidgets due to deficiency, cardiopalmus, forgetful, urinary obstruction; Poria has the effect of eliminating dampness and diuresis, invigorating the spleen and regulating the stomach, mind tranquilizing and the heart calming; Water Extract of Poria can improve the ability of learning and memory of resulted from chemical medicine learning memory disorder model mice; The Rhizoma Acori Graminei water extract can strengthen the ability of learning and memory of mice, increases cerebral tissue SOD active, reduces MDA content; Its main component polygalic acid of Radix Polygalae has defying age, antioxidation, antiinflammatory and immunostimulant isoreactivity and improves the effect of AD ability of learning and memory in mice; Monomer component ligustrazine in Rhizoma Chuanxiong strengthens cortex and Hippocampus ChAT is active, raise Hippocampus NMDA receptor number improves the ability of learning and memory of Alzheimer disease model mice; Fructus Schisandrae Chinensis has the effect of tranquillizing and allaying excitement; Semen Cuscutae extract has certain antioxidant activity.
Mental precious ball has the effects such as nourishing the liver and kidney, tranquilizing by nourishing the heart.Be mainly used in that forgetful insomnia, irritated dream due to deficiency of the liver and kindey, lack of preservation of spirit is many, hectic fever night sweat, physical fatigue and lassitude of spirit, neurasthenia belongs to above-mentioned patient.Its clinical practice and main component progress point out it may be suitable for treating senile dementia, but have not yet to see mental precious ball to the report of spatial cognition obstacle and learning and memory function improvement, the system experimentation research and the clinical research that are used for senile dementia prevention and cure also have no report.
Summary of the invention
The object of the present invention is to provide the new purposes of a kind of " mental precious ball ", its application in preparation control medicine for senile dementia.
Good effect of the present invention is:
The present invention with diving tower experiment and Morris water maze laboratory observe mental precious ball to the mouse memory acquired disturbance due to scopolamine, the mouse memory due to NaNO2 is consolidated the improvement effect that the mouse memory due to obstacle and ethanol reproduces obstacle, result shows that mental precious ball has certain effect that improves learning and memory.Adopt in addition APP/PS1 double transgenic mice to verify further that by the Morris water maze laboratory mental precious ball has certain improvement effect to dysmnesia.Above experimental result all shows can be with mental precious ball for the preparation of the senile dementia prevention and cure medicine, has the characteristics such as stable curative effect, drug safety, toxic and side effects are little, low price.
Description of drawings
Fig. 1 is that the APP/PS1 mouse brain is organized Hippocampal CA 1 HE colored graph (* 200) (1: negative control group, 2: model group, 3: mental precious ball low dose group, 4: dosage group in mental precious ball, 5: mental precious ball high dose group, 6: the Huperzine A-Zhulin Antun group);
Fig. 2 is that the APP/PS1 mouse brain is organized Hippocampal CA 1 A β immunohistochemical staining figure (* 200) (1: negative control group, 2: model group, 3: mental precious ball low dose group, 4: dosage group in mental precious ball, 5: mental precious ball high dose group, 6: the Huperzine A-Zhulin Antun group).
The specific embodiment
For understanding better the technology of the present invention, understand mechanism of action and the essence of the effective senile dementia prevention and cure of mental precious ball, the inventor improves the animal model of memory acquisition disturbance to mental precious ball---scopolamine induced mice memory acquisition disturbance Senlie dementia model, improve the animal model that obstacle is consolidated in memory---NaNO
2The induced mice memory is consolidated the obstacle Senlie dementia model, is improved animal model---the 40% ethanol induced mice memory represents obstacle Senlie dementia model of memory represents obstacle, and APP/PS1 double transgenic model mice conducts in-depth research respectively.
Laboratory animal
SPF level Kunming mouse, body weight 18-22g, male and female half and half, the quality certification number: the Guangdong word 2011-0029 that checks and affirm, zoopery occupancy permit number: SYXX(Guangdong) 2007-0081.Female 25, male 28 of SPF level APP/PS1 mices are provided by Nanjing University's model animal institute, credit number: SCXK(Soviet Union) 2010-0001, the quality certification number: 0007562.
Experimental drug
Mental precious ball is provided by Guangdong Wannianqing Pharmaceutical Co., Ltd., 100 ball/bottles, specification: 0.2g/ ball, product batch number: 111080.Positive control drug: Huperzine A-Zhulin Antun, is Henan Buddhist nun's Pharmaceutical limited company product too, product batch number: 100905 by 48/box.Scopolamine hydrobromide injection is provided by Guangzhou Baiyunshan Mingxing Pharmaceutical Co., Ltd., specification: 1ml/ props up, 0.3mg/ml.Product batch number: 101101.0.9% sodium chloride injection (NS, normal saline), echo must East Asia drugmaker of group (Jiangxi) be produced, product batch number: 2010081564.NaNO
2, the Beijing Chemical Plant produces, product batch number: 110427.Dehydrated alcohol, Guangzhou Chemical Reagent Factory production, product batch number: 20110702-2.
Experimental apparatus
DT-200 mice diving tower instrument, Sichuan Province Chengdu TME Technology Co., Ltd.; Morris water maze, VEDIO-PCI-XR image acquisition device, camera head, video tracer, behavioristics's data processing software, Chinese Academy of Sciences institute of materia medica.
Experimental procedure and result
4.1 the impact of mental precious ball on scopolamine induced mice memory acquisition disturbance Senlie dementia model
Adopt scopolamine induced mice memory acquisition disturbance Senlie dementia model, the experiment of mice diving tower and the performance testing of Morris water maze, studied mental precious ball to the impact of scopolamine hydrobromide induced mice memory acquisition disturbance.
The healthy adult kunming mice is 64 after screening, body weight (18-22) g, male and female half and half, be divided at random 6 groups by body weight: i.e. Normal group, model group, mental precious ball low (0.18g/kg), in (0.36g/kg), high (0.72g/kg) dosage group and Huperzine A-Zhulin Antun group (huperzine A, 0.06mg/kg).After each treated animal adaptability is fed 3d, gastric infusion, Normal group and model control group gavage respectively give the equal-volume normal saline, administration every day 1 time, gavage volume 0.2mL/10g body weight, successive administration 21 days.1 h begins to carry out the diving tower training after administration in the morning in the 13rd day, 20min before training, and Normal group lumbar injection equivalent normal saline, all the other respectively organize equal lumbar injection scopolamine hydrobromide 2mg/kg, begin training, diving tower method test learning outcome after 24h.Experimental result sees Table 1.Compare with normal group, obviously shorten the incubation period of model group mice diving tower (
p＜0.01), errors number obviously increase (
p＜0.01); The school grade of the middle and high dosage group of mental precious ball all obviously be better than model group (
p＜0.05), be certain dose-effect relationship.Positive drug Huperzine A-Zhulin Antun group school grade all obviously be better than model group (
p＜0.05 or
p＜0.01).Prompting, mental precious ball has some improvement to mouse memory acquired disturbance model.
Annotate: compare with Normal group,
△ p＜0.05,
△ △ p＜0.01; Compare * with model group
p＜0.05, * *
p＜0.01.
Mice carries out the performance testing of Morris water maze in the time of the 16th day, wherein positioned the navigation experiment in 16-19 days, carries out space exploration and tests in the 21st day.Position front 20 min of navigation experiment equal lumbar injection scopolamine hydrobromide (2mg/kg) except the blank group at every turn, cause the memory deficits in mice model.The Morris water maze laboratory carries out according to a conventional method, positioned the navigation experiment since the 16th day, follow-on test 4d, recording mice searches out platform in 90 s time is escape latency, swimming distance, in the swimming time ratio of original platform place quadrant, across the number of times (number of times namely shuttles back and forth) of original platform position with arrive for the first time time of original platform.Experimental result sees Table 2-4.
Annotate: compare with Normal group,
△ p＜0.05,
△ △ p＜0.01; Compare * with model group
p＜0.05, * *
p＜0.01.
Annotate: compare with Normal group,
△ p＜0.05,
△ △ p＜0.01; Compare * with model group
p＜0.05, * *
p＜0.01.
Annotate: compare with Normal group,
△ p＜0.05,
△ △ p＜0.01; Compare * with model group
p＜0.05, * *
p＜0.01.
In Morris water maze cognitive training, in the cognitive training of 4 days by a definite date, along with the prolongation of training time, each swimming incubation period and swimming distance of organizing mice all shortens gradually; And since the 3rd day, the scopolamine model group was compared with matched group, mice swimming incubation period and swimming distance obviously extend (
p＜0.05 or
p＜0.01), illustrate that the memory deficits in mice model successfully sets up; Compare with model group, all have the incubation period of each dosage group mice of mental precious ball shortening, its high dose have remarkable shortening (
p＜0.05); Swimming distance also shorten, wherein the middle and high dosage of mental treasured have obvious significant difference (
p＜0.05).Positive drug Huperzine A-Zhulin Antun group can make mice swimming incubation period and swimming distance obviously shorten (
p＜0.05).
Measure at the Morris water maze that the spatial memory experimental result shows due to scopolamine: compare with control group mice, the model group mice obviously shorten at the swimming time of original platform place quadrant (
p＜0.05) time that, reaches platform for the 1st time obviously extend (
p＜0.01), the mice number of times that passes through the original platform position obviously reduce (
p＜0.01).And the middle and high dosage group of mental precious ball mice the swimming time of original platform place quadrant have obvious prolongation trend (
p0.05), the time that mice reaches platform for the 1st time obviously shortens (middle and high dosage group
p＜0.05), the mice number of times that passes through original platform have obvious prolongation trend (
p0.05).The time that positive drug Huperzine A-Zhulin Antun group can make mice reach platform for the 1st time obviously extend (
p＜0.05), the mice number of times that passes through the original platform position obviously reduce (
p＜0.05).The prompting scopolamine has damaged the spatial memory capacity of mice, and the turning scopolamine of mental precious ball is to the damage of mice spatial memory function.
Mental precious ball is to NaNO
2
The impact that the obstacle Senlie dementia model is consolidated in the induced mice memory
Adopt NaNO
2Obstacle Senlie dementia model, the experiment of mice diving tower are consolidated in the induced mice memory, have studied mental precious ball to NaNO
2Due to the memory impact of consolidating obstacle, animal is divided into 6 groups at random by body weight: i.e. Normal group, model group, mental precious ball low (0.18g/kg), in (0.36g/kg), high (0.72g/kg) dosage group and Huperzine A-Zhulin Antun group (huperzine A, 0.06mg/kg); Successive administration 12 days.1 h begins to carry out the diving tower training after administration in the morning in the 13rd day, carries on the back immediately cervical region subcutaneous injection NaNO after training
2120mgkg-1, diving tower method test after 24h.
Experimental result sees Table 5: mental precious ball is to NaNO
2The induced mice memory is consolidated obstacle and is had some improvement, and middle and high dosage group and model group more all have significant difference (p＜0.05).
Annotate: compare with Normal group,
△ p＜0.05,
△ △ p＜0.01; Compare * with model group
p＜0.05, * *
p＜0.01.
4.3 the impact of mental precious ball on 40% ethanol induced mice memory represents obstacle Senlie dementia model
Adopt 40% ethanol induced mice memory represents obstacle Senlie dementia model, the experiment of mice diving tower, studied mental precious ball to the impact of the memory represents obstacle due to ethanol, animal is divided into 6 groups at random by body weight: i.e. Normal group, model group, the basic, normal, high dosage group of mental precious ball and Huperzine A-Zhulin Antun group (huperzine A, 0.06mg/kg), successive administration 12 days.1h begins to carry out the diving tower training after administration in the morning in the 13rd day, test after 24h, and equal gavage 40% ethanol of 30min before test, administration volume 0.1mL10g-1 causes animal memory represents obstacle.
Experimental result sees Table 6: compares with normal group, give that obviously shorten the incubation period of model group mice diving tower after 40% ethanol (
p＜0.01), errors number obviously increase (
p＜0.01); The school grade of mental each dosage group of precious ball all is better than model group, wherein in the dosage errors number obviously reduce (
p＜0.05).The positive control drug Huperzine A-Zhulin Antun errors number obviously reduce (
p＜0.05), obviously extend incubation period (
p＜0.05).Prompting, mental precious ball has slight improvement effect to ethanol induced mice memory represents obstacle.
Annotate: compare with normal control,
△ p＜0.01,
△ △ p＜0.01; Compare * with model group
p＜0.05, * *
p＜0.01.
" mental precious ball " impact on APP/PS1 double transgenic model mice
64 mices are divided into 7 groups at random, i.e. negative control group (C57,11), model group (APP/PS1,11), mental precious ball high dose group (APP/PS1,0.72g/kg, 10), middle dosage group (APP/PS1,0.36g/kg, 11), low dose group (APP/PS1,0.18g/kg, 10) and Huperzine A-Zhulin Antun group (huperzine A, 0.06mg/kg, 11).Remove negative control and model group gavage and give distilled water (0.2 mL/10 g), other each groups give corresponding medicine, every day gastric infusion once, after continuous 11 weeks, carry out Morris water maze orientation navigation and space exploration experiment, hippocampus liver histopathological analysis (Fig. 1) is carried out in detection SOD in serum and MDA, cerebral tissue acetylcholine esterase active, conventional H E dyeing, A β dyeing SABC detects cerebral tissue senile plaque deposition (Fig. 2).
Experimental result sees Table 7-9: mental precious ball can improve APP/PS1 double transgenic mice spatial memory dysfunction, and middle and high dosage group has been compared significant difference (p＜0.05) with model group; Mental precious ball has scavenging action preferably to APP/PS1 mice free radical, and certain antioxidation is arranged, and middle and high dosage group has been compared significant difference (p＜0.05) with model group; Mental precious ball can reduce acetylcholine esterase active (TChE) in APP/PS1 mouse brain tissue, and the acetylcholine hydrolyzation speed in cerebral tissue is slowed down, and improves learning memory disorder; Mental precious ball is expressed APP/PS1 double transgenic CA 1 Zone of Hippocampus in Mouse A β 40 certain reducing effect, and high dose group and model group comparison CA 1 Zone of Hippocampus in Mouse A β 40 positive cells obviously reduce, and average gray value obviously reduces (p＜0.05).
Annotate: compare with negative control group,
△ p＜0.05,
△ △ p＜0.01; Compare * with model group
p＜0.05, * *
p＜0.01.Compare with Huperzine A-Zhulin Antun,
# p＜0.01,
## p＜0.01.
Annotate: compare with negative control group,
△ p＜0.05,
△ △ p＜0.01; Compare * with model group
p＜0.05, * *
p＜0.01.
Annotate: compare with negative control,
△ p＜0.01,
△ △ p＜0.01; Compare * with model group
p＜0.05, * *
p＜0.01.
Genetics research is found, app gene on No. 21 chromosomes is amyloid beta-protein precursor (amyloid precursor protein, APP) mutant gene, presenilin l (presenilin-l, PSl) gene on No. 14 chromosomes is main relevant with early onset (60 years old former) AD; APP shows typical similar to mankind AD encephalopathy reason with PSl double transgenic mice to be changed, can simulate the partial nerve pathological characters such as formation, glial cells hyperplasia and decrease of synapses of the age-dependent senile plaque of AD, and show clinical similar behavioristics's obstacle to AD.The pharmacodynamic study experiment results proved of mental precious ball, mental precious ball has certain effect that improves learning and memory, and its effect may be with antioxidation, reduce acetylcholine esterase active in cerebral tissue, improves the circulation of brain inner blood, alleviate tissue pathologies change, reduce the senile plaque deposition relevant; The present invention can develop the application of mental precious ball in preparation control medicine for senile dementia.
Above experimental result shows that all the mental precious ball of Rohdea japonica Roth board can improve the dysmnesia of each model mice, has certain nootropic effect, can be used for senile dementia prevention and cure.
Mental precious ball is comprised of the 10 flavor medicines such as Radix Rehmanniae, Fructus Schisandrae Chinensis, Semen Cuscutae, Radix Polygalae, Rhizoma Acori Graminei, Poria, Cortex Lycii, Rhizoma Chuanxiong, vitamin E, vitamin B, and every ball (plain ball) is 0.2 gram heavily approximately, tool nourishing the liver and kidney, the effect of tranquilizing by nourishing the heart.Its dosage on senile dementia prevention and cure is similar to existing treatment neurasthenia dosage, and concrete using method is:
Middle-aged and elderly people or patients of senile dementia, oral, 4 balls, 3 times on the one; Can take by the control course for the treatment of and prescribed dose, have no side effect.
Claims (1)
1. the application of mental precious ball in preparation senile dementia prevention and cure medicine.
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| CN112274625A (en) * | 2020-12-01 | 2021-01-29 | 精华制药集团股份有限公司 | Application of Wangshi Baochi pill in preparation of medicine for preventing, relieving and/or treating dementia |
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Application publication date: 20130515 |