CN102188438A - Application of acetagastrodine in preparing medicines to prevent and treat vascular dementia (VD) and Alzheimer disease (AD) - Google Patents
Application of acetagastrodine in preparing medicines to prevent and treat vascular dementia (VD) and Alzheimer disease (AD) Download PDFInfo
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Abstract
Relating to the medicine field, the invention discloses the use of acetagastrodine in preparing medicines to prevent and treat vascular dementia and Alzheimer disease. The invention also provides a medicinal composition for preventing and treating senile dementia and its capsule as well as sustained release agent. Animal tests show that: acetagastrodine can substantially enhance the learning and memory abilities of rats with vascular dementia, reduce the activity of AchE in brains, enhance the vitality of ChAT in brains, and remarkably reduce Glu content; acetagastrodine has significant protective effect on damaged PC12 cells caused by H2O2 by enhancing the vitality of SOD and total ATP enzyme in PC12 cells and reducing the content of MDA and LD; acetagastrodine can substantially enhance the learning and memorizing abilities of AD model rats, enhance the CAT content in brains of the model rats, reduce the MAO vitality and simultaneously prevent the decrease of neurotransmitters. Acetagastrodine is better than gastrodin in terms of the treatment effects on VD and AD, and enjoys good clinical application prospect.
Description
Technical field
The present invention relates to field of medicaments, be specifically related to the new purposes of acegastrodine in preparation treatment of vascular dementia and Alzheimer disease drug.
Background technology
Senile dementia be occur in the senilism phase and senile be the intelligence infringement syndrome that the disordered brain function of feature produces with the progressive dementia.Comprise that alzheimer disease is Alzheimer's disease (Alzheimerdisease, be called for short AD) and vascular dementia (Vascular dementia, abbreviation VD) two classes again.Wherein AD is a kind of constitutional central nervous system regression disease that betides middle-aged and elderly people; VD is the dementia that cerebral lesion caused that causes because of cerebrovascular disease.The cause of disease of VD relates to two aspects, i.e. cerebrovascular and risk factor.Risk factor comprises that risk factor (hypertension, hyperlipidemia, heart disease, diabetes, universality arteriosclerosis, smoking), apoplexy, ischemic leukodystrophy, advanced age and the schooling of cerebrovascular is low etc.
According to incompletely statistics, the ratio of suffering from the severe alzheimer disease in the over-65s crowd is 5%～8%, and by 80 years old, this ratio just rose to 15%～20%.China alzheimer disease patient has 6,000,000 people at present, account for 1/3 of global patient's sum, about 1,800,000 people of annual neopathy, dead 105.6 ten thousand people, the morbidity situation is very severe, having become modern society and caused the main cause that the old people is disabled and can not live on one's own life, is one of four big diseases of serious threat senior health and fitness.
Regrettably, treat alzheimer disease up to now and still do not have good plan, if the drug main cholinergic drug that has or be about to appear on the market on the present domestic and international market, common mainly is cholinesterase inhibitor, the metabolism that postpones acetylcholine by acetylcholine esterase inhibition is decomposed, increase the cholinergic function of neurons of release in the brain, prolong the excitement of postsynaptic receptor, thereby improve Alzheimer patient's cognition effect.Tacrine (trade name group can cause) is first kind of medicine that is approved for senile dementia treatment, but the hepatotoxicity of this medicine is bigger, now gradually not by clinical use.Donepezil (trade name aricept) compare with tacrine safer effectively, general recommendations preceding clothes of sleeping at night, but the patient of insomnia is then advised taking medicine daytime.Rivastigmine-hydrogentartrate (trade name Exelon) also is the critical treatment medicine of old people's cognitive disorder.Clinical experiment both at home and abroad also points out cognitive symptom and the ADL tool of this medicine to dementia patients to have some improvement, and few side effects.Huperzine A (trade name huperzine A) is a kind of alkaloid that institute of materia medica, Chinese Academy of Sciences Shanghai extracts from Herba Lycopodii serrati (Huperzia serrata.), is a kind of high selectivity cholinesterase inhibitor, tool the have some improvement memory and the effect of cognitive function.
Rhizoma Gastrodiae (Gastrodia elata BL.) has another name called rhizoma gastrodiae, DINGFENGCAO etc., belongs to orchid." Chinese pharmacopoeia is put down in writing its function and is the suppressing the hyperactive liver to relieve the wind syndrome relieving convulsion with curing mainly.It is dizzy to be used to have a headache, numb limbs and tense tendons, infantile convulsion, epilepsy clonus, tetanus.Show that through pharmacodynamic study the Rhizoma Gastrodiae main active is a gastrodine.1880s, Kunming Medicine Group Stock Co., Ltd carries out structure of modification to gastrodine, exclusively developed the highly active acegastrodine (acetagastrodine) that has fat-solubility, central nervous system, cardiovascular system diseases are all had the active treatment effect, chemistry is by name: 4-methylol benzene-2 ', 3 ', 4 ', 6 '-four-O-acetyl-β-D-pyranglucoside, molecular formula C
21H
26O
11, molecular weight 454.42, U.S. chemical abstract are served society's accession number and are: 105054-56-6, and structural formula is as follows:
Acegastrodine has not yet to see the research report to the prevention and the therapeutical effect of senile dementia.
Summary of the invention
The purpose of this invention is to provide the new purposes of acegastrodine, for vascular dementia and Alzheimer's disease provide new prevention and therapeutic scheme at treatment of vascular dementia and Alzheimer's disease.
The present invention also provides the pharmaceutical composition of a kind of prevention and treatment vascular dementia and Alzheimer's disease, comprises acegastrodine and acceptable accessories.
Preferably, acegastrodine contains 30mg～500mg in each preparation unit.
Preferably, acegastrodine content is 50mg～300mg in each preparation unit.
The present invention also provides the capsule of described pharmaceutical composition, and its content consists of:
Acegastrodine 30mg～500mg
Dispersant 100mg～1000mg.
Preferably, described dispersant is any one in soybean oil, Semen Maydis oil, Oleum Arachidis hypogaeae semen, oleum lini, fish oil, Radix Oenotherae erythrosepalae oil, alpha-linolenic acid, gamma-Linolenic acid, docosahexenoic acid (DHA) and the eicosapentaenoic acid (EPA).
Preferably, its softgel shell consists of:
Gelatin 60mg
Glycerol 20mg
Ethylparaben 0.01mg～0.3mg.
The present invention also provides the slow releasing tablet of described pharmaceutical composition, and it consists of:
Acegastrodine 30mg～500mg
Skeleton agent 100mg～1000mg
Filler 30mg～2000mg
Magnesium stearate 1mg～5mg
As preferably, described skeleton agent is any one or the two or more mixture in hydroxypropyl emthylcellulose, stearic acid, ethyl cellulose, the Cera Flava.
As preferably, described filler is any one or the two or more mixture in lactose, pregelatinized Starch, microcrystalline Cellulose, the micropowder silica gel.
Find through animal experiment, test cell line:
Acegastrodine treatment group can significantly reduce the activity of AchE in the brain, and improves the activity of ChAT enzyme in the brain, thereby increases Ach content in the brain, improves cholinergic systemic-function in the brain, thereby improves ability of learning and memory.
Acegastrodine treatment group can significantly reduce Glu content in the brain, reduces its excitatory toxicity, and brain neuron cell is played a very good protection.
Acegastrodine can improve H
2O
2Cell survival rate after the damage reduces spilling of LDH, strengthens SOD vigor in the cell, reduces lipid peroxide MDA content, shows antioxidant activity.
Acegastrodine can improve H
2O
2Total atpase activity in the PC12 cell of damage back, inferring its neuroprotective and strengthen the brain neuroblastoma cell supply can be closely related.Research is also found: acegastrodine can significantly improve the ability of learning and memory of AD rat model, improve the content of CAT in the rat model brain, reduce the activity of MAO, the antagonism oxidation reaction, prevent the minimizing of monoamine neurotransmitter simultaneously, thereby play the effect of control AD.
Retinue is carried out gastrodine comparative study and is found that the dull-witted effect of acegastrodine treatment vascular dementia and nerve is better than gastrodine, can be used for preparing the medicine of treatment of vascular dementia and Alzheimer's disease.
The specific embodiment
Below in conjunction with embodiment, further set forth the present invention.The invention discloses the purposes of acegastrodine at preparation treatment of vascular dementia and Alzheimer's disease.The present invention also provides pharmaceutical composition and the capsule and the slow release formulation of control senile dementia, and those skilled in the art can use for reference this paper content, suitably improves technological parameter and realizes.Special needs to be pointed out is that all similarly replace and change apparent to those skilled in the art, they all are regarded as being included in the present invention.The method of the invention is described by preferred embodiment, and the related personnel obviously can change or suitably change and combination methods described herein in not breaking away from content of the present invention, spirit and scope, realizes and use the present invention.
Embodiment 1: the capsular preparation of acegastrodine
Prescription (1000):
Content:
Acegastrodine 30g
Soybean oil 100g
Softgel shell:
Gelatin 60.2g
Glycerol 19.8g
Water is an amount of
Ethyl hydroxybenzoate (ethyl hydroxybenzoate) 0.12g
Method for making: get acegastrodine, add in the soybean oil, stirring is dissolved it fully, the compacting soft capsule, and drying is made 1000, promptly gets the product that specification is 30mg.
Embodiment 2: the acegastrodine preparation of soft capsule
Prescription (1000):
Content:
Acegastrodine 200g
Semen Maydis oil 200g
Softgel shell:
Gelatin 60.2g
Glycerol 19.8g
Water is an amount of
Ethyl hydroxybenzoate (ethyl hydroxybenzoate) 0.12g
Method for making: get acegastrodine, add in the Semen Maydis oil, stirring is dissolved it fully, the compacting soft capsule, and drying is made 1000, promptly gets the product that specification is 200mg.
Embodiment 3: the acegastrodine preparation of soft capsule
Prescription (1000):
Content:
Acegastrodine 500g
Alpha-linolenic acid 1000g
Softgel shell:
Gelatin 60.2g
Glycerol 19.8g
Water is an amount of
Ethyl hydroxybenzoate (ethyl hydroxybenzoate) 0.12g
Method for making: get acegastrodine, add in the Oleum Arachidis hypogaeae semen, stirring is dissolved it fully, the compacting soft capsule, and drying is made 1000, promptly gets the product that specification is 500mg.
Embodiment 4: the preparation of acegastrodine slow releasing tablet
Prescription (1000):
Acegastrodine 60g
Hydroxypropyl emthylcellulose 100g
Microcrystalline Cellulose 30g
Pregelatinized Starch 30g
Micropowder silica gel 1g
Magnesium stearate 1g
Method for making: material is crossed 100 mesh sieves respectively, take by weighing material by recipe quantity, mix homogeneously stirs the system soft material, and the 18-24 mesh sieve is granulated, 70 ℃ of following aeration-dryings, and tabletting, the bag film-coat promptly gets the product that specification is 60mg.
Embodiment 5: the preparation of acegastrodine slow releasing tablet
Prescription (1000):
Acegastrodine 100g
Stearic acid 1000g
Lactose element 30
Pregelatinized Starch 30
Micropowder silica gel 20g
Magnesium stearate 1g
Method for making: material is crossed 100 mesh sieves respectively, take by weighing material by recipe quantity, mix homogeneously stirs the system soft material, and the 18-24 mesh sieve is granulated, 70 ℃ of following aeration-dryings, and tabletting, the bag film-coat promptly gets the product that specification is 100mg.
Embodiment 6: the preparation of acegastrodine slow releasing tablet
Prescription (1000):
Acegastrodine 300g
Ethyl cellulose 1000g
Microcrystalline Cellulose 1500g
Pregelatinized Starch 400g
Micropowder silica gel 50g
Magnesium stearate 5g
Method for making: material is crossed 100 mesh sieves respectively, take by weighing material by recipe quantity, mix homogeneously stirs the system soft material, and the 18-24 mesh sieve is granulated, 70 ℃ of following aeration-dryings, and tabletting, the bag film-coat promptly gets the product that specification is 300mg.
Embodiment 7: the preparation of acegastrodine slow releasing tablet
Prescription (1000):
Acegastrodine 400g
Cera Flava 1000g
Lactose 1500g
Pregelatinized Starch 400g
Magnesium stearate 5g
Method for making: material is crossed 100 mesh sieves respectively, take by weighing material by recipe quantity, mix homogeneously stirs the system soft material, and the 18-24 mesh sieve is granulated, 70 ℃ of following aeration-dryings, and tabletting, the bag film-coat promptly gets the product that specification is 400mg.
Embodiment 8: acegastrodine is inquired into the experimentation and the mechanism of the preventive and therapeutic effect of experimental vascular dementia VD
1. experiment material
1.1 laboratory animal: SD rat, body weight 160～200g, male and female are regardless of, the cleaning level, provide by unming Medical College's Experimental Animal Center, laboratory animal is produced and occupancy permit number: laboratory animal production and occupancy permit number are respectively: SCXK (Yunnan) 2005-0009 number, SYXK (Yunnan) 2009-0001 number.
1.2 cell strain: rat adrenal chromaffin tumor PC12 cell strain, pharmaceutical college of Fudan University buys.
1.3 medicine and reagent: acegastrodine, Kunming Medicine Group Stock Co., Ltd, lot number: 20081008.CMC-Na with 0.5%, facing with before being made into concentration is that 10% suspension solution is standby; Gastrodine, Kunming Medicine Group Stock Co., Ltd, lot number: 20080812, use water dissolution, be made into concentration and be 10% aqueous solution and be stored in 4 ℃ of refrigerators standby.Nimodipine tablet (Shanxi Yabao Pharmaceutical Co., Ltd.); Vitamin E (Qingdao Double Whale Pharmaceutical Co., Ltd.).Tetrazolium bromide (MTT): Bioisystech Co., Ltd is sought in Nanjing; DMEM culture medium: U.S. Cellgro company; Calf serum: Sijiqing Bioengineering Material Inst., Hangzhou City; Trypsin: Jinan Ya Kanglinuo biological engineering company limited; The test used kit all builds up bio-engineering research institute available from Nanjing; Other reagent are commercially available analytical pure.
1.4 experimental apparatus: Shimadzu UV-2450 ultraviolet-uisible spectrophotometer (day island proper Tianjin company), MG-Y labyrinth stimulator (Zhangjagang City education experiment apparatus factory).DG3022A type enzyme-linked immunosorbent assay instrument (East China Electronics Co., Ltd pipe factory); XSZ-D inverted microscope (optical instrument factory, Chongqing); BB-16 type CO2 incubator.
2. experimental technique and result
2.1 the making of vascular dementia model
With reference to the Longa method, 10% chloral hydrate (3.5mL.kg-1) anesthesia separates left side external carotid artery (ECA), internal carotid artery (ICA), common carotid artery (CCA), occipital artery (OA), superior thyroid artery (STA).Ligation is also cut off OA and STA, ligation ECA distal end.Go into the cranium direction in ECA trunk otch to ICA and insert nylon wire (long 40mm, diameter 0.26mm).Insertion depth is advisable with distance CCA crotch (18 ± 0.5) mm, can feel the bending and the stretching of tangible resistance and nylon wire, and reach in the anterior cerebral artery this moment, all blood supply sources.All blood supply sources of middle cerebral artery (MCA) have been blocked.The record Ischemia Time is tightened the ECA root, extracts nylon wire behind the ischemia 30min, is perfusion beginning again.Pseudo-operation group is only done passivity and is separated not inaccessible MCA.
2.2 animal grouping and dosage regimen
Get 72 of bull rats, divide 6 groups at random: pseudo-operation group, MACO model group, nimodipine group (3mg.kg-1); Gastrodine group (50mg.kg-1); Dosage group (50mg.kg-1) acegastrodine high dose group (100mg.kg-1) in acegastrodine low dose group (25mg.kg-1), the acegastrodine; Each organizes gastric infusion, for three days on end, performs the operation behind the 3rd day administration 30min, and administration 4 days again after the operation was carried out behavioristics and detected on the 8th day.Experimental data adopts the sided t check to organize a significance relatively.
2.3 acegastrodine is to the influence of VD rat behavior
When behavioristics's detection method is trained rat is put into labyrinth adaptation 3min rear-guard and rush to the starting area.Opening the sluices and giving to shock by electricity stimulates, and rat escapes to the place of safety, allows it stop and consolidates memory in 30 seconds.It is correct response that rat directly escapes to the place of safety, enters the place of safety again for " mistake " by other zones or after running helter-skelter.Write down the correct number of times in continuous 10 training, the record accuracy.Test once more after 24 hours 10 times, write down correct response number of times in 10 times.
Table 1: acegastrodine to VD rat labyrinth electricity irritation test (x ± s, n=12)
| Group | Dosage (mg.kg -1) | Learning and memory accuracy % | Learning and memory accuracy % |
| Operative control group | / | 78.4±10.8 | 91.2±8.8 |
| Model group | / | 48.3±13.4 | 68.7±11.3 |
| The nimodipine group | 3 | 64.3±10.8 * | 92.7±6.8 ** |
| The gastrodine group | 50 | 60.7±13.8 * | 86.5±14.3 ** |
| The acegastrodine low dose group | 25 | 66.4±13.9 | 91.4±8.8 * |
| Dosage group in the acegastrodine | 50 | 58.2±7.0 * | 86.4±10.5 ** |
| The acegastrodine high dose group | 100 | 52.7±10.8 ** | 70.0±13.8 ** |
Annotate: compare * p＜0.05, * * p＜0.01 with model group
The result shows that the high, medium and low dosage group of acegastrodine can significantly improve VD rat electricity irritation ability of learning and memory, relatively has significant difference (p＜0.05 or p＜0.01) with model group, and obviously is better than gastrodine.
2.4 acegastrodine is to the influence of AChE, ChAT, Glu in the VD rat cerebral tissue
The detection of AChE, ChAT, Glu: the rat broken end is got brain, will measure AChE, ChAT activity and Glu content with spectrophotometer method after the brain tissue homogenate.
The result shows, AChE of model group rat cerebral tissue and Glu content are apparently higher than puppet operation group, ChAT content is starkly lower than pseudo-operation group (p＜0.01), the middle and high dosage group of acegastrodine can significantly reduce AChE and Glu content, improve ChAT content, relatively have significant difference (p＜0.05 or p＜0.01) with model group.
Table 2: acegastrodine to AChE, ChAT activity and the Glu content influence of VD rat cerebral tissue (x ± s, n=9)
| Group | Dosage (mg/kg) | AChE activity (U/mg pront) | ChAT activity (U/g) | Glu (μmol/g?prot) |
| Operative control group | / | 0.95±0.15 | 146.5±32.5 | 244.4±51.6 |
| Model group | / | 1.32±0.18 | 103.4±21.1 | 326.4±61.6 |
| The nimodipine group | 3 | 1.02±0.14 ** | 133.6±31.7 * | 254.2±44.0 ** |
| The gastrodine group | 50 | 1.06±0.13 * | 137.8±28.6 * | 250.2±43.6 * |
| The acegastrodine low dose group | 25 | 1.22±0.15 | 127.5±23.9 | 275.4±44.6 |
| Dosage group in the acegastrodine | 50 | 1.10±0.17 * | 120.5±18.6 * | 254.4±50.1 * |
| The acegastrodine high dose group | 100 | 1.01±0.12 ** | 132.5±18.7 ** | 248.3±45.7 ** |
Annotate: compare * p＜0.05, * * p＜0.01 with model group
2.5 acegastrodine is to the influence of PC12 cellular oxidation stress damage model
Frozen PC12 cell recovery is inoculated in the 100mL culture bottle, and all DMEM complete mediums include 100U/mL penicillin, 100 μ g/mL streptomycins, 10% calf serum, 37 ℃, 5% CO
2Leave standstill cultivation.After treating that cell 80% converges in flakes, go down to posterity with 0.25% trypsinization.
The PC12 cell inoculation in 24 well culture plates, 37 ℃, 5% CO
2Leave standstill to be cultured to and cover with monolayer, abandon original fluid, cleanse gently 2 times, add final concentration and be respectively 10 with phosphate buffer
-5, 10
-6, 10
-7The gastrodine of mol/L, acegastrodine and the effect of 10-6mol/L vitamin E added H2O2 (final concentration is 300 μ mol/L) in 1 hour again and put 37 ℃, 5% CO
2Continue in the incubator to cultivate 4 hours, the results are shown in Table 3
Table 3: acegastrodine to the influence of PC12 cellular oxidation stress damage model (x ± s, n=6)
| Group | Concentration mol/L | OD 570 | Suppression ratio % | LDH(kU/L) | Suppression ratio (%) |
| Operative control group | / | 0.55±0.04 | 871.3±74.6 | ||
| Model group | / | 0.43±0.05 | 1432.1±113.7 | ||
| The vitamin E group | 10 -6 | 0.53±0.04 ** | 87.4 | 1086.8±83.1 * | 60.2 |
| The gastrodine group | 10 -5 | 0.54±0.05 ** | 96.0 | 931.4±76.4 ** | 91.1 |
| The acegastrodine group | 10 -5 | 0.48±0.04 ** | 99.0 | 920.5±77.3 ** | 95.2 |
| The acegastrodine group | 10 -6 | 0.50±0.03 * | 82.4 | 1012.8±113.3 * | 76.3 |
| The acegastrodine group | 10 -7 | 0.58±0.05 | 60.1 | 1312.8±143.6 | 50.2 |
Annotate: compare * p＜0.05, * * p＜0.01 with model group
The result shows that in the oxidative stress damage model, the PC12 cell viability descends, OD
570Value is starkly lower than matched group (p＜0.01).Acegastrodine height, middle concentration group and vitamin E group cell viability are significantly higher than model group (p＜0.05, or p＜0.01), and along with the reduction of drug level, suppression ratio reduces successively, show that its protective effect presents the concentration dependence; PC12 cell LDH activity shows that apparently higher than matched group (p＜0.01) cell is subjected to the oxidative stress damage in the model.Acegastrodine height, middle concentration and vitamin E group are compared active (p＜0.05 that obviously reduces of LDH with model group; or p＜0.01); illustrate that acegastrodine has protective effect; reduction along with drug level; the LDH activity raises successively and suppression ratio reduces successively, shows that its protective effect presents the concentration dependence.
2.6 acegastrodine is to H
2O
2The influence of SOD, total ATP enzyme activity and MDA, LD content in the inductive PC12 cell
After modeling is finished, discard each hole supernatant, add 1%TritionX-100 in 40 ℃ of cell lysis after the phosphate buffer washed twice with ice, collect lysate, measure SOD in the cell, total ATP enzyme activity and MDA, LD content respectively, the results are shown in Table 4 by test kit.
Table 4: acegastrodine is to H
2O
2The influence of SOD, total ATP enzyme activity and MDA, LD content in the inductive PC12 cell (x ± s, n=3)
| Group | Concentration (mol/L) | SOD(U/mL) | MDA(nmol/mL) | LD(mmol/g) | T-ATP(U/mg) |
| Operative control group | / | 115.7±6.5 | 2.14±0.85 | 0.22±0.01 | 8.24±0.88 |
| Model group | / | 83.1±7.4 | 7.19±0.45 | 0.34±0.03 | 3.87±0.32 |
| The vitamin E group | 10 -6 | 100.7±9.3 * | 3.19±0.57 ** | 0.27±0.02 * | 6.78±0.23 ** |
| The gastrodine group | 10 -5 | 101.2±6.5 * | 3.39±0.75 ** | 0.24±0.02 | 6.04±0.44 |
| The acegastrodine group | 10 -5 | 110.5±5.7 ** | 3.30±0.35 ** | 0.20±0.02 ** | 6.00±0.31 ** |
| The acegastrodine group | 10 -6 | 100.2±4.5 * | 5.20±0.55 * | 0.26±0.03 * | 5.88±0.54 * |
| The acegastrodine group | 10 -7 | 97.7±6.3 | 6.30±0.35 | 0.32±0.03 | 5.74±0.34 |
Annotate: compare * p＜0.05, * * p＜0.01 with model group.
The result shows, in the oxidative stress damage model, SOD and total ATP enzyme activity are starkly lower than normal control group (p＜0.01) in the PC12 cell, SOD and total ATP enzyme activity are significantly higher than model group (p＜0.05 in acegastrodine and the vitamin E group cell, and present certain concentration dependent or p＜0.01); Each group of acegastrodine height, middle concentration and vitamin E significantly reduces MDA and LD content (p＜0.05, or p＜0.01) in the born of the same parents, and presents certain concentration dependent.
Embodiment 9: acegastrodine is to the improvement effect of the learning and memory function of Alzheimer's disease rat model
1 materials and methods
1.1 animal and grouping
45 of healthy 4 monthly age Wistar male rats, body weight 180～250g, unming Medical College's medical experiment animal center provides, and laboratory animal production and occupancy permit number are respectively: SCXK (Yunnan) 2005-0009 number, SYXK (Yunnan) 2009-0001 number.Be divided into blank group, model control group, nimodipine group (3mg.kg-1) at random with the table of random number method; Dosage group (50mg.kg-1) acegastrodine high dose group (100mg.kg-1) in gastrodine group (50mg.kg-1) acegastrodine low dose group (25mg.kg-1), the acegastrodine, every group 10, each organizes gastric infusion, for three days on end, perform the operation behind the 3rd day administration 30min, administration 4 days again after the operation was carried out behavioristics and is detected on the 8th day.
1.2 medicine and reagent
Acegastrodine, Kunming Medicine Group Stock Co., Ltd, lot number: 20091008., the CMC-Na with 0.5%, facing with before being made into concentration is that 10% suspension solution is standby; Gastrodine, Kunming Medicine Group Stock Co., Ltd, lot number: 20090812, use water dissolution, be made into concentration and be 10% aqueous solution and be stored in 4 ℃ of refrigerators standby.Nimodipine tablet (Shanxi Yabao Pharmaceutical Co., Ltd.).
1.3 instrument
Self-control diving tower instrument; The HANGPING electronic scale (model: JY4001), balance equipment factory of company of last Nereid section; The low temperature-controlled refrigerator, Haier; Electric-heated thermostatic water bath (model: HHS21-4), Shanghai No.5 Medical Equipment Factory; Uv-spectrophotometric instrument (model: Shimadzu 2450), day island proper Tianjin; High speed centrifuge (model: 1-14ED), Sigma company.
1.4 modeling and administration
In the 1st week, blank group, model control group give the equal-volume normal saline, all the other respectively organize 10mL/kg administration every day, the 2nd～4 week, blank group, model group give the equal-volume normal saline, all the other respectively organize administration cervical region injection of d-galactose [pressing 5mL/ (kgd), concentration 1%] simultaneously except that the blank group.The 5th～6 week stopped the D-galactose, changed lumbar injection scopolamine [2mL/ (kgd), concentration 0.3mg/mL] into, and behind last 1 administration 2h, each is organized rat and carries out the diving tower test.
1.5 behavioristics's test
The diving tower method is used in behavioristics's test: rat is placed in the diving tower case, switches on behind the adaptation 5min, jump to safety board from rat and begin to clock, up to jumping off from safety board, this section period is incubation period; The rat biped contacts the copper grid simultaneously and is considered as wrong reaction when jumping off, training 5min and write down incubation period in the 5min and errors number as the study index.In the end carry out 1 diving tower test behind 1 administration 2h, electric shock latent time and errors number in the rat 5min respectively organized in record.
1.6 collection of specimens and processing
Fasting on the same day behind diving tower, the 2nd day every group select 8 rats (in the experimentation altogether natural death 2) at random, behind the 1% sodium pentobarbital 35mg/kg intraperitoneal injection of anesthesia, row common carotid artery intubate blood sampling back sacrificed by decapitation, the last taking-up of Yu Bingtai cerebral tissue, use normal saline flushing, cut along sagittal suture, add 9 times of normal saline after partly weighing in a left side and make 10% homogenate, with the centrifugal 15min of 3000r/min, get supernatant, frozen to be measured.
1.7 the detection of catalase, monoamine oxidase, MAO
Adopt chemical colorimetry to measure the activity of CAT, MAO, assay method carries out according to the test kit read-me.
1.8 statistical method
SPSS11.0 software is adopted in data statistics, and each is organized data and represents that with x ± s mean relatively adopts the variance analysis check between group,, P＜0.05 or P＜0.01 is for there being statistical significance.
Table 5: each organizes the comparison (x ± s) of learning and memory in rats ability
| Group | Dosage (mg.kg -1) | Incubation period (s) | Errors number (inferior/5min) |
| The blank group | / | 298.4±76.8 | 0.64±0.28 |
| Model group | / | 148.3±63.2 ** | 1.78±0.63 ** |
| The nimodipine group | 3 | 274.3±70.8 ## | 0.72±0.38 ## |
| The gastrodine group | 50 | 250.7±68.8 ## | 0.85±0.32 ## |
| The acegastrodine low dose group | 25 | 236.4±73.9 ## | 0.97±0.43 ## |
| Dosage group in the acegastrodine | 50 | 248.2±77.0 ## | 0.89±0.35 ## |
| The acegastrodine high dose group | 100 | 256.7±66.8 ## | 0.80±0.28 ## |
Annotate: compare * P＜0.05, * * P＜0.01 with the blank group; Compare #P＜0.05, ##P＜0.01 with model control group
Table 6: each organizes the comparison (x ± s) of CAT in the big rat brain tissue homogenate, MAO content
| Group | Dosage (mg.kg -1) | CAT(U/mg) | MAO(U/mg) |
| The blank group | / | 18.14±4.35 | 2.34±0.88 |
| Model group | / | 8.53±3.24 ** | 3.78±0.93 * |
| The nimodipine group | 3 | 16.83±4.88 ## | 1.22±0.75 # |
| The gastrodine group | 50 | 16.05±6.8 ## | 2.85±0.82 # |
| The acegastrodine low dose group | 25 | 15.64±3.9 ## | 2.97±0.95 # |
| Dosage group in the acegastrodine | 50 | 15.92±5.0 ## | 2.89±0.69 # |
| The acegastrodine high dose group | 100 | 16.57±7.4 ## | 2.08±0.78 # |
Annotate: compare * P＜0.05, * * P＜0.01 with the blank group; Compare #P＜0.05, ##P＜0.01 with model control group
This experiment adopts the cervical region injection of d-galactose to cause the subacute old and feeble lumbar injection scopolamine damage M type cholinoceptor that merges, and prepares compound AD model, and the more single factor AD model of this composite model is more pressed close to its complicated pathological change process.This experimental result shows that acegastrodine can improve the ability of learning and memory of rat model, improves the content of CAT in the rat model brain, reduces the activity of MAO, and the antagonism oxidation reaction prevents the minimizing of monoamine neurotransmitter simultaneously, thereby plays the effect of control AD.
Claims (10)
1. the application of acegastrodine in preparation prevention and treatment vascular dementia and Alzheimer disease drug.
2. a pharmaceutical composition that prevents and treat vascular dementia and Alzheimer's disease is characterized in that, comprises acegastrodine and acceptable accessories.
3. pharmaceutical composition according to claim 2 is characterized in that acegastrodine contains 30mg～500mg in each preparation unit.
4. pharmaceutical composition according to claim 3 is characterized in that, acegastrodine content is 50mg～300mg in each preparation unit.
5. the capsule of pharmaceutical composition according to claim 2 is characterized in that, its content consists of:
Acegastrodine 30mg～500mg
Dispersant 100mg～1000mg.
6. capsule according to claim 5, it is characterized in that described dispersant is any one in soybean oil, Semen Maydis oil, Oleum Arachidis hypogaeae semen, oleum lini, fish oil, Radix Oenotherae erythrosepalae oil, alpha-linolenic acid, gamma-Linolenic acid, docosahexenoic acid and the eicosapentaenoic acid.
7. according to claim 5 or 6 described capsules, it is characterized in that its softgel shell consists of:
Gelatin 60mg
Glycerol 20mg
Ethylparaben 0.01mg～0.3mg.
8. according to the slow releasing tablet of each described pharmaceutical composition of claim 2-4, it is characterized in that it consists of:
Acegastrodine 30mg～500mg
Skeleton agent 100mg～1000mg
Filler 30mg～2000mg
Magnesium stearate 1mg～5mg.
9. slow releasing tablet according to claim 8 is characterized in that, described skeleton agent is any one or the two or more mixture in hydroxypropyl emthylcellulose, stearic acid, ethyl cellulose, the Cera Flava.
10. slow releasing tablet according to claim 8 is characterized in that, described filler is any one or the two or more mixture in lactose, pregelatinized Starch, microcrystalline Cellulose, the micropowder silica gel.
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| CN103385884A (en) * | 2013-07-05 | 2013-11-13 | 昆明医科大学 | Application of gastrodin to preparing medicaments for preventing and treating Alzheimer's disease |
| CN104628796A (en) * | 2013-11-07 | 2015-05-20 | 刘力 | Gastrodin medicine, and composition and use thereof |
| CN105664146A (en) * | 2016-01-16 | 2016-06-15 | 杜志政 | Medicament for enhancing immunity and preparation method thereof |
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| CN106619667A (en) * | 2016-11-19 | 2017-05-10 | 昆药集团股份有限公司 | Application of acegastrodine and acegastrodine derivative |
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| CN114159452A (en) * | 2021-12-28 | 2022-03-11 | 昆明医科大学 | Application of high-dose gastrodin |
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| CN103385884A (en) * | 2013-07-05 | 2013-11-13 | 昆明医科大学 | Application of gastrodin to preparing medicaments for preventing and treating Alzheimer's disease |
| CN104628796A (en) * | 2013-11-07 | 2015-05-20 | 刘力 | Gastrodin medicine, and composition and use thereof |
| CN104628796B (en) * | 2013-11-07 | 2018-09-04 | 刘力 | Gastrodin class drug and combinations thereof and purposes |
| CN105664146A (en) * | 2016-01-16 | 2016-06-15 | 杜志政 | Medicament for enhancing immunity and preparation method thereof |
| CN106074580A (en) * | 2016-06-18 | 2016-11-09 | 昆药集团股份有限公司 | A kind of new application of acegastrodine derivant |
| CN106074580B (en) * | 2016-06-18 | 2018-10-09 | 昆药集团股份有限公司 | A kind of new application of Acegastrodine derivative |
| CN106619667A (en) * | 2016-11-19 | 2017-05-10 | 昆药集团股份有限公司 | Application of acegastrodine and acegastrodine derivative |
| CN107286210A (en) * | 2017-06-19 | 2017-10-24 | 昆药集团股份有限公司 | A kind of Acegastrodine compound and preparation method thereof, preparation and application |
| CN112858697A (en) * | 2021-03-29 | 2021-05-28 | 鲁东大学 | Application of ALG-2-interacting protein X in preparation of molecular marker |
| CN112858697B (en) * | 2021-03-29 | 2024-03-01 | 鲁东大学 | Application of ALG-2-interacting protein X in preparation of molecular markers |
| CN114159452A (en) * | 2021-12-28 | 2022-03-11 | 昆明医科大学 | Application of high-dose gastrodin |
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