CN1481808A - Composition of active parts of traditional Chinese medicine for preventing and treating senile dementia and preparation method thereof - Google Patents
Composition of active parts of traditional Chinese medicine for preventing and treating senile dementia and preparation method thereof Download PDFInfo
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- CN1481808A CN1481808A CNA031322026A CN03132202A CN1481808A CN 1481808 A CN1481808 A CN 1481808A CN A031322026 A CNA031322026 A CN A031322026A CN 03132202 A CN03132202 A CN 03132202A CN 1481808 A CN1481808 A CN 1481808A
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Abstract
一种防治老年痴呆的中药组合物，主要由茯苓和/或白术和/或当归中的多糖、正丁醇提取物和/或挥发油的有效部位组成，可与药学上适用载体混合，制成各种制剂，本发明还包括可工业化应用的提取分离方法。A traditional Chinese medicine composition for preventing and treating senile dementia, mainly composed of polysaccharides in Poria cocos and/or Atractylodes macrocephala and/or angelica, effective parts of n-butanol extract and/or volatile oil, which can be mixed with pharmaceutically applicable carriers to make various The preparation, the present invention also includes an industrially applicable extraction and separation method.
Description
Technical field
The present invention relates to a kind of Chinese medicine compound effective site of preventing and treating senile dementia and preparation method thereof, be the active component composition of the control senile dementia of extraction separation from DANGGUI SHAOYAO SAN side of simplifying and prescription medicine thereof specifically, but and the extraction separation method of industrial applications.
Background technology
DANGGUI SHAOYAO SAN (Danggui Shaoyao San) is recorded in Chinese Zhang Zhongjing " Medical Treasures of the Golden Chamber ".It consists of Radix Angelicae Sinensis 3g, Radix Paeoniae Alba 16g, Rhizoma Chuanxiong 8g, Poria 4g, Rhizoma Atractylodis Macrocephalae 4g and Rhizoma Alismatis 8g.The effect of DANGGUI SHAOYAO SAN is soothing the liver for nourishing blood, invigorating spleen to remove dampness.Clinical curing mainly: stagnation of QI blood-deficiency type alzheimer disease, disease are seen dull as stupid, forgetful, absentminded, and speaking incoherently is in a very depressed state or irritability uncomfortable in chest, sighs being about to cry due to sadness, restlessness of asrhenia type and insomnia, lack of appetite asthenia, abdominal distention loose stool, pale tongue, stringy and thready pulse again and again.Modern medicine study shows, senile dementia is mainly A Ercaimo disease (Alzheimer ' s disease, be called for short AD) and vascular dementia (vascular dementia is called for short VD) two major types.DANGGUI SHAOYAO SAN all has certain curative effect to AD and VD.
The inventor has utilized the modern pharmacology laboratory facilities, to treating the ancient prescription DANGGUI SHAOYAO SAN side of tearing open that senile dementia has certain curative effect, promptly study the Six-element crude drug of forming the DANGGUI SHAOYAO SAN prescription respectively, carry out preferred compositions again, obtain a kind of Chinese medicine composition of preventing and treating senile dementia, it is characterized in that being made up of Poria, the Rhizoma Atractylodis Macrocephalae, Radix Angelicae Sinensis three flavor crude drug, its crude drug ratio is: Poria 2-6 part: Rhizoma Atractylodis Macrocephalae 1-3 part: Radix Angelicae Sinensis 0.5-1.5 part; The preferred ratio of its crude drug is: 4 parts in Poria: 2 parts of the Rhizoma Atractylodis Macrocephalaes: 1 part of Radix Angelicae Sinensis.(referring to CN02112711.5, a kind of Chinese medicine composition of preventing and treating senile dementia) comparative experiments confirms that the ancient prescription DANGGUI SHAOYAO SAN of being made up of the Six-element medical material is three flavors simplifying aspect the control senile dementia disease, and the side of simplifying is called for short FBD.The side of simplifying FBD obviously is better than former side (being called for short DSS) to the prevention effect of VD.
Summary of the invention
The technical issues that need to address of the present invention are: be to suffer from the senile dementia patient of VD, research more possesses medicine targetedly, so that symptomatic treatment more exactly, thereby improves therapeutic effect to senile dementia.And, also provide good prophylactic for the sickness rate that is about to step into senile middle age prevention or reduce senile dementia.
Because no matter prevent the morbidity of senile dementia or the senile dementia patient that treatment has been fallen ill, all need to take medicine for a long time, so on the basis that guarantees curative effect, should reduce dosage as far as possible, improve pharmaceutical dosage form, reduce cost of drugs and price.
For further guarantee curative effect stable, reduce dosage, improve pharmaceutical dosage form, just need analyze the side of simplifying FBD and composition medical material thereof, extraction separation has the effective site of curative effect, and extraction and separation process reasonable in design.To the extraction separation of the side of simplifying FBD and composition medical material effective site thereof, be that the side of simplifying FBD is understood the preliminary of its treatment mechanism from chemical nature, also be the basis of formulating the exact mass standard.
In order to solve this technical problem, the present invention utilizes the modern pharmacology laboratory facilities, to treating the ancient prescription DANGGUI SHAOYAO SAN side of simplifying FBD and the square Chinese crude drug thereof that senile dementia has certain curative effect, after carrying out multiple compatibility, research has the type of the chemical constituent of pharmacological action, promptly study the effective site of the 3 flavor medical materials of forming the DANGGUI SHAOYAO SAN side of simplifying respectively, carry out preferred compositions again, obtain following technical scheme.
A kind of Chinese medicine composition of preventing and treating senile dementia, it is characterized in that: mainly form, perhaps mainly form by the polysaccharide in one or both crude drug that are selected from Poria, the Rhizoma Atractylodis Macrocephalae and the Radix Angelicae Sinensis, n-butanol extract and/or volatile oil effective site by Poria, the Rhizoma Atractylodis Macrocephalae and polysaccharide, n-butanol extract and/or volatile oil effective site in the crude drug that is grouped into.
Described Chinese medicine composition, it is characterized in that: mainly by Poria or the Rhizoma Atractylodis Macrocephalae or Radix Angelicae Sinensis, or the Poria and the Rhizoma Atractylodis Macrocephalae, perhaps Poria and Radix Angelicae Sinensis, the perhaps Rhizoma Atractylodis Macrocephalae and Radix Angelicae Sinensis, perhaps the polysaccharide in Poria, the Rhizoma Atractylodis Macrocephalae and the Radix Angelicae Sinensis, n-butanol extract and/or volatile oil effective site are formed.
Described Chinese medicine composition can be: mainly by Poria 2-6 part: Rhizoma Atractylodis Macrocephalae 1-3 part: polysaccharide, n-butanol extract and/or volatile oil in Radix Angelicae Sinensis 0.5-1.5 part are formed, and the ratio of polysaccharide, n-butanol extract and/or volatile oil is 1～1.5 gram: 5～10 grams: 0.4～1.2 milliliter.
Described Chinese medicine composition proportioning preferably is: mainly by 4 parts in Poria: 2 parts of the Rhizoma Atractylodis Macrocephalaes: polysaccharide, n-butanol extract and/or volatile oil in 1 part of the Radix Angelicae Sinensis are formed, and the ratio of polysaccharide, n-butanol extract and/or volatile oil is 1.1～1.2 grams: 7～8 grams: 0.6～0.8 milliliter.
Aforementioned Chinese medicine composition preparation method is as follows:
Get Poria, the Rhizoma Atractylodis Macrocephalae and Radix Angelicae Sinensis, perhaps be selected from Poria, the Rhizoma Atractylodis Macrocephalae and the Radix Angelicae Sinensis one or both, CO
2Supercritical extraction extracts volatile oil, medicinal residues with water extraction after, add ethanol precipitation, obtain polysaccharide, merge volatile oil and polysaccharide;
Perhaps, get Poria, the Rhizoma Atractylodis Macrocephalae and Radix Angelicae Sinensis, perhaps be selected from Poria, the Rhizoma Atractylodis Macrocephalae and the Radix Angelicae Sinensis one or both, CO
2Supercritical extraction extracts volatile oil, medicinal residues with water extraction after, add ethanol precipitation, obtain polysaccharide, supernatant use n-butanol extraction after reclaiming ethanol, merging volatile oil, polysaccharide and n-butanol extract;
Perhaps, get Poria, the Rhizoma Atractylodis Macrocephalae and Radix Angelicae Sinensis, perhaps be selected from Poria, the Rhizoma Atractylodis Macrocephalae and the Radix Angelicae Sinensis one or both, water decocts, after aqueous extract concentrates, add ethanol precipitation, get polysaccharide, supernatant is used n-butanol extraction after reclaiming ethanol, gets n-butanol portion, merges polysaccharide and n-butanol extract.
Described Chinese medicine composition preparation method is specially: get the Poria or the Rhizoma Atractylodis Macrocephalae or Radix Angelicae Sinensis, perhaps get the Poria and the Rhizoma Atractylodis Macrocephalae, perhaps get the Rhizoma Atractylodis Macrocephalae and Radix Angelicae Sinensis, perhaps get Poria and Radix Angelicae Sinensis, perhaps get Poria, the Rhizoma Atractylodis Macrocephalae and Radix Angelicae Sinensis; CO2 supercritical extraction pressure tank 8.0-25.0Mpa, entrainer be with ethanol, ethyl acetate and/or hexane, carry secretly dosage by volume/weight ratio is the 30.0-150% of spice amount; Add ethanol to the time precipitation polysaccharide that contains determining alcohol for 45-95%.In the described Chinese medicine composition preparation method: get Poria 2-6 part: Rhizoma Atractylodis Macrocephalae 1-3 part: Radix Angelicae Sinensis 0.5-1.5 part, the ratio of gained polysaccharide, n-butanol extract and/or volatile oil are 1～1.5 gram: 5～10 grams: 0.4～1.2 milliliter.
In the aforementioned Chinese medicine composition preparation method, it is characterized in that: the ratio of gained polysaccharide, n-butanol extract and/or volatile oil is 1.1～1.2 grams: 7～8 grams: 0.6～0.8 milliliter.Gained polysaccharide, n-butanol extract and/or volatile oil, can with pharmaceutically be suitable for component and mix, make various preparations.Gained polysaccharide, n-butanol extract and/or volatile oil can mix with suitable carrier pharmaceutically, make various preparations.
Oral formulations adjuvant commonly used can select for use, and disintegrating agent is as hydroxypropyl starch, hyprolose, carboxymethyl starch sodium, carboxymethylcellulose calcium, polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose etc.; Filler is as lactose, sucrose, mannitol, microcrystalline Cellulose, dextrin, starch, calcium phosphate, calcium hydrogen phosphate, calcium sulfate, calcium carbonate, cyclodextrin, micropowder cellulose etc.; Wetting agent and binding agent are as ethanol, pregelatinized Starch, polyvidone, sodium carboxymethyl cellulose, hypromellose; Lubricant is as Pulvis Talci, stearic acid, magnesium stearate, calcium stearate, micropowder silica gel, hydrogenated vegetable oil, Macrogol 4000 and 6000; Wetting agent is as sodium lauryl sulphate, Tween 80.
For sake of convenience, with technical scheme Poria of the present invention, the Rhizoma Atractylodis Macrocephalae, abbreviate FBD as when the Chinese medicine composition that is grouped into.Poria is called for short F, the Rhizoma Atractylodis Macrocephalae is called for short B, Radix Angelicae Sinensis abbreviation D.
On two kinds of dissimilar VD models, carried out the FBD prescription analysis.2 experimental results prove that the full side effect of FBD prescription is better than other combinations; FD and FB effect are better than BD; F, B, D all have each self-applying, and F is a principal agent among the FBD.Cerebrospinal fluid (CSF) pharmaceutical research is also found, 10%CSF-FBD, FB, FD, BD, F, B, D all can improve sodium sulfite and sodium glutamate damage PCCN cell viability; Wherein, CSF-FBD and CSF-FB all have protective effect to 2 kinds of cell injury; F, B, single time spent of D, the CSF-F oxygen lack resistant function is the most remarkable, and the effect of CSF-D ischemia resisting is the strongest; The three share in twos, and enhancing is not seen in effect substantially.
The pharmacological evaluation of following three flavor medical materials combinations respectively or is in twos done with its decocting liquid, does not separate its three effective kind part, if still experimentize by technology of the present invention, can assign to three effective kind parts equally.
One, the prescription analysis of the DANGGUI SHAOYAO SAN side of simplifying treatment of vascular dementia
(1) the anti-persistency bilateral ligation in the DANGGUI SHAOYAO SAN side of simplifying and brain repeatedly ischemia-reperfusion cause the preparation FBD of prescription analysis 1 experiment material 1.1FBD water extract of mice vascular dementia according to different 8 combination: FBD, F+B+D (F, B, D divide fry in shallow oil merging), FB, FD, BD, F, B and the Z of being divided into of preparation with prescription.It is an amount of to get 8 composite reagents, and customary merceration extracts, and preparation concentration is respectively 4.60,4.60,3.84,3.32,2.04,2.56,1.28, FBD, the F+B+D of 0.76g crude drug/100ml, FB, FD, BD, F, B, Z water extract, preserves standby down for 4 ℃.1.2 the animal male mouse of kunming, 25 ± 2g; 37 ± 3g provides by the new middle new drug research center of China Medicine University.1.3 instrument passive avoidance reflectometer is developed by China Academy Of Traditional Chinese Medicine Traditional Chinese Medicine Research Institute; SMG-2 type watermaze protocol auto-controller is developed by institute of Materia Medica,Chinese Academy of Medical Sciences, and behavioristics tests 1.0 softwares and carries out data acquisition.The Z323K high-speed refrigerated centrifuge, German Hermle labor tecknik; DU640 nucleic acid-protein analyser, U.S. Beckman coulter; XHF-1 high speed dispersion device, the Shanghai gold reaches biochemical instrument factory; Electric-heated thermostatic water bath, Medical Apparatus ﹠ Instruments Factory Jiangsu Prov..20010315), malonaldehyde (MDA) measures test kit (lot number: 20010315) build up bio-engineering research institute available from Nanjing 1.4 reagent quantification of protein test kit (lot number:.1.5 statistical analysis uses NDST4.4 software to add up, data are represented with x ± s.The timing data with the harmonic mean method with data to number conversion after t or t ' check between the row group, t or t ' check between measurement data row group.2 methods and result's 2.1 persistency bilateral ligation cause mice VD methodology and set up, referring to: Liu Huibo etc. bilateral ligation is to learning and memory function and the morphologic influence of hippocampal tissue. preclinical medicine and clinical, 1998,18 (4): 54-57; Model essay brightness etc., the animal model of vascular dementia and cholinergic mechanism research thereof. Third Military Medical University's journal, 2000,22 (4): 314-317
Get 20 of male mice in kunming, body weight 25 ± 2g is divided into sham operated rats and model group at random, fasting 10h before the art, the anesthesia of ip1g/kg20% urethane, 75% medical alcohol sterilization cervical region, dorsal position is fixed, the about 2cm of neck split shed, passivity is isolated bilateral carotid, do not peel off vagus nerve, dual silk thread ligation, wound place drop gentamycin 2.5 * 10
4U/kg2-3 drips, and sews up wound; Sham operated rats only appears bilateral carotid, and other handles same model group.
Revive in the postoperative model mice 10h, but the minimizing of appetite drinking-water, fur is fluffy, weight loss; , vascular ligation raises two evaginations, aganoblepharon or lift unable because of causing intracranial pressure or intraocular pressure.
Postoperative 10d begins to detect mice space resolution capability with the continuous 4d of water maze procedure auto-control instrument, and water temperature is controlled at 27.5-28 ℃, cecum (blind termination, bt) number increases day by day from 1-4bt, and record mice swimming time is estimated mice space resolution capability with swimming time.
Experiment shows: (p＜0.05-0.01), the hints model mice continues to exist space resolution capability obstacle to the swimming time that model mice is finished the work in water maze, and it is remarkable day by day to increase difference with task difficulty than sham-operation mice significant prolongation; But the motion function of model mice and balance performance do not occur meeting the VD clinical manifestation unusually, and model prepares successfully.2.2FBD anti-persistency bilateral ligation (PBCAO) causes mouse memory obstacle prescription analysis
Sieve is got 100 of qualified mices, is divided into 10 groups at random: sham operated rats, model group, FBD group, F+B+D group, FB group, FD group, BD group, F group, B group, D group.D1 carries out PBCAO operation, the corresponding 8 kinds of water extracts of the continuous ig of d2-d6, bid * 5d, dosage 0.5ml/20g body weight to mice.D6 keeps away dark training with the passive avoidance reflectometer to mice, and the same time detecting mice of d7 is kept away errors number in dark incubation period and the 5min; D7-9 every morning is carried out the 1-3bt swimming instruction with water maze day by day to mice, writes down the mice swimming time every afternoon, swimming time threshold setting: 1bt:30s; 1bt:60s; 3bt:90s.
Table 1, the anti-persistency bilateral ligation of FBD and brain ischemia-reperfusion repeatedly cause the prescription analysis (x ± s) of mice vascular dementia
Group dosage (g/kg/d) n Latency (Logs) No.of errors
Sham operated rats 11 2.26 ± 0.39 1.0 ± 1.2
Model group 7 1.50 ± 0.36
The Δ Δ3.1 ± 2.0
Δ
FBD???????????2.30??????????11?????????2.17±0.51
**????0.7±1.2
**
F+B+D?????????2.30??????????7??????????2.10±0.39
*?????0.7±0.8
*
FB????????????1.92??????????7??????????1.84±0.66???????1.6±1.7
FD????????????1.66??????????9??????????2.11±0.56
*?????0.7±0.7
**
BD????????????1.02??????????9??????????1.25±0.26???????1.9±0.8
F?????????????1.28??????????7??????????2.11±0.53
*?????0.4±0.5
*
B?????????????0.64??????????8??????????2.37±0.29
**????0.3±0.5
**
D 0.38 8 1.88 ± 0.59 0.9 ± 1.0
* ΔP＜0.05,
The Δ ΔP＜0.01vs sham operated rats;
*P＜0.05,
*P＜0.01vs model group stimulate parameters:125ms, 38V.PP
Mice PBCAO operation back 1w keeps away in the dark task and significantly to be longer than normal mouse incubation period, and errors number increases significantly that (p＜0.05-0.01), prompting PBCAO causes damage to the mouse memory capacitation; The 8 kinds of various combinations of FBD and preparation water extract be lengthening model mice incubation period and/or reduce errors number in various degree all, wherein with the remarkable (p＜0.05-0.01) of FBD, F+B+D, FD, F, B, the effect of D water extract.The results are shown in Table 1.
Table 2, FBD and each component to the influence of model mice swimming time in the water maze swimming task (x ± s, n=7-9)
Swimming?time(Logs)
Group dosage (g/kg/d) n
1bt????????????2bt???????????3bt
Sham operated rats 7 0.99 ± 0.18 1.17 ± 0.15 1.21 ± 0.31
Model group 7 1.19 ± 0.18
Δ1.31 ± 0.30 1.65 ± 0.23
Δ
FBD??????????????2.30?????????8????????1.04±0.20?????1.37±0.17????1.39±0.22
*
F+B+D????????????2.30?????????7????????1.24±0.24?????1.43±0.31????1.76±0.29
FB???????????????1.92?????????7????????1.34±0.14?????1.62±0.20????1.49±0.45
FD???????????????1.66?????????8????????1.22±0.23?????1.42±0.23????1.73±0.30
BD???????????????1.02?????????9????????1.24±0.22?????1.43±0.22????1.49±0.18
F????????????????1.28?????????7????????1.33±0.22?????1.55±0.33????1.22±0.43
*
B????????????????0.64?????????8????????1.02±0.26?????1.27±0.20????1.64±0.33
D 0.38 7 1.22 ± 0.18 1.32 ± 0.23 1.72 ± 0.39
ΔP＜0.05vs sham operated rats;
*P＜0.05vs model group; Water temperature:25-26 ℃
By table 2 as seen, the model mice swimming time significantly is longer than sham operated rats (p＜0.05) in the water maze swimming task, and prompting PBCAO causes mice space resolution capability obstacle; Increase with the water maze task difficulty, the F group significantly shortens (p＜0.05) with FBD group mice swimming time than model group, shows that F and FBD water extract can resist PBCAO and cause mice space resolution capability obstacle; Other 6 kinds of FBD prescriptions or preparation effect are indeterminate or certain improvement trend arranged.2.3FBD anti-brain ischemia-reperfusion repeatedly causes mouse memory obstacle prescription analysis
Eliminate defective mice with water maze, 100 of qualified mices are divided into 10 groups: sham operated rats, model group, FBD group, F+B+D group, FB group, FD group, BD group, F group, B group, D group, every group of 9-12 mice.5d before the operation, the corresponding 8 kinds of water extracts of ig, bid * 5d, dosage 0.5ml/20g body weight.Water 10h is can't help in fasting before the operation, and to the customary 15minI-15minR-15minI ischemia-reperfusion operation of mice, but operation is without losing blood and hot conditions, with further raising experiment collimation.
Operation back 2d continues corresponding each the water extract of ig, bid * 5d.D4 keeps away dark training to mice, and d5 detects errors number in mice incubation period and the 5min; D6 puts to death mice and gets cerebral tissue mensuration MDA content, with the neural biochemical indicator of MDA as oxidative damage.
Table 3, FBD and each component thereof are carried out behind cerebral ischemia reperfusion injury mice and are kept away dark task incubation period and wrong inferior influence
(step-through)( x±s)
Group dosage n Latency (Logs) errors number
(g/kg/d)
Sham operated rats 7 1.99 ± 0.39 0.7 ± 0.8
Model group 6 1.56 ± 0.56
The Δ Δ2.5 ± 1.4
Δ
FBD?????????2.30????????6??????1.99±0.51?????????0.8±1.2
*
F+B+D???????2.30????????5??????2.14±0.26?????????0.6±0.5
*
FB??????????1.92????????10?????2.13±0.39
*???????0.5±0.8
**
FD??????????1.66????????6??????2.32±0.01
*???????0.0±0.0
**
BD??????????1.02????????5??????1.89±0.51?????????1.0±1.0
F???????????1.28????????7??????2.28±0.13
*???????0.1±0.4
**
B???????????0.64????????8??????2.23±0.23
*???????0.4±0.7
**
D 0.38 6 2.32 ± 0.01
*0.2 ± 0.4
ΔP＜0.05vs sham operated rats;
*P＜0.05,
*P＜0.01vs model group; Stimulate parameters:125ms, 38V.PP
Revive in the average 10h of operation back mice, the minimizing but appetite is drunk water, weight loss, activity is comparatively normal, and there have the minority mice to occur to be dead, average 2-3/organize; Ordinary circumstance makes moderate progress after the administration.
Table 3 shows, mice is carried out behind cerebral ischemia reperfusion injury and keeps away dark task and be longer than sham operated rats incubation period, and errors number is significantly more than sham operated rats (p＜0.05), and the capacitation obstacle appears remembering in the prompting mice; But F, B and D singly keep away dark incubation period with equal significant prolongation mice separately, reduce errors number (p＜0.05-0.01), have the obstructive action of the mouse memory of improvement capacitation; When F, B and D share in twos, FB and the FD effect that also has clear improvement; Though three medicines share the back to the having clear improvement effect of memory capacitation obstacle, act on and do not demonstrate the Synergistic effect, and three medicines are fried in shallow oil altogether and fried in shallow oil amalgamation with branch and do not have significant difference (p＞0.05).
Experiment shows that mice is behind cerebral ischemia reperfusion injury, and cerebral cortex organizes MDA content to be elevated to 14.22 ± 2.94nmol/mg by 10.71 ± 5.13nmol/mg, shows that oxidative damage may participate in memory impairment; To the unusual rising of MDA content, FBD and FB water extract have remarkable inhibitory action (p＜0.05); Other 6 kinds of FBD prescription water extracts have certain inhibition trend or act on uncertain unusual rising of MDA.
Conclusion: investigate 8 kinds of FBD prescriptions or preparation water extract to mice PBCAO operation back memory capacitation obstacle and spatial resolving power obstacle improvement effect, can find that full side FBD closes decocting liquid and is better than the F+B+D branch and fries in shallow oil amalgamation liquid; Full side FBD is better than F, B, D 5 usefulness and single usefulness in twos, and the compatibility advantage is arranged; When F, B and D share in twos, find that the FD effect is better than FB and BD, and effect is better than F and the single usefulness of D; Relatively F, B, single the using of D act on, and the F effect is better than B and D, may be the FBD principal agent.
Investigate 8 kinds of FBD prescriptions or preparation water extract to mouse brain memory capacitation obstacle improvement effect and antioxidation behind the ischemia-reperfusion repeatedly, can find that full side FBD closes decocting liquid and is better than F+B+D and divides and fry in shallow oil amalgamation liquid; Full side FBD antioxidation is better than F, B, D to be share and single usefulness in twos, and certain compatibility advantage is arranged.When F, B and D share in twos, find that the BD effect is worse than FB and FD; Relatively F, B, single the using of D act on, and the F effect is better than B and D, may be the FBD principal agent.
This research has been carried out the DSS side of simplifying FBD prescription analysis on two kinds of dissimilar VD models.2 experimental results prove that the full side effect of FBD prescription is better than other combinations; FD and FB effect are better than BD; F, B, D all have each self-applying, and F is a principal agent among the FBD.
(2) the stripped level experiment prescription analysis of the DANGGUI SHAOYAO SAN side of simplifying treatment of vascular dementia
FBD shows at the prescription analysis of 2 kinds of mice VD of integral level control: when three medicines share, close and fry in shallow oil the effect of water extract and be better than branch and fry in shallow oil amalgamation liquid; When two medicines share, FB and FD effect were better than BD; Single time spent, F, B, D all have effect separately, and outstanding with the F effect.
(excitatory amino acid, EAA) grade can be damaged the relevant brain district cerebral cortex of memory and hippocampal formation and function, plays an important role in the VD pathogeny for ischemia/anoxia (ischemia/anoxia), excitatory amino acid.Be checking and the prescription analysis that FBD control VD integral level deeply is described, 2 kinds of cell hypoxia/ischemia models of this research Preliminary Applications have carried out the prescription analysis of FBD at 2 kinds of cell injury models of cellular level control.The preparation of 1 experiment material 1.1FBD7 kind pastille cerebrospinal fluid
Radix Angelicae Sinensis, Radix Paeoniae Alba (parched), Poria, Rhizoma Atractylodis Macrocephalae (parched), Rhizoma Chuanxiong, stir-fry Rhizoma Alismatis are all available from Nanjing medical material company.Through identifying that former plant is respectively Angelica sinensis (Oliv.) Diels., Paeonia lactiflora Pall., Poria cocos (Schw) Wolf, Atractylodesmacrocephala Koidz., Ligusticum chuanxiong Holt., Alisma orientale (Sam.) Juzep..Each survival dose of FBD is in proportion: Radix Angelicae Sinensis: Poria: the Rhizoma Atractylodis Macrocephalae=3: 10: 5.Distilled water is macerated medical material 1h, and the little 20min that boils of suitable quantity of water inclines and gets thick water extract, repeats 6 times, merges evenly interval FBD, FB, FD, BD, F, B, the thick water extract of D 6 times, and 2400rcf * 5min is centrifugal, merges supernatant, and 4 ℃ store for future use.
2kg body weight large ear rabbit, difference ig 0.78,0.64,0.55,0.34,0.43,0.22,0.13g/kg FBD, FB, FD, BD, F, B, D water extract, dosage 10ml/kg.Behind the 1h, ip 20% urethane 5ml/kg anesthesia, cut off the rabbit hair behind the brain, 70% medical alcohol or 0.1% bromo geramine sterilization skin are used the 1ml asepsis injector, from the beginning puncture with the collare connecting place, attention should make the curved low head of rabbit as far as possible, so that syringe needle enters cerebellomedullary cistern by Foramen magnum (Foramen occipitale magnum), syringe needle is taken out piston to make negative pressure in the syringe after passing behind the skin gently, then slowly deeply, in case syringe needle enters the oblongata pond, (cerebrospinal fluid CSF) will pour in needle tubing to 600-800 μ l cerebrospinal fluid, extract syringe needle rapidly out, ip10ml/ short rabbit recovery of normal saline subsequently, 6000rcf * 10min centrifugal 7 kinds of pastille CSF (CSF-FBD, FB, FD, BD, F, B, D) take off cell ,-20 ℃ freezing standby down.1.2 it is commercial that reagent and medicine are.Statistical analysis uses NDST4.4 software to add up, and data are represented with x ± s, capable t of comparable group differences or t ' check.2 methods and result's 2.1 former generation ru-shu-pi confluent monolayer cells (primary cerebral cortex neurons, PCCN) cultivations
Take out and give birth to 1-4d SD rat cerebral cortex, with D-Hanks liquid washing 2-3 time, shred the back and digest 15min down at 37 ℃ with 0.125% pancreatin, the centrifugal 7-10min of 1000rpm abandons supernatant, after cleaning with Hanks liquid, cross 100 μ m aperture wire nettings, centrifugal again, blow and beat repeatedly with high sugared DMEM culture fluid, making cell density is 1-10 * 10
5/ ml is inoculated on 96 well culture plates that scribble poly-D-lysine, places 37 ℃, 5%CO
2Cultivate in the saturated humidity incubator, add 10 μ mol/L cytosine arabinoside effect 2-3d behind the 5-7d, to suppress non-neuronal hyper-proliferative.2.2MTT colorimetric analysis
In the 96 porocyte culture plates that contain 100 μ l/ hole culture fluid, after adding final concentration 0.5mg/mlMTT solution 10 μ l/ holes continue to cultivate 4h, carefully draw supernatant 90 μ l, add 50 μ l DMSO again, the 5min that vibrates on the microoscillator, the ELISA instrument is measured absorbance value, wavelength 490nm.The principle of MTT colorimetric analysis is to utilize the living cells mitochondrial dehydrogenase that dyestuff MTT is reduced into first a ceremonial jade-ladle, used in libation granule, and the shade that is presented after dissolving with granule is (with OD
490Value representation) quantity of reflection living cells and the active degree of cellular metabolism.
2.3CSF-FBD, FB, FD, BD, F, B, D induce the influence of PCCN damage to sodium dithionite, referring to: Watanabe H, NiJW, Sakai Y, et al.Permanent occlusion of bilateral internal carotid arteries produces cognitive deficits intwo learning behavior tasks.Nihon Shinkei Seishin Yakurigaku Zasshi, 1996,16 (1): 19-24; Ni JW, OhtaH, Matsumoto K, et al.Progessive cognitive impairment following chronic cerebral hypoperfusioninduced by permanent occlusion of bilateral carotid arteries in rats.Brain Res, 1994,653:231
Get long 96 well culture plates that DIV10 PCCN is arranged, abandon original fluid, Earle ' s washed cell 1 time adds serum-free DMEM and joins 10% (v/v) CSF-FBD, FB, FD, BD, F, B, D and final concentration be 2mmol/L newly join Na
2S
2O
4The combined effect cell is established 10%CSF and is made negative control.Mtt assay is observed CSF-FBD behind the 12h, FB, FD, BD, F, B, the influence of D pair cell damage.
Experiment shows, compares deoxidizer Na with normal group
2O
2S
4Obviously reduce model group PCCN cell OD
490(p＜0.05), the damage of anoxia sample appears in prompting PCCN; 10%CSF-FBD, FB, FD, BD, F, B, D all can improve damage PCCN cell viability (p＜0.05-0.001).Wherein, the CSF-F effect is the most remarkable, and CSF-B and CSF-D effect be highly significant also; The three share effect in twos and does not see enhancing substantially; The three share and acts on also highly significant, does not also see collaborative the enhancing.
2.4CSF-FBD, FB, FD, BD, F, B, D induces the influence of PCCN damage to sodium glutamate, referring to: De Reuck JL.Evidence for chronic ischaemia in the pathogenesis of vascular dementia:from neuroPATH to neuroPET.Acta Neurol Belg, 1996,96 (3): 228-31; De Deyn PP, Goeman J, Engelborghs S, et al.From neuronal andvascular impairment to dementia.Pharmacopsychiatry, 1999,32 Suppl 1:17-24
Get long 96 well culture plates that DIV13 PCCN is arranged, abandon original fluid, serum-free DMEM washed cell 1 time adds no Mg
2+Molten 500 μ mol/L MSG and the cytosiies of-Earle ' s behind the 20min, discard effect liquid, and serum-free DMEM washed cell 1 time changes serum-free DMEM and joins 10%CSF-FBD, FB, and FD, BD, F, B, D100 μ l/ hole is established 10%CSF and is made negative control.Mtt assay is observed CSF-FBD behind the 16h, FB, FD, BD, F, B, the influence of D pair cell damage.
Experiment shows, obviously reduces model group PCCN cell OD with normal group comparison MSG
490(p＜0.05), the damage of ischemia sample appears in prompting PCCN; 10%CSF-FBD, FB, FD, BD, F, B, D all can improve damage PCCN cell viability in various degree.Wherein, compare with model group, CSF-FBD, CSF-FB and CSF-D effect be (p＜0.05) significantly; CSF-F and the CSF-B effect of share strengthens; List is better than CSF-F or CSF-B with the CSF-D effect.
Originally discover: 10%CSF-FBD, FB, FD, BD, F, B, D all can improve sodium sulfite and sodium glutamate damage PCCN cell viability; Wherein, CSF-FBD and CSF-FB all have protective effect to 2 kinds of cell injury; F, B, single time spent of D, the CSF-F oxygen lack resistant function is the most remarkable, and the effect of CSF-D ischemia resisting is the strongest; The three share in twos, and enhancing is not seen in effect substantially.Yet, use the horizontal FBD of 0.1,0.01 μ g/ml, FB, FD, BD, F, B, D pastille artificial cerebrospinal fluid (artificial CSF when ACSF) resisting sodium glutamate, finds ACSF-FBD, FB, and FD, BD, F, B, D all has protective effect to neuronal damage.And effect trend is similar to pastille CSF effect, and as F, B, single time spent of D, the effect of ACSF-F ischemia resisting is the most remarkable; ACSF-F and ACSF-D have synergism.
VD is the card of simulataneous insufficiency and excessive, and basic characteristics of incidence is expectorant, the stasis of blood, void.FBD reuses Poria and is monarch by Poria, the Rhizoma Atractylodis Macrocephalae, when being grouped in the side, the eliminating phlegm dampness removing is had one's ideas straightened out, the spleen-benefiting mind-tranquilizing Fructus Alpiniae Oxyphyllae; Rhizoma Atractylodis Macrocephalae invigorating the spleen and benefiting QI, the dampness diuretic helps the capable humidifying expectorant of Poria, and system blood Bao Mai goes up logical clear sun; The Radix Angelicae Sinensis blood stasis dispersing and fresh blood promoting, beneficial intensive culture marrow can help the capable humidifying expectorant of Poria.The shared removing blood stasis that reduces phlegm in full side, benefiting QI and nourishing blood, and receive the Fructus Alpiniae Oxyphyllae of calming the nerves, have one's ideas straightened out and remove slow-witted merit.
Use permanent ligation of bilateral common carotid arteries and brain ischemia-reperfusion difference preparation experiment low perfusion dementia and multi-infarct dementia model repeatedly, the different prescriptions of FBD have been investigated, be FBD, FB, FD, BD, F, B, D, to the protective effect of 2 kinds of whole VD models, the result shows that FBD, FB, FD, BD, F, B, D all have protective effect to 2 kinds of whole VD models; The full side effect of FBD prescription is better than other combinations; FD and FB effect are better than BD; F, B, D all have each self-applying, and F is a principal agent among the FBD.
Use sodium dithionite and sodium glutamate and induce neonatal rat cortical cell anoxia sample of former generation and the damage of ischemia sample respectively, investigate of the protective effect of the different prescription pastille of FBD cerebrospinal fluid to two kinds of stripped VD models, the result shows 10%CSF-FBD, FB, FD, BD, F, B, D all can protect 2 kinds of cell injury in various degree; CSF-FBD and CSF-FB all have remarkable protective effect to 2 kinds of cell injury; F, B, single time spent of D, the CSF-F oxygen lack resistant function is the most remarkable, and the effect of CSF-D ischemia resisting is the strongest; The three share in twos, and enhancing is not seen in effect substantially.
The level of exsomatizing experiment prescription analysis and integral experiment prescription analysis be basically identical as a result, has any different slightly.F is as the anti-VD principal agent of FBD, and is consistent with the anti-VD result of orthogonal design FBZ, proves that F is not only anti-VD principal agent among the FBD, also is anti-VD principal agent among the DSS.
Two, one of effective site research of the anti-ageing term dementia of FBD
In order to explore the effective site of the anti-ageing term dementia of FBD, the chemical constituent of each herbal medicine during FBD writes out a prescription by literature search, the Pharmacological action study data determines to contain in the Poria triterpene and polysaccharide, contain volatile oil and polysaccharide in the Rhizoma Atractylodis Macrocephalae, contain volatile oil, organic acid and polysaccharide in the Radix Angelicae Sinensis.According to the chemical constituent that contains among the FBD, FBD is divided into 3 positions:
(1) FDB CO
2Supercritical extraction part P2 (be micromolecule and low polar molecule, contain the Rhizoma Atractylodis Macrocephalae, Radix Angelicae Sinensis volatile oil, organic acid and Poria triterpene);
(2) the molten part P3 of FBD water extracting alcohol (being the high polarity part);
(3) FBD water extract-alcohol precipitation part P1 (being mainly polysaccharide).
Combine by whole animal model (scopolamine brings out mouse memory obstacle, brain ischemia-reperfusion inducing mouse dysmnesia repeatedly) and cell model (pastille serum is to the influence of PC12 cell hypoxia ischemic injuries), carry out the screening of effective site.
(part, P) character, yield and consumption see Table 4 at FBD3 chemical position.
Table 4, each position yield and prescribed dose
Character yield position, chemistry position consumption
Total polysaccharides (P1) powder 3.8g/100g crude drug 1.10g
Volatile oil (P2) grease 2.29ml/100g crude drug 0.66ml
Extractum (P3) extractum 26.6g/100g crude drug 7.65g
The experiment grouping
According to the extraction yield at 3 chemical positions of FBD prescription, calculate the dosage of corresponding experiment mice, see Table 5.
Table 5, sample concentration and animal dosage
Division of Chemistry site concentration dosage
FBD???????????28.75g/500ml??????????????1.15g/kg
P1+P2+P3??????1.10g+0.66ml+7.65g/500ml??43.7mg/kg+26.3μl/kg+305.9mg/kg
P1+P2?????????1.10g+0.66ml/500ml????????43.7mg/kg+26.3μl/kg
P1+P3?????????1.10g+7.65g/500ml?????????4.37mg/kg+305.9mg/kg
P2+P3?????????0.66m1+7.65g/500ml????????26.3μl/kg+305.9mg/kg
P1????????????1.10g/500ml???????????????43.7mg/kg
P2????????????0.66ml/500ml??????????????26.3μl/kg
P3????????????7.65g/500ml???????????????305.9mg/kg
Use 2 kinds of experimental animal models 8 samples are carried out the pharmacodynamics investigation, preliminary clear and definite main effective site.
Experimental model
(1) scopolamine brings out the mouse memory obstacle;
(2) brain ischemia-reperfusion inducing mouse dysmnesia repeatedly;
The combination of experimental technique and result (1) different chemical position, FBD3 position is to the brain amnemonic influence of ischemia-reperfusion inducing mouse repeatedly
Get male ICR mouse, carrying out repeatedly the preposition single cecum water maze training of ischemia-reperfusion, water temperature 21-23 ℃, motion function and space resolution capability when observing mice swimming, time surpasses 15s person, may have motion function, balance performance and space resolution capability defective, and discarding need not.Qualified mice is divided into 10 groups at random.1-8 organizes continuous igbid * 6d, the normal saline of capacity such as (9)-(10) group ig.D4-5 undergos surgery, water is can't help in the 10h fasting before the art, 1-8 group ip in mice 1.2g/kg10% urethane makes anesthesia, after treating righting reflex loss, it is fixing to face upward the position, 75% medical alcohol sterilization cervical region, the row median incision, passivity is separated bilateral carotid, under 38 ± 1 ℃, successively implements 10min cutout (ischemia), 10min irritates (reperfusion) again, 10min stop again (ischemia) (10minI-10minR-10minI) perform the operation, and block in the nearly 1cm of Mus tail place, make about 10% whole blood volume of losing blood, (1) group mice only separates tremulous pulse, continues to flow to irritate again and does not also lose blood.Notice in the art that cervical region wound surface drop 2-3 drips 2.50 * 104u/kg gentamycin.Observe operation back mouse death rate, estimate the anti-acute cerebral ischemia effect of medicine with this.
Make up the brain amnemonic influence of ischemia-reperfusion inducing mouse repeatedly at table 6, different chemical position, FBD3 position
Group No.of pre-IR No.of post-IR Viability (%)
FBD???????????????12???????????????8?????????????????66.6
P1+P2+P3??????????12???????????????8?????????????????66.6
P1+P2?????????????12???????????????7?????????????????58.4
P1+P3?????????????12???????????????9?????????????????75.0
P2+P3?????????????12???????????????4?????????????????33.3
P1????????????????12???????????????6?????????????????50.0
P2????????????????12???????????????6?????????????????50.0
P3????????????????12???????????????8?????????????????66.6
Sham operated rats 88 100
The influence of mouse memory obstacle is brought out in the combination of different chemical position, model group 16 7 43.8 (2) FBD3 position to scopolamine
The configuration of scopolamine: get 0.3mg/ml scopolamine injection, dilute at 1: 3 0.075mg/ml.Dosage is 20ml/kg (ip).
Kunming mice is divided into 10 groups at random, continuous ig qd * 10d, d7 1-8 in the morning, 10 groups of ip Scop1.5mg/kg, 9 groups of capacity normal saline such as ip are kept away secretly (step-through) training with the passive avoidance reflectometer behind the 15min, and parameter is that square wave stimulates: ripple is wide: 125ms; Amplitude: 38V.PP (darkness avoidance test) measures mice enters the darkroom from bright chamber incubation period under the quiet environment behind the 24h, weigh learning and memory abilities in aging mice with this.
The combination of table 7, different chemical position, FBD3 position to scopolamine bring out the mouse memory obstacle influence (x ± s, n=8)
Group dosage Latency (Lgs, x ± s)
FBD??????????1.15g/kg?????????????????????????1.82±0.46
P1+P2+P3?????43.7mg/kg+26.3μl/kg+305.9mg/kg??1.87±0.43
P1+P2????????43.7mg/kg+26.3μl/kg?????????????2.27±0.05
*
P1+P3????????4.37mg/kg+305.9mg/kg?????????????2.02±0.34
P2+P3????????26.3μl/kg+305.9mg/kg????????????1.59±0.44
P1???????????43.7mg/kg????????????????????????2.06±0.27
P2???????????26.3μl/kg???????????????????????2.03±0.33
P3???????????305.9mg/kg???????????????????????2.19±0.23
*
Sham operated rats-2.25 ± 0.08
Different chemical position, model group-1.81 ± 0.44 Δ (3) FBD3 position combination pastille serum is to the influence of PC12 cell hypoxia ischemic injuries
The blood sampling of d10 eye frame, 3500rcf * 10min centrifugalize pastille serum, 56 ℃, 30min water-bath inactivated serum are used for the serum pharmacological research of anti-PC12 cell hypoxia ischemic injuries.
The PC12 cell strain is provided by Chinese Academy of Sciences's cell physiological institute, is stored in-80 ℃ of ultra cold storage freezers.Test preceding 37 ℃ of recoveries fast, 1000rpm * 5min is centrifugal, serum-free DMEM washing, and 1000rpm * 5min secondary centrifuging is inoculated in the 75ml culture bottle that scribbles poly-D-lysine with 10%NCS DMEM, treats 37 ℃, 5%CO
2Under grow up to monolayer after, with 0.25% trypsinization 3-5min, 10%NCS DMEM stop digestion, blow and beat into cell suspension repeatedly, be inoculated in 96 well culture plates that scribble poly-D-lysine, 37 ℃, 5%CO
2Under grow up to monolayer.
Get 96 well culture plates that cover with monolayer PC12, abandon original fluid, Earle ' s washed cell 1 time, with final concentration be 2mmol/L newly join the molten Na of D-Hanks
2S
2O
4With cytosis 1h, cause the cell hypoxia damage; Na
2S
2O
4Behind cytosis 1h, abandon Na
2S
2O
4Effect liquid, Earle ' s washed cell 1 time changes serum-free DMEM.Add the pastille serum of 10% concentration FBD, 3 position various combination mices, 10% blank serum is made negative control, and 10%FBD pastille serum is made positive control, and every group 6 porocyte all acts on 18h, and mtt assay is observed the influence of pastille serum pair cell anoxia-induced apoptosis.
Get 96 well culture plates that cover with monolayer PC12, abandon original fluid, Earle ' s liquid washed cell 1 time, no Mg
2+Molten 500 μ mol/LMSG and the cytosiies of-Earle ' s liquid discard effect liquid behind the 20min, Earle ' s liquid washed cell 1 time changes serum-free DMEM.Add the pastille serum of 10% concentration FBD, 3 position various combination mices, 10% blank serum is made negative control, and 10%FBD pastille serum is made positive control, and every group 6 porocyte all acts on 18h, and mtt assay is observed the influence of pastille serum pair cell anoxia-induced apoptosis.
Table 8, different chemical position, FBD 3 position combination pastille serum are to 2mmol/LNaS
2O
4And 0.5mmol/LMSG induces the PC12 cell
The influence of Hypoxia and ischemia damage (x ± s, n=6)
OD
490
Group
Hypoxia and ischemia
Matched group 0.376 ± 0.069 0.438 ± 0.051
Model group 0.109 ± 0.014
Δ Δ Δ0.257 ± 0.037
Δ Δ Δ
Serum-FBD 0.165 ± 0.028
*0.342 ± 0.052
*
Serum-(P1+P2+P3) 0.152 ± 0.023
*0.323 ± 0.052
*
Serum-(P1+P2) 0.171 ± 0.021
* *0.334 ± 0.045
*
Serum-(P1+P3) 0.154 ± 0.036
*0.324 ± 0.049
*
Serum-(P2+P3) 0.128 ± 0.024
*0.307 ± 0.047
Serum-P1 0.139 ± 0.020
*0.321 ± 0.037
*
Serum-P2 0.148 ± 0.023
*0.316 ± 0.047
*
Serum-P3 0.139 ± 0.022
*0.311 ± 0.025
* Δ Δ ΔP＜0.001vs matched group;
*P＜0.05,
*P＜0.01,
* *Water extract position and n-butyl alcohol extract thereof, residue water extract bring out the influence of mouse memory obstacle in the middle of p＜0.001vs model group (4) FBD to scopolamine
With water extract position (P3) in the middle of the n-butanol extraction FBD, get n-butyl alcohol extract (P3-n-Bu) and residue water extract (P3-H2O), yield is respectively 14.9g/100g crude drug and 6.8g/100g crude drug.
Get 42 of male mouse of kunming, be divided into 7 groups at random, 6/group, each position combined drug liquid is all by the 0.5ml/20g administration.1-7 organizes continuous igbid * 7d, d4 2-7 in morning group ip Scop2.0mg/kg, and capacity normal saline such as (1) group ip are kept away secretly (step-through) training with the passive avoidance reflectometer behind the 20min, and parameter is that square wave stimulates: ripple is wide: 125ms; Amplitude: 35V.PP (darkness avoidance test) measures mice enters the darkroom from bright chamber incubation period and the errors number in the 3.5min (No.of errors) under the quiet environment behind the 24h, weigh learning and memory abilities in aging mice with incubation period and errors number.
Water extract position and n-butyl alcohol extract thereof, residue water extract bring out scopolamine in the middle of table 9, the FBD
The influence of mouse memory obstacle (x ± s, n=6)
Group dosage ((Lgs) errors number incubation period of bid * 3d)
Normal?????????????????????????????????????????2.29±0.07??????0.2±0.4
Model group 1.80 ± 0.36
Δ1.6 ± 0.5
The Δ Δ
P1+P2+P3????????(43.7mg+26.3μl+305.9mg)/kg????1.92±0.54??????0.6±0.5
*
P1+P2???????????(43.7mg+26.3μl)/kg????????????2.06±0.28??????0.8±0.4
*
P3??????????????305.9mg/kg?????????????????????2.14±0.28??????0.3±0.5
**
P1+P2+P3-n-Bu???(43.7mg+26.3μl+78.2mg)/kg?????2.20±0.28??????0.2±0.4
**
P1+P2+P3-H
2O (43.7mg+26.3 μ l+171.4mg)/kg 1.63 ± 0.39 1.2 ± 0.4
ΔP＜0.05,
The Δ ΔP＜0.01vsnormal;
*P＜0.05,
*Water extract position and n-butyl alcohol extract thereof in the middle of the p＜0.01vs model group (5) FBD, residue water extract pastille serum are to the influence of PC12 cell hypoxia ischemic injuries
The eye frame was taken a blood sample after d7 finished the behavior pharmacological experiment, 3500rcf * 10min centrifugalize pastille serum, and 56 ℃, 30min water-bath inactivated serum are used for the serum pharmacological research of anti-PC12 cell hypoxia ischemic injuries.Experimental technique is with experiment (3).
Table 10, FBD n-butyl alcohol extract, water extract pour into the influence (darkness avoidance test) that causes the mouse memory obstacle again to hydropenia
Group Latency (Logs)
Sham operated rats 2.38 ± 0.00
Model group 2.23 ± 0.18
*
FBD????????????????????????????????2.31±0.18
P1+P2??????????????????????????????2.30±0.20
P1+P2+P3-n-Bu??????????????????????2.28±0.25
P1+P2+P3-Wa????????????????????????2.26±0.31
Table 11, FBD n-butyl alcohol extract, water extract pour into the influence (water maze method) that causes the mouse memory obstacle again to hydropenia
1bt???????????????????????2bt??????????????????????????3bt
Learn?????????memory????????learn?????????memory????????learn?????????memory
Sham operated rats 1.07 ± 0.21 0.90 ± 0.22 1.33 ± 0.31 1.24 ± 0.26 1.47 ± 0.26 1.67 ± 0.31
Model group 1.44 ± 0.23
##1.32 ± 0.24
##1.66 ± 0.23
#1.46 ± 0.24 1.66 ± 0.23
#1.75 ± 0.33
FBD????????????1.17±0.28????1.14±0.19????1.35±0.30????1.26±0.25????1.55±0.26????1.53±0.43
P1+P2??????????1.31±0.37????1.04±0.25
*??1.33±0.27????1.32±0.23????1.64±0.21????1.60±0.32
P1+P2+P3-n-Bu??1.19±1.26????1.08±0.23????1.41±0.31????1.41±0.31????1.63±0.27????1.78±0.26
P1+P2+P3-Wa????1.28±0.32????1.13±0.19????1.57±0.23????1.57±0.23????1.69±0.28????1.71±0.34
Table 12, FBD n-butyl alcohol extract, the pastille serum of residue water extract is to the effect of PC12 cell injury model
OD
490
Group
Hypoxia and ischemia
Matched group 0.597 ± 0.031 0.583 ± 0.036
Model group 0.284 ± 0.043
###0.272 ± 0.059
Serum-(P1+P2+P3) 0.321 ± 0.034 0.314 ± 0.017
Serum-(P1+P2) 0.340 ± 0.053 0.364 ± 0.040
*
Serum-(P1+P2+P3-n-Bu) 0.306 ± 0.055 0.340 ± 0.044
*
Serum-(P1+P2+P3-Wa) 0.312 ± 0.037 0.344 ± 0.056
Comprehensive above experiment determines that P1+P2 is the effective site that FBD prevents and treats alzheimer disease among the FBD, and its preparation technology is: FBD is through CO
2Behind the supercritical extraction, get P2 position and medicinal residues respectively.The slag of getting it filled is used decocting, water extract, add ethanol, be precipitated as (P1, the main polysaccharide that contains), supernatant is P3.
P1+P2 is carried out The Chemical Constituents, for from now on quality standard lays the foundation.
The side of simplifying FBD effective site has not only kept but also has strengthened the effect of control senile dementia, particularly to the prevention effect of VD.
The crude drug of the side of simplifying FBD effective site has reduced half than former side DSS, so the cost of medicine reduces greatly, the dose that patient takes reduces, but curative effect is identical, and some aspect even obvious the enhancing are particularly useful for the patient of VD type senile dementia.
FBD effective site in the side of simplifying is more targeted to the patient treatment of VD type senile dementia, and medication is more accurate, raising evident in efficacy.
FBD effective site in the side of simplifying is preparing various dosage forms, is especially not only having advantage than former side but also than the side of simplifying FBD aspect the modern preparation of preparation.Simultaneously, because impurity in the side of the simplifying FB effective site and the composition that do not have a dementia effect reduce, make that quality-monitoring and control are also relatively easy.
Three, two of the effective site research of the anti-ageing term dementia of FBD
Though experimental results show that P1+P2 is the effective site that FBD prevents and treats alzheimer disease, yet in research process, also find that wherein P3 is the molten part of water extracting alcohol, to the integrality effect of being significantly improved of mice.And then, P3 is partly used n-butanol extraction, behind the concentrated butanol extraction liquid, partly make up with P1+P2 again.Experiment shows: the n-butyl alcohol extract of P1+P2+P3 part, not only have and prevent and treat the alzheimer disease curative effect significantly, but and the mice whole body mental status also have clear improvement.
Four, three of the effective site research of the anti-ageing term dementia of FBD
Consider industrializing implementation,, on above-mentioned research basis, FBD effective site and extracting method thereof are screened once more for further simplifying technology.Preparation FBD water extract different chemical position, cause mice senile dementia model discrimination effective site with scopolamine, annotate thrombus model with the senile rat external carotid artery and detect the therapeutical effect of effective site, and rat cerebral infarction is caused amnemonic influence multiple cerebral infarction dementia.Find that polysaccharide+n-butanol portion and polysaccharide+water position cause the mouse memory obstacle to scopolamine significant protective effect is arranged, polysaccharide+n-butanol portion has the obvious treatment effect to multiple cerebral infarction dementia.1.FBD the extraction process at chemical position and yield:
FBD water extract gets total polysaccharides position (Ps) through water extract-alcohol precipitation, and residue extractum position (Ex) gets n-butanol portion (nBu) and water position (Wa) with n-butanol extraction.4 chemical positions of FBD, the extraction process flow chart is as follows, and character, yield see Table 13.
FBD extracts flow process in each chemical position and describes in detail: get FBD, steeped 1 hour with 10 times of volume water loggings, boil, keep little and boiled 1 hour, filter, get medicinal residues and supernatant (1).The slag of getting it filled adds 8 times in water, after boiling and keeping 1 hour, filters, and medicinal residues discard, supernatant (2).Merge supernatant (1) and concentrate, in concentrated solution, add 95% ethanol with supernatant (2) back, precipitate polysaccharide, filter and with washing with acetone gained polysaccharide (Ps, content 56%).Get the supernatant of filtering polysaccharide precipitation, reclaim the extract (Ex) behind the ethanol,, obtain n-butanol portion (nBu) and water position (Wa) respectively with water saturated n-butanol extraction 5 times.
Polysaccharide is a dry powder in the inventive method, and n-butanol extract is an extractum, if can guarantee the crude drug quality, and technology fixes, and can keep constant ratio and repeatability in general.
The character at table 13, FBD and each chemical position and yield
2. laboratory animal:
| The chemistry position | Character | Yield |
| FBD water extract | Extractum | 32.6g/100g crude drug |
| Total polysaccharides (Ps) | Powder | 5.3g/100g crude drug |
| Extractum (Ex) | Extractum | 22.9ml/100g crude drug |
| N-butanol portion (nBu) | Extractum | 1.62g/100g crude drug |
| Water position (Wa) | Extractum | 17.6g/100g crude drug |
Male ICR mouse 18-22g, China Medicine University's Animal House provides, male SD rat (350-400g), Green Dragon mountain, Nanjing Animal House provides, the quality certification number: SCXK Soviet Union-20020018.3. each chemical position of experimental technique and result: 3.1FBD causes the influence of mouse memory obstacle to scopolamine:
Male ICR mouse 18-23g, random packet, and group and dosage such as table 14 (qd, 0.2mL/10g), successive administration 6 days, normal and model group gives the equivalent distilled water, 2h after the administration in the 6th day, ip scopolamine 3mg/kg, keep away dark training behind the 20min, voltage 38V detects behind the 24h and keeps away errors number in dark incubation period and the 5min, and is as shown in Table 15.
Table 14, mice group and dosage (all sites dosage all is equivalent to mice crude drug dosage 2.3g/kg)
Annotate: all medicines are all directly prepared with distilled water, and the aqueous solution that contains n-butanol portion has a little indissoluble thing, uses ultrasonic hydrotropy.
| Group number | The chemistry position | Concentration | Dosage |
| ????1 | Normal group | ||
| ????2 | Model group | ||
| ????3 | ????FBD | ????3.75％ | ????750mg/kg |
| ????4 | ????Ps | ????0.61％ | ????122mg/kg |
| ????5 | ????Ex | ????2.53％ | ????506mg/kg |
| ????6 | ????n-Bu | ????0.19％ | ????37.3mg/kg |
| ????7 | ????Wa | ????2.03％ | ????405mg/kg |
| ????8 | ????P1+nBu | ????0.61+0.19％ | ????122mg/kg+37.3mg/kg |
| ????9 | ????P1+Wa | ????0.61+2.03％ | ????122mg/kg+405mg/kg |
Table 15, FBD and each chemical position cause the influence (x ± s) of mouse memory obstacle to scopolamine
| Group | ????n | Dosage | ??Latency(s) | In the errors number 5 minutes |
| Normal group | ????11 | ??190±132 | ??0.55±0.69 | |
| ????Scop | ????9 | ??51±39 ΔΔ | ??1.67±0.87 ΔΔ | |
| ????Scop+FBD | ????9 | ????750mg/kg | ??61±98 | ??1.90±1.29 |
| ????Scop+Ps | ????11 | ????122mg/kg | ??77±96 | ??1.09±0.30 |
| ????Scop+Ex | ????11 | ????506mg/kg | ??43±53 | ??2.09±0.94 |
| ????Scop+n-Bu | ????11 | ????37.3mg/kg | ??74±104 | ??1.09±0.54 |
| ????Scop+Wa | ????10 | ????405mg/kg | ??56±78 | ??1.40±0.70 |
| ???Scop+Ps+nBu | ????11 | ????122mg/kg+37.3mg/kg | ??146±129 * | ??0.91±0.54 * |
| ???Scop+Ps+Wa | ????9 | ????122mg/kg+405mg/kg | ??121±97 * | ??1.13±0.64 |
Annotate:
The Δ ΔP＜0.01vsnormal;
*P＜0.05vs model group.
Scopolamine causes Model of Dementia (Scop) and prepares successfully, but the mouse memory obstacle that is caused by scopolamine is not significantly improved at FBD and single chemical position thereof, polysaccharide (P1) is relative better with n-butanol portion (nBu) improvement effect, P1+nBu and P1+Wa combination have the significant dysmnesia effect that improves, consider that nBu position yield has only 1/10 of Wa position, consumption is less relatively, and Wa part complicated component not only, sugar content is higher, active ingredient is difficult for purifying, and the yield height can cause dosage too big.So P1+nBu is further investigated the amnemonic improvement effect of animal that it causes different models as effective site.
3.2P1+nBu the influence that thrombosis causes the rat multi-infarct dementia is annotated to external carotid artery in the position:
Male SD rat (300-400g), reference literature (Mei Jianxun etc., the improvement and the application of multi-infarct dementia (MID) animal model, apoplexy and sacred disease magazine, 1999,16 (2): 100-102) through the modeling of improving one's methods, changing thrombosis concentration is 10mg/mL, the successful rat random packet of performing the operation, group and dosage (qd shown in table 16,0.7mL/100g), sham operated rats is only separated tremulous pulse, does not annotate the bolt operation.Postoperative continuous irrigation stomach 10 days; sham operated rats is given the equivalent distilled water; (daurisoline such as Liu Jinggen is to the protective effect of mice and rat cerebral ischemia to press document on the 7th day; the Chinese Pharmacological circular; 1998; 14 (1): 18-21) carry out the rat behavior scoring; kept away dark training on the 8th day; voltage 45V; detect behind the 24h and keep away dark incubation period, press literature method (Zhang Juntian, combined publication society of China Concord Medical Science University of modern pharmacology experimental technique Beijing Medical University: 1241) carry out cerebral tissue TTC and dye on the 10th day; the careful infarct area of separating is measured the ratio that the cerebral infarction zone accounts for full brain.Behavior scoring result, the measurement result of keeping away dark achievement and cerebral tissue infraction ratio see Table 17.
Table 16, rat grouping and dosage (all sites dosage all is equivalent to rat crude drug dosage 1.3g/kg)
| Group number | Medicine | Concentration | Dosage |
| ????1 | Sham operated rats | ||
| ????2 | Model group | ||
| ????3 | Duxil | 0.83％ | ????58mg/kg |
| ????4 | ?Ps+nBu(L) | 1.79+0.55％ | ????143mg/kg+43.7mg/kg |
| ????5 | ?Ps+nBu(H) | 0.90+0.27％ | ????71.5mg/kg+22mg/kg |
Annotate: duxil is coated tablet (duxil, French Les Laboratoires servier production.Every contains almitrine dimethanesulfonate 30mg and raubasine 100mg), ultrasonic hydrotropy becomes suspension behind the desaccharide clothing.
Table 17, P1+nBu position are annotated the influence (x ± s) that thrombosis causes the rat multi-infarct dementia to external carotid artery
| Group | Dosage | Behavior scoring (full marks 10) | ?Latency(s) | The cerebral infarction ratio |
| Sham operated rats | ??0.0±0.0(n＝7) | ?282±31(n＝7) | ??0.00±0.00(n＝7) | |
| Model group | ??3.4±2.4 ΔΔ(n＝6) | ?43±37 ΔΔ?(n＝5) | ??2.34±1.20 ΔΔ??(n＝6) | |
| Duxil | ????58mg/kg | ??0.8±0.7 *(n＝6) | ?185±121 *?(n＝6) | ??0.53±0.63 **??(n＝6) |
| ??Ps+nBu(H) | ????143mg/kg+43.7mg/kg | ??1.0±1.1 *(n＝8) | ?241±96 **?(n＝8) | ??0.46±0.62 **??(n＝8) |
| ??Ps+nBu(L) | ????71.5mg/kg+22mg/kg | ??1.8±1.1(n＝8) | ?164±138 *?(n＝8) | ??0.60±0.82 **??(n＝8) |
Annotate:
The Δ ΔP＜0.01Vs sham operated rats;
*P＜0.05VS model group;
*P＜0.01VS model group; Ps+nBu (L) is converted by the FBD clinical dosage, and the behavior scoring score value is high more, shows that behavior disorder is serious more.Marked simultaneously by two operators, the meansigma methods that both give a mark is got in mutually noninterfere.
Experiment shows the retrograde injection of external carotid artery thrombosis, and tangible behavior disorder, dysmnesia, the cerebral infarction that causes accounts for full brain ratio obviously than sham operated rats height.Low dosage at positive drug duxil and Ps+nBu position (L) and high dose (H) are to the above model obstacle effect of having clear improvement, compare obvious minimizing cerebral infarct size with model group, but the Ps+nBu position does not present dose-effect relationship, and the dosage design of visible P1+nBu should be reduced.
The specific embodiment
Embodiment 1
Get Poria 25g Rhizoma Atractylodis Macrocephalae 12g Radix Angelicae Sinensis 7g, after the mixing, water decocts, and after aqueous extract concentrates, adds ethanol precipitation, get polysaccharide (2.3g), supernatant is used n-butanol extraction after reclaiming ethanol, gets n-butanol portion (0.71g), merges polysaccharide and n-butanol extract, after adding appropriate amount of auxiliary materials, be pressed into tablet.
Embodiment 2
Get Poria 25g Rhizoma Atractylodis Macrocephalae 12g, after the mixing, the water decoction, after aqueous extract concentrated, the adding ethanol precipitation got polysaccharide, and supernatant is used n-butanol extraction after reclaiming ethanol, gets n-butanol portion, merges polysaccharide and n-butanol extract, after the adding appropriate amount of auxiliary materials, is pressed into tablet.
Embodiment 3
Get Poria 25g Radix Angelicae Sinensis 7g, after the mixing, the water decoction, after aqueous extract concentrated, the adding ethanol precipitation got polysaccharide, and supernatant is used n-butanol extraction after reclaiming ethanol, gets n-butanol portion, merges polysaccharide and n-butanol extract, after the adding appropriate amount of auxiliary materials, is pressed into tablet.
Embodiment 4
Get Poria 25g, the water decoction, after aqueous extract concentrated, the adding ethanol precipitation got polysaccharide, and supernatant is used n-butanol extraction after reclaiming ethanol, gets n-butanol portion, merges polysaccharide and n-butanol extract, after the adding appropriate amount of auxiliary materials, is pressed into tablet.
Embodiment 5
Get Radix Angelicae Sinensis 7g, the water decoction, after aqueous extract concentrated, the adding ethanol precipitation got polysaccharide, and supernatant is used n-butanol extraction after reclaiming ethanol, gets n-butanol portion, merges polysaccharide and n-butanol extract, after the adding appropriate amount of auxiliary materials, is pressed into tablet.
Embodiment 6
Get Poria 50g Rhizoma Atractylodis Macrocephalae 40g Radix Angelicae Sinensis 20g, after the mixing, CO
2Supercritical extraction extracts volatile oil (2.5ml), and control extraction pot pressure is 10.0MP, and temperature is 35 ℃, and extraction time is 2 hours.Medicinal residues with water extraction after, adding ethanol to the alcohol amount of containing is 90%, precipitation obtains total polysaccharides (4.2g), supernatant use n-butanol extraction after reclaiming ethanol, merges volatile oil, total polysaccharides and n-butanol extract (7.5g) add appropriate amount of auxiliary materials, capsule is recorded in granulation.
Embodiment 7
Get Poria 50g, Radix Angelicae Sinensis 20g, after the mixing, the entrainer hexane carries out CO
2Supercritical extraction extracts volatile oil, and control extraction pot pressure is 9.0MP, and temperature is 32 ℃, and extraction time is 3 hours.Medicinal residues with water extraction after, adding ethanol to the alcohol amount of containing is 95%, precipitation obtains total polysaccharides, supernatant use n-butanol extraction after reclaiming ethanol, merges volatile oil, total polysaccharides and n-butanol extract add appropriate amount of auxiliary materials, capsule is recorded in granulation.
Embodiment 8
Get Rhizoma Atractylodis Macrocephalae 40g Radix Angelicae Sinensis 20g, after the mixing, the CO2 supercritical extraction extracts volatile oil, and control extraction pot pressure is 14.0MP, and temperature is 32 ℃, and extraction time is 1 hour.Medicinal residues with water extraction after, adding ethanol to the alcohol amount of containing is 75%, precipitation obtains total polysaccharides, supernatant use n-butanol extraction after reclaiming ethanol, merges volatile oil, total polysaccharides and n-butanol extract add appropriate amount of auxiliary materials, capsule is recorded in granulation.
Embodiment 9
After getting Poria 50g Rhizoma Atractylodis Macrocephalae 40g mixing, the CO2 supercritical extraction extracts volatile oil, and control extraction pot pressure is 12.0MP, and temperature is 35 ℃, and extraction time is 2 hours.Medicinal residues with water extraction after, adding ethanol to the alcohol amount of containing is 85%, precipitation obtains total polysaccharides, supernatant use n-butanol extraction after reclaiming ethanol, merges volatile oil, total polysaccharides and n-butanol extract add appropriate amount of auxiliary materials, capsule is recorded in granulation.
Embodiment 10
Get Radix Angelicae Sinensis 20g, as entrainer, carry out CO with ethyl acetate
2Supercritical extraction extracts volatile oil, and control extraction pot pressure is 8.0MP, and temperature is 40 ℃, and extraction time is 3 hours.Medicinal residues with water extraction after, adding ethanol to the alcohol amount of containing is 90%, precipitation obtains total polysaccharides, supernatant use n-butanol extraction after reclaiming ethanol, merges volatile oil, total polysaccharides and n-butanol extract add appropriate amount of auxiliary materials, capsule is recorded in granulation.
Embodiment 11
Get Poria 40g Rhizoma Atractylodis Macrocephalae 20g Radix Angelicae Sinensis 10g, after the mixing, water decocts, and after aqueous extract concentrates, adds ethanol precipitation, get polysaccharide (3.7g), supernatant is used n-butanol extraction after reclaiming ethanol, gets n-butanol portion (1.1g), merges polysaccharide and n-butanol extract, after adding appropriate amount of auxiliary materials, record capsule.
Embodiment 12
Get Poria 40g Rhizoma Atractylodis Macrocephalae 20g, after the mixing, the water decoction, after aqueous extract concentrated, the adding ethanol precipitation got polysaccharide, and supernatant is used n-butanol extraction after reclaiming ethanol, gets n-butanol portion, merges polysaccharide and n-butanol extract, after the adding appropriate amount of auxiliary materials, records capsule.
Embodiment 13
Get Rhizoma Atractylodis Macrocephalae 20g Radix Angelicae Sinensis 10g, after the mixing, the water decoction, after aqueous extract concentrated, the adding ethanol precipitation got polysaccharide, and supernatant is used n-butanol extraction after reclaiming ethanol, gets n-butanol portion, merges polysaccharide and n-butanol extract, after the adding appropriate amount of auxiliary materials, records capsule.
Embodiment 14
Get Poria 40g Radix Angelicae Sinensis 10g, after the mixing, the water decoction, after aqueous extract concentrated, the adding ethanol precipitation got polysaccharide, and supernatant is used n-butanol extraction after reclaiming ethanol, gets n-butanol portion, merges polysaccharide and n-butanol extract, after the adding appropriate amount of auxiliary materials, records capsule.
Embodiment 15
Get Poria 40g, the water decoction, after aqueous extract concentrated, the adding ethanol precipitation got polysaccharide, and supernatant is used n-butanol extraction after reclaiming ethanol, gets n-butanol portion, merges polysaccharide and n-butanol extract, after the adding appropriate amount of auxiliary materials, records capsule.
Embodiment 16
Get Poria 40g Rhizoma Atractylodis Macrocephalae 20g Radix Angelicae Sinensis 12g, after the mixing,, carry out CO with the ethanol entrainer
2Supercritical extraction extracts volatile oil (1.64ml), medicinal residues with water extraction after, add ethanol precipitation, obtain total polysaccharides (2.74g), supernatant is used n-butanol extraction (4.9g) after reclaiming ethanol, merges volatile oil, total polysaccharides and n-butanol extract, add appropriate amount of starch, granulate, record 16 of capsules.Taking dose: took 2 times each 2 on the 1st.
Embodiment 17
Get Poria 50g Rhizoma Atractylodis Macrocephalae 25g Radix Angelicae Sinensis 15g, after the mixing, water decocts, and after aqueous extract concentrates, adds ethanol precipitation, get polysaccharide (4.77g), supernatant is used n-butanol extraction after reclaiming ethanol, gets n-butanol portion (1.46g), merges polysaccharide and n-butanol extract, after adding appropriate amount of auxiliary materials, make 18 in tablet.Taking dose: took 2 times each 2 on the 1st.
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Cited By (3)
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| CN101062068B (en) * | 2006-04-28 | 2010-08-25 | 四川科伦药业股份有限公司 | Medicinal composition for treating dysmenorrhea and preparation process thereof |
| CN101167901B (en) * | 2006-10-26 | 2012-11-07 | 中国人民解放军军事医学科学院毒物药物研究所 | Chinese angelica and peony formula extraction, preparation and medical use thereof |
| CN108210818A (en) * | 2018-04-16 | 2018-06-29 | 成都中医药大学 | A kind of pharmaceutical composition for preventing neurodegenerative disease and its preparation method and application |
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| CN101601710B (en) * | 2005-12-20 | 2011-02-02 | 上海中药制药技术有限公司 | Application of traditional Chinese medicine composition in preparation of medicament for preventing and treating cerebral ischemia |
| CN101439072B (en) * | 2005-12-20 | 2011-01-19 | 上海中药制药技术有限公司 | Application of a traditional Chinese medicine composition in preparation of medicine for preventing and treating thrombus |
| CN101439073B (en) * | 2005-12-20 | 2011-01-19 | 上海中药制药技术有限公司 | Application of a traditional Chinese medicine composition in the preparation of medicines for preventing and treating memory impairment and improving memory |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101062068B (en) * | 2006-04-28 | 2010-08-25 | 四川科伦药业股份有限公司 | Medicinal composition for treating dysmenorrhea and preparation process thereof |
| CN101167901B (en) * | 2006-10-26 | 2012-11-07 | 中国人民解放军军事医学科学院毒物药物研究所 | Chinese angelica and peony formula extraction, preparation and medical use thereof |
| CN108210818A (en) * | 2018-04-16 | 2018-06-29 | 成都中医药大学 | A kind of pharmaceutical composition for preventing neurodegenerative disease and its preparation method and application |
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