CN1310649C - Application of ginsenoside Re for preparing medicine for curing dysmnesia - Google Patents
Application of ginsenoside Re for preparing medicine for curing dysmnesia Download PDFInfo
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Abstract
The present invention relates to a medicine application of ginsenoside Re, particularly to an application of ginsenoside Re for preparing medicine for treating dysmnesia. Researchers of the present invention respectively observe the memory improvement function of ginsenoside Re from various memory disorder models of adults, old people and mouses with various praxiology methods, and simultaneously observe the synapse long-term potentiation (LTP) function of the Re with an electrophysiological method. The summed conclusion is that the ginsenoside Re not only can improve memory disorders which are caused by scopolamine and other chemicals, but also has effect on the improvement of memory disorders which are caused by natural senility, A beta, etc., the enhancement of base synaptic transmission and the promotion of LTP forming.
Description
Technical field
The present invention relates to a kind of ginsenoside Re as the application in the amnemonic medicine of preparation treatment, particularly, ginsenoside Re of the present invention not only can improve dysmnesia due to the chemicals (scopolamine etc.), and has a naturally-aged of improvement, dysmnesia and strengthen basic synapse transmission, promote the effect that LTP forms due to the A β etc.
Background technology
Prior art discloses the ginsenoside's of part type medicinal usage, for example:
CN99122651 discloses " pseudo-ginsenoside F
11Medical usage, the document points out, Ginsenoside A1 can suppress the dysmnesia that morphine causes significantly and have the stronger animal learning dysmnesia effect that improves intact animal and drug-induced.
CN98102890 discloses that " ginsenoside Re's extraction process and new medicinal usage thereof, the document point out, the ginsenoside Re has a wide range of applications in preparation treatment arrhythmia, myocardial ischemia and reperfusion injury medicine.
CN98103433 discloses " 20 (S)-panaxoside Rgs
3Semisynthesis and medicinal usage thereof ", the document is pointed out, 20 (S)-panaxoside Rgs
3Be particularly suitable at preparation treatment pulmonary carcinoma, melanoma, S
180Use in sarcoma, colon cancer and the antiviral drug.
CN99814933 discloses and " has contained the Ginsenoside Rb
1Brain cell or nerve cell-protective agents ", the document is pointed out, uses the Ginsenoside Rb
1Or its salt is specially adapted to treatment, prevention or handles brain and sacred disease as the preparation of cytoprotective.
CN01102117 discloses " panaxoside Rg
2Application in the preparation treatment heart, cerebrovascular disease medicament ", the document is pointed out, the panaxoside Rg of extraction separation from Stem and leaf of Radix Ginseng
2Multiple shock, heart failure, myocardial ischemia and cerebral ischemia are had the obvious treatment effect, and its effect is better than known SHENMAI ZHUSHEYE; Be used for the treatment of diseases such as shock, heart failure, coronary heart disease, cerebral infarction and alzheimer disease.
But, more than these open source literatures all be not specifically related to indication of the present invention or only propose notion and do not have concrete experiment parameter and effect parameter.
Summary of the invention
The objective of the invention is to realize the application of ginsenoside Re on medicine, specifically, the objective of the invention is to realize that the ginsenoside Re improves dysmnesia due to naturally-aged, the A β etc. and strengthens basic synapse transmission, promotes the application on the medicine that LTP forms in preparation.
Because ginsenoside Re's extraction process and other some medicinal usages are open in the prior art, and major technique content of the present invention is the effect of checking ginsenoside Re on indication of the present invention, therefore, ginsenoside Re's of the present invention extraction process can be referring to the disclosed content of CN98102890.The present invention adopts multiple behavioristics method and electric physiology method commonly used in the world, respectively at the memory effect that improves of growing up, observed on senile rat and the multiple dysmnesia model ginsenoside Re, adopt electrophysiological method to observe the effect of Re simultaneously to synapse long time journey enhancing (LTP), concrete visible following embodiment, by embodiment, can further understand the present invention.
Description of drawings
Accompanying drawing 1 is the mice water maze schematic representation of apparatus of using among the present invention.
By Figure of description and in conjunction with particular content of the present invention, can be expressly understood the present invention.
The specific embodiment
What present embodiment related to is that the ginsenoside Re promotes the mice of naturally-aged and the research of learning and memory in rats effect.
(1) ginsenoside Re resists the effect of the memory acquisition disturbance that naturally-aged causes in the mice water maze
Get 64 of the old male mices of SPF Kunming kind, body weight 50 ± 2g divides 5 groups at random, normal aged control, the ginsenoside Re organizes (12.5mg/kg, 25mg/kg and 50mg/kg), piracetam group (500mg/g), and add the normal young matched group of a SPF Kunming mouse.Normal old age and young matched group gavage water.All the other per os gavage administration, and the training of mice water maze was carried out in administration in the 11st day to the 15th day, and the sketch map in labyrinth is referring to accompanying drawing 1.
By accompanying drawing 1 as seen, (73 * 42 * 20cm) form water maze, wherein form the labyrinth by some dividing plates by a black lucite cuboid tank; Wherein 1,2,3,4 is cecum, and one jiao of rank of organizing a performance in labyrinth are terminal point.During experiment, to pour water depth of water 10cm, 24 ± 1 ℃ of water temperatures in the labyrinth.
The carrier frequency channel break of with dividing plate A point and B being ordered in first day in training, mice at first is placed in step last 10 second, make it understand the existence of this safety zone, then mice is put in starting point A, allow its free swimming, the time (being incubation period) of writing down its number of times that enters cecum 1 (being errors number) and climbing up safety bench is if the person that do not find the step as yet in training time 2min, will be directed into the safety bench place, be designated as 2min its incubation period.Take a momentary rest after the training for the first time by for the second time with the quadrat method training.Train other mice successively.
In training second day places the B point with dividing plate, and the swimming starting point of mice is the B point, writes down the errors number that mice enters cecum 1,2,3 in the 2min respectively, climbs up the incubation period of safety bench, the training 2 times continuously of every mice.If the person that can not find the step in 2min will be directed into terminal point, be designated as 2min its incubation period.
The swimming starting point of training the 3rd to four day mice is the C point, and mice enters the errors number of cecum 1,2,3,4 and finds every mice incubation period of safety bench to train secondary continuously in the record 2min.
Table 1 ginsenoside Re resists the effect of the memory acquisition disturbance that naturally-aged causes in the mice water maze
| Incubation period (second) | Aged Mice (n=14) | Young mice (n=13) | Piracetam 500mg.kg (n=13) | Ginsenoside Re 12.5mg/kg (n=11) | Ginsenoside Re 25mg/kg (n=14) | Ginsenoside Re 50mg/kg (n=12) |
| D1 | 26.3±23.0 | 50.7±37.8 ** | 23.4±23.2 | 20..6±9.7 | 17.3±11.2 * | 14.0±12.9 * |
| D2 | 88.2±31.9 | 86.5±41.2 | 66.9±35.7 * | 65.6±43.5 * | 77.7±42.2 | 70.8±43.7 |
| D3 | 91.8±36.0 | 79.3±43.9 | 71.7±43.3 * | 75.5±43.8 | 64.4±44.4 * | 71.0±44.6 * |
| D4 | 55.0±40.4 | 53.6±43.3 | 55.9±42.4 | 51.6±39.0 | 35.6±27.3 * | 57.0±46.3 |
(2) ginsenoside Re's effect of keeping away in the dark experiment memory acquisition disturbance that the antagonism naturally-aged causes mice
Get 64 of SPF Kunming kind Aged Mice, body weight 50 ± 2g, male, divide 5 groups at random, normal aged control, the ginsenoside Re organizes (12.5mg/kg, 25mg/kg and 50mg/kg), piracetam group (500mg/kg), and add a normal young matched group.Normal old age and young matched group gavage water.All the other per os gavage administration, administration the 16th and carried out mice on the 17th day and keep away dark training.
Experimental provision is a trained reflex case, is divided into light and shade two parts, has a small holes that mice can be had free passage in two Room, and the copper grid are arranged at the bottom of the case, and wherein the copper grid of bottom, darkroom pass to 36V voltage.During experiment mice put into bright chamber and darkroom dorsad, because of the mice dark and habit of getting into the cave in the family way,, when entering into darkroom four-footed contact copper grid, mice one will be shocked by electricity so can repeatedly pierce the darkroom at the experiment training period, this behavior is mistake, and its normal reaction is for managing to withdraw from the darkroom at once.During training in first day, the record mice entered the number of times in darkroom and enters the time of camera bellows for the first time in 3 minutes.Do experiment after 24 hours again, observing the time that mice in 5 minutes enters camera bellows first is incubation period, and the number of times that mice enters camera bellows is an errors number.
As seen from Table 2, the ginsenoside Re of low middle high dose is in that significant difference is all arranged aspect incubation period and the errors number, and is more remarkable with the ginsenoside Re of high dose.
The effect that table 2 ginsenoside Re keeps away the memory acquisition disturbance that the antagonism naturally-aged causes in the dark experiment mice
| Aged Mice (n=14) | Young mice (n=13) | Piracetam 500mg.kg (n=13) | Ginsenoside Re 12.5mg/kg (n=11) | Ginsenoside Re 25mg/kg (n=14) | Ginsenoside Re 50mg/kg (n=12) | |
| Incubation period | 170.8±136.6 | 198.2±113.8 | 257.5±89.5 * | 268.3±82.5 * | 257.1±79.6 * | 300±0 ** |
| Errors number | 1.2±1.3 | 0.7±09 | 0.2±0.4 * | 0.4±0.7 * | 0.3±0.5 * | 0±0 ** |
(3) effect of ginsenoside Re's memory acquisition disturbance that the antagonism naturally-aged causes in the test of rat Morris water maze
Get male 56 of SD senile rat, about divide 5 groups at random, normal aged control, the ginsenoside Re organizes (6.25mg/kg, 12.5mg/kg and 25mg/kg), piracetam group (250mg/kg), and add a normal young matched group.Normal old age and young matched group gavage water.All the other per os gavage administration, and the training of rat water maze was carried out in administration in the 15th day to the 19th day.
The cylindricality pond, garden that the Morris water maze is mainly made by a rustless steel and the platform of a removable position are formed.The sky, pond is connected with computer with monitor by a video camera.When the training time of setting to or animal climbed up platform, computer stops to follow the tracks of or stopping record, and note the swimming track and calculate the distance that animal is swum across automatically in the pond, find required time of platform (being incubation period) and initial angle (going into the angle between instant water rat cephalocaudal axis and the place of entry platform line).
In the pond, inject clear water in advance, add the aqueous solution that is dissolved with the fresh milk powder of 1kg then, make Chi Shui become opaque milky, the clear water that reinjects makes the water surface exceed platform 1cm, and water is wet to be controlled at 24 ± 0.5 ℃, and platform places the centre of a certain quadrant, an optional place of entry in other three quadrants, every day is trained secondary in experiment, adopts different place of entry at every turn, trains the scheme of 1min at every turn.If animal do not find platform as yet within 1min, then take animal on the platform and make it stop 15s in the above, if rat is found platform within 1min, also be allowed to condition at platform and stop 15s, reef knot Shu Yici training.So training is five days, writes down the incubation period of every animal respectively, the distance of swimming across.In the last day of training, platform is removed, every rat is only swum 1min, respectively with every rat of stopwatch record for the first time through platform time-also be incubation period, and can write down the number of times of every rat process platform in 1min and the time of in platform place quadrant (first quartile), staying, latter two index is big more if the incubation period of certain rat is short more, illustrates that then this rat is clever more.
Table 3 ginsenoside Re tests in the first five day at rat Morris water maze
The effect of the memory acquisition disturbance that the antagonism naturally-aged causes
| Incubation period (second) | Senile rat (n=12) | Young rat (n=14) | Piracetam 250mg.kg (n=11) | Ginsenoside Re 6.25mg/kg (n=9) | Ginsenoside Re 12.5mg/kg (n=11) | Ginsenoside Re 25mg/kg (n=13) |
| D1 | 51.9±15.6 | 44.6±17.7 | 48.1±20.7 | 57.2±8.2 | 51.4±16.2 | 55.2±9.4 |
| D2 | 43.4±22.0 | 25.0±19.9 ** | 43.0±19.3 | 49.0±17.8 | 47.4±19.5 | 37.3±21.0 |
| D3 | 43.4±23.9 | 20.0±21.3 ** | 31.5±204 * | 36.3±22.9 | 35.3±25.9 | 32.2±21.4 |
| D4 | 278±21.2 | 16.1±14.5 * | 24.6±17.3 | 23.1±20.6 | 26.4±20.9 | 16.8±10.7 * |
| D5 | 25.9±21.0 | 152±16.6 * | 28.5±22.1 | 21.9±21.2 | 29.7±22.7 | 16.5±15.7 * |
| Swimming distance (cm) | Senile rat (n=12) | Young rat (n=14) | Piracetam 250mg.kg (n=11) | Ginsenoside Re 6.25mg/kg (n=9) | Ginsenoside Re 12.5mg/kg (n=11) | Ginsenoside Re 25mg/kg (n=13) |
| D1 | 1139±387 | 1054±417 | 98/3±454 | 992±206 | 927±369 * | 930±216 * |
| D2 | 936±513 | 604±483 | 994±486 | 1053±391 | 1078±543 | 790±448 |
| D3 | 953±564 | 498±525 ** | 671±482 * | 714±477 | 749±665 | 675±463 * |
| D4 | 470±395 | 364±302 | 453±310 | 413±316 | 500±530 | 379±298 |
| D5 | 548±503 | 454±519 | 737±779 | 435±389 | 632±624 | 403±337 |
Table 4 ginsenoside Re rat Morris water maze test the 8th day right
The effect of the memory acquisition disturbance that anti-naturally-aged causes
| Senile rat (n=12) | Young rat (n=14) | Piracetam 250mg.kg (n=11) | Ginsenoside Re 6.25mg/kg (n=9) | Ginsenoside Re 12.5mg/kg (n=11) | Ginsenoside Re 25mg/kg (n=13) | |
| Incubation period #(second) | 38.5±22.1 | 11.3±14.8 ** | 198±14.2 * | 24.0±18.2 | 21.3±15.9 * | 29.4±20.8 |
| Cross the platform number of times | 1.0±1.2 | 1.8±1.0 * | 1.5±10 | 1.3±09 | 2.0±1.3 * | 1.9±1.5 |
| The first quartile time ## | 13.4±6.9 | 16.3±3.3 | 16.1±2.6 | 16.9±4.4 | 17.7±6.8 | 19.1±5.7 * |
| Initial angle (°) | 65.2±39.4 | 34.5±35.7 * | 520±26.1 | 45.2±36.8 | 52.3±32.6 | 53.4±34.4 |
| Swimming distance (cm) | 1243±364 | 1415±204 | 1204±254 | 1270±271 | 1254±427 | 1190±200 |
Incubation period
#: physical record is to remove rat behind the platform swims across the position of platform for the first time in 1min time here, also just is equivalent to train the incubation period of the first five day.
The first quartile time
##: the temporal summation that stops in first quartile when being meant rats'swimming just accounts for the ratio of total time in the first quartile time of staying.
In above rat water maze laboratory, senile rat compare with young rat the training second day to last day aspect incubation period, second and the 3rd day swimming distance aspect, the 3rd day of training with last day significant difference all being arranged aspect the platform number of times aspect the initial angle and crossing of last day of training, this senile rat model establishment is described.The piracetam group is in the 3rd day and last day of training, the Re of high dose the training the 4th and the 5th day aspect incubation period, the Re of piracetam group and high dose organizes at the 3rd day that trains aspect the swimming distance and aspect the initial angle, the Re of high dose last day of training at first quartile aspect the time of staying, the Re of middle dosage all has significant difference in last day of training comparing with senile rat aspect incubation period and the mistake platform number of times.
What present embodiment related to is the ginsenoside Re causes rat spatial discrimination obstacle to A β 25-35 improvement effect.
Senile dementia is main pathological characteristics with the formation of the deposition of senile plaque, neurofibrillary tangles and neuron loss and is the main clinical performance with memory, cognitive dysfunction.Beta amyloid peptide (β-amyloid peptide, A β) (being made up of 1-40 aminoacid) is an important constituent of senile plaque, has direct neurotoxic effect.The peptide chain A β 25-35 that is made up of these 11 aminoacid of the 25th to 35 among the A β also has cohesion ability and neurotoxicity, and we utilize the A β 25-35 of intracerebroventricular injection condensed state to cause the space learning dysmnesia and observe ginsenoside Re's improvement effect.
Male Wistar rat body weight 200g ±, A β 25-35 is available from Sigma company, and the preparation of the A β 25-35 of condensed state is that the A β 25-35 with 1mg is dissolved in the distilled water of 3.14ml sterilization final concentration 3mmol.L
-1120h in the rearmounted 37 ℃ of incubators of (15mmol/5 μ l) sealing.
48 rats are divided into four groups, it is operative control group, model group, 25mg/kg Re group, 12.5mg/kg Re group, animal is fixed on the stereotaxic instrument after with chloral hydrate (150mg/kg) or urethane (750mg/kg) intraperitoneal injection of anesthesia, shave hair and spill smart sterilization skin tailing edge fore-and-aft direction center with 75% and cut off the about 2cm of calvarium skin, carefully peeling off subcutaneous tissue and periosteum, fully expose skull, is A with electric drill at the elements of a fix
0.8, L
1.8The position, aperture at right side cranial drill one diameter 1.5mm, remove bone bits back and carefully needle cerebral dura mater with the tip tweezers, subsequently under the stereotaxic instrument guiding, the little steel pipe of external diameter 0.8mm is inserted the ventricles of the brain, slowly extract 5 μ l A β 25-35 or equivalent sterile distilled water (contrast) out little steel pipe and a small amount of penicillin powder of wine on the aperture surrounding cranial bone behind (3min) injection tricorn 2min, rapid skin suture, postoperative begins to irritate stomach every day once next day, successive administration carries out the training of Morris water maze after 14 days, trained altogether 5 days, wherein removed in the 5th day platform record animal find the platform required time be incubation period and remove platform after time of in the quadrant of former placement platform, stopping of animal and arrive the strategy (orthoscopic that platform is taked, the trend formula, marginal mode, random mode).
Morris water maze device and test are referring to embodiment 1.
Table 5 ginsenoside Re is in the Morris water maze test
Improvement effect to spatial discrimination obstacle due to the A β 25-35
| Incubation period (second) (mean+SD) | |||||
| Natural law | Aβ25-35 | Re25mg/kg | Re12.5mg/ | Contrast | |
| 1 | 52.5±16.7 | 51.1±14.5 | 36.4±25.1 * | 37.6±21.5 * | |
| 2 | 40.7±23.2 | 21.5±16.7 ** | 19.0±19.3 ** | 20.6±22.3 ** | |
| 3 | 21.6±13.4 | 11.5±13.1 * | 10.0±6.4 ** | 12.8±7.5 * | |
| 4 | 17.5±13.5 | 8.5±6.6 ** | 7.3±4.5 * | 7.5±8.3 ** | |
| 5 | 25±7％ | 37.6±8.5％ ** | 41.3±7.1％ ** | 33.6±6.7％ ** | |
The 5th day measurement result represents to remove animal time of staying in former placement platform quadrant behind the platform.
Present embodiment relates to the effect that the ginsenoside Re keeps away the memory acquisition disturbance that the antagonism scopolamine causes in dark experiment, mice water maze, the test of Morris water maze mice.
The effect that the ginsenoside Re keeps away the memory acquisition disturbance that the antagonism scopolamine causes in the dark experiment mice is as follows, get 72 of SPF Kunming mouses, body weight 20 ± 2g, male, divide 6 groups at random, the normal control group, scopolamine model group, piracetam group, the ginsenoside Re organizes (12.5mg/kg, 25mg/kg and 50mg/kg), per os gavaged administration 9 days, and normal control group and scopolamine model group gavage water, administration the 9th and carried out mice on the 10th day and keep away dark training.The method of testing that is adopted is the same.
Referring to table 6, from experimental result as can be seen, piracetam and ginsenoside Re keep away the effect that has the memory acquisition disturbance that causes of antagonism scopolamine in the dark experiment mice, and be wherein more remarkable with the effect of middle dosage group.
The effect (n=12) that table 6 ginsenoside Re keeps away the memory acquisition disturbance that the antagonism scopolamine causes in the dark experiment mice
| Dosage | Scopolamine | Incubation period (second) | Errors number (inferior) | |
| The normal control group | 163.1±119.2 * | 0.6±0.5 * | ||
| The scopolamine model group | 5mg/kg | 79.9±80.4 | 1.5±0.8 | |
| The piracetam group | 500mg/kg | 5mg/kg | 131.9±113.4 * | 0.8±0.4 * |
| Ginsenoside Re's low dose group | 12.5mg/kg | 5mg/kg | 206.1±103.7 * | 0.6±0.6 * |
| Dosage group among the ginsenoside Re | 25mg/kg | 5mg/kg | 251.0±78.2 ** | 0.4±0.6 * |
| Ginsenoside Re's high dose group | 50mg/kg | 5mg/kg | 189.7±113.0 * | 0.7±0.6 * |
Compare with the scopolamine model group,
*P＜0.05,
*P＜0.01
The ginsenoside Re resists the effect of the memory acquisition disturbance that scopolamine causes in the mice water maze specific as follows: get 72 of SPF Kunming mouses, body weight 20 ± 2g, male, divide 6 groups at random, normal control group, scopolamine model group, the piracetam group, the ginsenoside Re organizes (25mg/kg, 50mg/kg and 100mg/kg), and per os gavaged administration 17 days, and normal control group and scopolamine model group gavage water.The training of mice water maze was carried out in administration in the 14th day to the 18th day.Five groups of except the normal control group all the other in preceding four days of training every day 20min lumbar injection scopolamine (5mg/kg) before training, all animals are not all injected scopolamine before five days of training.Method of testing is the same.
The swimming starting point of training the 3rd to five day mice is the C point, and mice enters the errors number of cecum 1,2,3,4 and finds every mice incubation period of safety bench to train 2 times in the record 2min.
As can be seen from Table 7, there were significant differences aspect incubation period and errors number to have only normal control group and scopolamine model group at the 4th day that trains, and the piracetam group is compared with model group only variant aspect incubation period.There were significant differences aspect incubation period and errors number in the 5th day normal control group of training and piracetam group and scopolamine model group, and compare ginsenoside's low dose group aspect incubation period and errors number with the scopolamine model group, middle dosage group is all variant aspect incubation period, as seen normal control group, piracetam group and the ginsenoside is low, in two dosage groups (25,50mg/kg) the antagonism amnemonic effect that scopolamine caused is arranged in the mice water maze laboratory.
Table 7 ginsenoside Re resists the effect (n=12) of the memory acquisition disturbance that scopolamine causes in the mice water maze laboratory
| Dosage (mg/kg) | Scopolamine (mg/kg) | Trained the 4th day | Trained the 5th day | |||
| Incubation period (second) | Errors number | Incubation period (second) | Errors number | |||
| The normal control group | 34.7±23.8 ** | 2.5±1.7 ** | 28.1±19.1 ** | 1.3±1.0 ** | ||
| The scopolamine model group | 5 | 111.3±22.1 | 10.2±4.2 | 69.9±27.4 | 6.0±2.1 | |
| The piracetam group | 500 | 5 | 89.3±36.7 * | 10.0±4.5 | 44.0±17.9 ** | 3.4±2.0 ** |
| Ginsenoside Re's low dose group | 25 | 5 | 113.4±12.2 | 12.8±1.7 | 51.5±20.8 * | 5.4±2.3 |
| Dosage group among the ginsenoside Re | 50 | 5 | 120±0 | 11.5±2.7 | 48.7±27.8 * | 3.9±2.1 * |
| Ginsenoside Re's high dose group | 100 | 5 | 96.6±33.2 | 9.3±3.4 | 78.0±43.9 | 4.4±2.0 * |
Compare with the scopolamine model group,
*P＜0.05,
*P＜0.01
The test of Morris water maze, specific as follows: get 72 of SPF Kunming mouses, body weight 20 ± 2g, male, divide 6 groups at random, the normal control group, scopolamine model group, piracetam group, the ginsenoside Re organizes (25mg/kg, 50mg/kg and 100mg/kg), per os gavaged administration 17 days, and normal control group and scopolamine model group gavage water, and the training of mice water maze was carried out in administration in the 14th day to the 18th day.Five groups of except the normal control group all the other in preceding four days of training every day 20min lumbar injection scopolamine (5mg/kg) before training, the first five day of training all animals all do not inject scopolamine.Method of testing is the same.
As can be seen from Table 8, training had only normal control group and scopolamine model group on the 4th day in incubation period and look for aspect the platform distance that there were significant differences, ginsenoside Re's low dose group is compared with model group only in discrepant trend aspect incubation period.Compare in incubation period with the scopolamine model group and look for aspect the platform distance variant in the 5th day normal control group of training, and ginsenoside Re's high dose group compare with the scopolamine model group aspect incubation period variant, the amnemonic effect that visible normal control group and ginsenoside's high dose group have certain antagonism scopolamine to be caused in the Morris water maze laboratory.
Table 8 ginsenoside Re is right in mice Morris water maze laboratory
The effect of the memory acquisition disturbance that anti-scopolamine causes (n=12)
| Dosage | Scopolamine | Trained the 4th day | Trained the 5th day | |||
| Incubation period (second) | Distance (cm) | Incubation period (second) | Distance (cm) | |||
| The normal control group | 50.9±25.4 * | 962±489 ** | 47.2±22.1 * | 938±418 * | ||
| The scopolamine model group | 5mg/kg | 65.3±20.8 | 1443±423 | 64.1±18.4 | 1287±517 | |
| The piracetam group | 500mg/kg | 5mg/kg | 66.6±15.4 | 1552±448 | 63.8±24.6 | 1465±492 |
| Ginsenoside Re's low dose group | 12.5mg/kg | 5mg/kg | 52.9±24.0 | 1269±528 | 512±25.1 | 1268±516 |
| Dosage group among the ginsenoside Re | 25mg/kg | 5mg/kg | 60.6±241 | 1487±591 | 48.1±28.7 | 1139±615 |
| Ginsenoside Re's high dose group | 50mg/kg | 5mg/kg | 64.5±27.0 | 1464±625 | 47.9±24.5 * | 1101±469 |
Compare with the scopolamine model group,
*P＜0.05,
*P＜0.01
Can draw as drawing a conclusion from present embodiment 3: its mouse oral gavages ginsenoside Re's low dosage (12.5mg/kg), and middle dosage (25mg/kg) and high dose (50mg/kg) are kept away in the dark experiment mice and can obviously be resisted the memory acquisition disturbance that scopolamine causes; In the mice water maze laboratory 25, the ginsenoside Re of 50mg/kg dosage has the effect of the memory acquisition disturbance that causes of antagonism scopolamine, in the mice water maze laboratory, the ginsenoside Re of 50mg/kg dosage has the effect of the memory acquisition disturbance that causes of antagonism scopolamine.
Embodiment 4
What present embodiment related to is that the ginsenoside Re causes amnemonic effect to the mice transient cerebral ischemia, and specific as follows: it is male to get Kunming mouse, body weight 18-22 gram, and after animal was weighed, sodium pentobarbital 60mg/kg intraperitoneal injection of anesthesia underwent surgery.Postoperative 24 hours is divided into 5 groups at random with animal, irritates stomach respectively and gives Re, dosage 6.25,12.5,25mg/kg body weight.Matched group and model group give solvent.After this, be administered once every day to behavioristics's off-test.Postoperative is blocked bilateral carotid fully after 48 hours, recover blood and supply after righting reflex loss appears in animal.The experiment of 24 hours laggard capable behavioristicss.
The transient cerebral ischemia model is got dorsal position after preparing Animal Anesthesia.The about 7mm of skin is cut off in the cervical region center, separates bilateral carotid, and in No. 0 white silk thread of left side tremulous pulse underlying, tremulous pulse underlying No. 0 black silk thread in right side is used for blocking blood flow.Each line two ends swallow is neat, and four terminals are passed through the about 5mm PE50 of segment length plastic tube.Pass skin by nape portion center, plastic tube is embedded in the skin.Pass the ring portion that black and white two lines entangle blood vessel with another black silk thread, skin is drawn by neck lower cut-out place in the two ends of this line, sews up the incision.With a tweezers flicking nape portion skin, strain four line terminals of black and white during ischemia, and four lines and skin are fixed, cause the cerebrum ischemia state with bulldog clamp.Ischemia finishes, and unclamps bulldog clamp, gently draws lead-in wire under the neck, can make carotid artery recover blood reperfusion fully.
Keep away preceding mice is placed of dark experiments experiment and keep away camera bellows endoadaptation 3min.During experiment the mice face is put into bright chamber in the hole dorsad, animal passes the hole and enters the darkroom and shocked by electricity, and takes out mice after 1 minute.Recast test after 24 hours, record enters incubation period of darkroom animal and the number of shocks in the 5min.
Water maze laboratory record animal arrives target area institute palpus time and the animal errors number that enters cecum during this period of time from the starting area, with these two indexs as the learning and memory achievement.Animal is trained once every day, and each 2min trained 4 days continuously.
The date processing data are represented with mean ± s, organize a t check.
The influence of the damage in learning and memory that table 9 ginsenoside Re causes cerebral ischemia re-pouring in keeping away dark experiment
| The incubation period/second | Errors number | |
| Sham operated rats | 224.0±105.90 * | 0.5±0.7 * |
| Model group | 105.1±134.9 | 1.6±1.4 |
| 6.25 | 74.5±119.5 | 1.5±1.1 |
| 12.5 | 157.2±119.9 | 0.9±0.7 |
| 25 | 116.4±109.6 | 1.0±0.7 |
The influence of the damage in learning and memory that table 10 ginsenoside Re causes cerebral ischemia re-pouring in water maze laboratory
| The 3rd day | The 4th day | |||
| Incubation period | Errors number | Incubation period | Errors number | |
| Sham operated rats | 80.1±40.1 | 6.1±3.4 | 57.6±21.6 * | 4.9±3.0 |
| Model group | 86.8±36.3 | 7.9±3.7 | 88.4±30.1 | 7.4±2.6 |
| 6.25 | 68.6±33.7 | 6.8±4.2 | 57.7±38.9 | 6.6±4.4 |
| 12.5 | 78.0±39.2 | 8.9±5.8 | 58.1±42.4 | 6.0±5.8 |
| 25 | 96.0±35.9 | 8.3±5.4 | 43.7±32.5 ** | 5.3±3.7 |
*P＜0.05
**P＜0.01
In keeping away dark test, sham operated rats is compared with model group, and significant difference is all arranged on behavioristics's indexs such as incubation period and errors number, and model is set up.Re12.5mg/kg, 25mg/kg can reduce errors number.
In water maze test, swimming sham operated rats incubation period was compared with model group in the 4th day, significantly shortened.The 25mg/kg group has been compared utmost point significant difference with model group, 6.25mg/kg, and the 12.5mg/kg group is shorter than model group incubation period, but significant difference is not arranged.
Embodiment 5
What present embodiment related to is the influence of ginsenoside Re to anesthetized rat hippocampal dentate basis synapse transduction activity, present research to nootropics, behavioristics's research evidence not only will be provided, also to adopt the electrophysiology technology to prove that it is to the plastic influence of nerve synapse, the main effect of observing synapse long time journey enhancing (LTP), it is considered to the cell model of central nervous system's learning and memory.
Concrete experiment is, the Wistar rat with 20% urethane 1.0g/kg intraperitoneal injection of anesthesia after, be fixed on the stereotaxic instrument.At the elements of a fix is AP
0.8, L1.8, H3.5 plant at the place basket pipe in tricorn, and at AO3.8, L2.5, H3.5 plant at the place recording electrode in the hippocampal dentate granular cell layer, at AP
7.5, L
4.2, H
3.5-4.0The place plant a stimulating electrode in entorhinal area perforated space path (perforant path, PP).Adjust the position of stimulating electrode, find to record maximum cluster spike potential amplitude under the constant stimulus intensity (population spike amplitude, the position in the time of PSA) maintains static.Testing stimulus is the square wave of the wide 0.2ms of ripple, and frequency is 1/30Hz, and stimulus intensity is the 1/3-1/2 that causes the required stimulus intensity of maximum PSA.Re is with 0.01% DMSO dissolving and be diluted to variable concentrations, gives by the basket pipe of implanting tricorn, and matched group is given 0.01%DMSO.The PSA of 30min before record is given approximately surveys thing at 5min meat with the spy of 5 μ l then and slowly is injected into tricorn, and the PSA after the record administration in the 60min gets 15min, 30min, 3 of 60min add up.Draw the meansigma methods of the preceding PSA of medicine and represent the preceding basic synapse transmission level of administration, the PSA of 15min, 30min, 60min each point draws each point PSA relative value (%) after this average removal administration of reuse.Average and standard deviation group catch cropping t check in the group.
As can be seen from Table 11, intracerebroventricular injection Re can make hippocampal dentate basis synapse transfer reaction strengthen.Re concentration is 10
-5Increase not clearly during M, when 60min, just reached 135 ± 20.6%; Along with the reduction of Re concentration, the amplification of PSA strengthens gradually, and 10
-6M has just reached 138.9 ± 10.6% at 30min; With 10
-7M concentration amplification maximum, 15min has reached 138.4 ± 18.0% after the administration, and continues to increase, and reaches 189.6 ± 63.0% during to 60min.Can be considered dose,optimum; 10
-8The PSA amplification of M is than 10
-7M descends again to some extent, but also reaches 152.2 ± 32.4% at 30min.10
-6M, 10
-7M, 10
-8Three dosage groups of M PSA amplification has all surpassed 30.
The influence that table 11 ginsenoside Re forms rat hippocampus LTP
| Handle | Number of animals | Population spike (PS) amplitude (%), means ± sd | |||
| n | Before the administration | 15min | 30min | 60min | |
| Control | 5 | 100 | 93.8±9.6 | 100.9±12.5 | 101.6±9.6 |
| Re10 -5M | 5 | 100 | 102.1±12.7 | 112.2±22.0 | 135.0±20.6 * |
| Re10 -6M | 5 | 100 | 116.4±11.0 | 138.9±10.6 *** | 165.4±13.9 *** |
| Re10 -7M | 6 | 100 | 138.4±18.0 *** | 165.5±40.1 ** | 189.6±63.0 * |
| Re10 -8M | 5 | 100 | 118.1±9.6 | 152.2±32.4 * | 179.9±48.5 * |
P＜0.05，
*P＜0.01，
***P＜0.01 vs control
The long time journey that synapse is transmitted strengthens that (long-term potentiation LTP) thinks cytology's model of central nervous system's learning and memory, becomes cytology's model of learning and memory, becomes the objective indicator of neuron physiological activity in the learning and memory process.This experiment finds that the ginsenoside Re is 10
-6M, 10
-7M, 10
-8The tricorn administration has potentiation to the synapse transmission of anesthetized rat hippocampal dentate basis under the M dosage, and can form the LTP image, and this result has enriched new content for the nootropic effect research of Radix Ginseng.
The ginsenoside Re is an important chemical constituent in the Radix Ginseng, it can improve dysmnesia due to the chemicals (scopolamine etc.), and improve naturally-aged, due to the A β etc. dysmnesia and strengthen basic synapse transmission, the effect that promotes LTP to form belongs to first and finding, provides experimental basis fully for the ginsenoside Re being developed to a nootropics.
Claims (4)
1, a kind of ginsenoside Re is as the application in the amnemonic medicine of preparation treatment.
2, a kind of ginsenoside Re improves application in the amnemonic medicine that naturally-aged causes as preparation.
3, a kind of ginsenoside Re is as the application in the amnemonic medicine due to the preparation treatment scopolamine.
4, the application in the amnemonic medicine that causes as preparation treatment cerebral ischemia of a kind of ginsenoside Re.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0789863A (en) * | 1993-09-24 | 1995-04-04 | Morishita Roussel Kk | Isolation refining method for ginsenoside re and antiarhythmic agent mainly composed of compound |
| CN1209996A (en) * | 1998-08-28 | 1999-03-10 | 吉林省集安制药有限公司 | Medicinal composition containing ginsenoside Re, preparation and usage thereof |
| CN1242374A (en) * | 1998-07-22 | 2000-01-26 | 北京市鑫利恒医药科技发展有限公司 | Process for extracting ginsenoside Re, and use of medicine thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0789863A (en) * | 1993-09-24 | 1995-04-04 | Morishita Roussel Kk | Isolation refining method for ginsenoside re and antiarhythmic agent mainly composed of compound |
| CN1242374A (en) * | 1998-07-22 | 2000-01-26 | 北京市鑫利恒医药科技发展有限公司 | Process for extracting ginsenoside Re, and use of medicine thereof |
| CN1209996A (en) * | 1998-08-28 | 1999-03-10 | 吉林省集安制药有限公司 | Medicinal composition containing ginsenoside Re, preparation and usage thereof |
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| 人参皂甙Rg1，Re对β-淀粉样蛋白诱导原代培养海马及皮质神经元损伤的保护作用 张晓冬 等，第二军医大学学报，第21卷第10期 2000 * |
| 人参皂甙Rg1，Re对β-淀粉样蛋白诱导原代培养海马及皮质神经元损伤的保护作用 张晓冬 等，第二军医大学学报，第21卷第10期 2000;人参皂甙对动物学习记忆影响的研究进展 杨国愉 等，中国行为医学科学，第9卷第3期 2000;小鼠暂时性脑缺血引起学习记忆障碍模型的制备及人参皂甙的保护作用 裘月 等，中国药理学通报，第11卷第4期 1995 * |
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