CN1511525A - Application of (+) North America coptisine - Google Patents
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- CN1511525A CN1511525A CNA021591709A CN02159170A CN1511525A CN 1511525 A CN1511525 A CN 1511525A CN A021591709 A CNA021591709 A CN A021591709A CN 02159170 A CN02159170 A CN 02159170A CN 1511525 A CN1511525 A CN 1511525A
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Abstract
The present invention relates to the application purify (+)-hydrastine in preparing medicine for preventing and treating dementia, promoting intelligence growth and raising oxygen lack resistance. Animal experiment shows that (+)-hydrastine can raise the learning memory of model mouse with dementia caused by scopolamine and pentobarbital sodium, raise the learning memory of health mouse and aged mouse and prolong the time of mouse in oxygen lack survival. The (+)-hydrastine has high activity and low toxicity.
Description
Technical field
The present invention relates to the application of (+) hydrastine in the medicine for preparing prevention and treatment dementia, the intelligence that promotes, raising hypoxia-bearing capability.Confirm that through zoopery (+) hydrastine can improve scopolamine, pentobarbital sodium causes the Model of Dementia learning and memory abilities in aging mice, improve the ability of learning and memory of normal mouse, aged mouse, improve the life span of anoxia mice.(+) hydrastine has the advantage that activity is high, therapeutic dose toxicity is little.
Background technology
The average life of China's population is above 70 years old at present.External scientific research prediction: the old people of 65 years old and over-65s will reach 18.8% during by 2025, and this numeral shows, surplus 20 year, per 5 philtrums just have 1 old people.Degenerative brain disorder (Alzheimer ' sDisease) mostly occurs year surplus 50.The multiple embolism dementia or the alzheimer disease that cause because of cerebrovascular disease mostly occurred after 60 years old.As seen, because the aging of population, the sickness rate of degenerative brain disorder and senile dementia also will increase.Old people and distinctive neurodegenerative disease thereof---various dementias will experience two kinds of death, at first are spiritual death, after be sensual death, suffer untold misery, bring heavy burden more for society and family.Aged tendency of population is considered to be only second to war, pestilence, famine, energy resource shortage and influence social development and stabile unfavorable factor.
Dull-witted (dementia) is the acquired and persistence disturbance of intelligence syndrome that produces owing to disordered brain function, disturbance of intelligence comprises that in various degree memory, language, visual space function, abnormality of personality and cognitive competence reduce, and dementia mainly comprises Alzheimer disease, vascular dementia etc.Control medicament categories old and feeble and the treatment senile dementia is various.Mainly use cholinergic drug clinically at present or cholinesterase inhibitor is treated, be aided with to improve cerebrovascular circulation, cerebral protective agent etc., effect is often not satisfactory.Strengthen in the medicine of choline systemic-function, the Ach precursor only has faint therapeutical effect, though Ach receptor stimulating agent and cholinesterase inhibitor have certain effect, acts on ofer short durationly, and toxic and side effects is bigger.Cerebral vasodilator help to provide energy and improve intelligence by improving cerebral blood flow, but real valuable cerebral vasodilator must have high selectivity, does not influence the brain metabolism, does not have " stealing blood " phenomenon, and antiplatelet aggregation and anti thrombotic action are arranged.Though the calcium antagonist nimodipine meets above-mentioned some condition, it only acts on the L-passage in the voltage dependent channel, and N type and T type calcium channel are not had influence.Multiple neuropeptide and nerve growth factor once were considered to the hope of treatment dementia, but clinical effectiveness is not good, may be mainly were difficult to enter in the brain by blood brain barrier owing to this class material play a role.After 2-Pyrrolidone acetamide (trade name piracetam) comes out, belong to the not novel nootropics of a class of arguement in early days in the document, reported both at home and abroad in recent years, this medicine slightly or does not still have final conclusion to all types of dysmnesia and senile dementia effect, it is a water soluble compound, the blood brain barrier percent of pass is low, is difficult for focusing on target spot and plays a role.
(+) hydrastine is from a kind of alkaloid monomer that extracts the geographic plant of NORTHWEST CHINA-straight stem Herba corydalis edulis (Corydalis stricta Steph.) that is grown in, be soluble in acid flux material, adjust pH value with alkaline solution and be no more than at 4 o'clock, biological activity is stable, and precipitation does not appear in long preservation.Known (the square departure of (+) hydrastine, Lin Mao, Weng Qingmei, Zhu Chaode, Liu Xin. the chemical research of four kinds of Corydalis plant alkaloids of the chemistry of Corydalis plant alkaloid---Part of Qinghai Plateau. Acta Pharmaceutica Sinica, 1981,16 (10): 798-800.), but the research of its biological activity aspect does not appear in the newspapers so far.
Summary of the invention
In order to overcome the deficiencies in the prior art, the object of the present invention is to provide the application of a kind of (+) hydrastine shown in general formula (I) in the medicine for preparing prevention and treatment dementia, the intelligence that promotes, raising hypoxia-bearing capability.
Another object of the present invention provides pharmaceutical composition, comprising as carrier commonly used in (+) hydrastine shown in general formula (I) of effective ingredient and the pharmaceutical field.
Chemical compound of the present invention comprises acceptable salt on its derivant, stereoisomer and the pharmacodynamics.
Specifically, one aspect of the present invention relates to the chemical compound shown in general formula (I)
(+) hydrastine can improve the learning memory disorder that multiple reason causes.Intraperitoneal administration 0.15mg/kg (be about median lethal dose(LD 50) 1/20) and oral administration 0.625mg/kg (be about median lethal dose(LD 50) 1/40), obviously prolong the incubation period that can make animal enter electric shock district, darkroom, and the errors number of appearance obviously reduces.The pharmacological results is presented in advance the abdominal cavity and awards behind (+) hydrastine 0.15mg/kg lumbar injection scopolamine 1.0mg/kg again, and the number of times of mistake is 0%.Return to the level of normal group incubation period fully, illustrates to have reversed the detrimental effect that scopolamine obtains mouse memory fully.Illustrate that (+) hydrastine can effectively improve the learning and memory obstacle that the anticholinergic agent scopolamine causes.
Equally, the learning memory disorder that pentobarbital sodium (Pentobarbital) is caused also has tangible inverting action.In darkroom test, mouse peritoneal injection (+) hydrastine 0.15mg/kg increases incubation period, and the number of times of mistake reduces, and is remarkable with the model group comparing difference.Illustrate that (+) hydrastine can effectively improve the learning and memory obstacle that pentobarbital sodium causes, and significantly be better than the cholinesterase inhibitor tacrine (Tacrine) and the calcium antagonist nimodipine (Nimodipine) of external listing.
In water maze test, the mice of oral 0.625mg/kg (+) hydrastine group is swum to the shortening of platform time ratio model group, and also lacks than the normal control group, and errors number is still lacked than the normal control group.With model group ratio, difference highly significant.Illustrate that (+) hydrastine can effectively improve the learning and memory obstacle that pentobarbital sodium causes, and be better than nimodipine.
For the intact animal, on the animal model of water maze, also shown the effect of good enhancing learning and memory.The animal of having given (+) hydrastine obviously strengthens than the normal control group ability of learning and memory of administration not, and it is short not only to arrive at the security platform required time, and it is also few to go to the wrong way the number of times of route in water maze.Through repeatedly repeating all to show this result.Result of the test shows no matter be that errors number is few than normal group, swimming time is short than normal group, demonstrates tangible nootropic effect.Effect is better than nimodipine and piracetam.
(+) hydrastine that further studies show that of the present invention can improve and strengthen aged learning and memory in rats and mice significantly.Aged male mice is poorer than young learning and memory abilities in aging mice really, and it is many and long that its errors number and trip reach all more young normal mouse of required time of security platform.But behind oral 0.625mg/kg (+) hydrastine, no matter be buck, or jenny, no matter be the time of arriving at security platform, the number of times that still makes a mistake has all shown the effect that improves and strengthen learning and memory.Not only compare significant difference, arrive at the time of security platform and the number of times that makes a mistake even all lack and lack than normal young control with the normal aged animal of not administration.
Except the ability of the learning and memory of above-mentioned raising animal, the present invention finds that also (+) hydrastine has tangible oxygen lack resistant function.No matter be an oral administration, or successive administration 30 days, all can prolong the life span of Hypoxia and ischemia animal head, and demonstrate dose-effect relationship preferably.
In addition, (+) hydrastine toxicity is low, and therapeutic dose is safe.
Therefore the present invention also relates to and containing as the chemical compound of the present invention of active ingredient and the pharmaceutical composition of conventional medicine excipient or adjuvant.Usually pharmaceutical composition of the present invention contains the The compounds of this invention of 0.1-95 weight %.
The pharmaceutical composition of The compounds of this invention can be according to method preparation well known in the art.When being used for this purpose, if desired, chemical compound of the present invention and one or more solids or liquid medicine excipient and/or adjuvant can be combined, make and can be used as suitable administration form or the dosage form that people's medicine or veterinary drug use.
The compounds of this invention or contain its pharmaceutical composition can the unit dosage form administration, route of administration can be intestinal or non-intestinal, as oral, muscle, subcutaneous, nasal cavity, oral mucosa, skin, peritoneum or rectum etc., preferred oral.
The compounds of this invention or the route of administration that contains its pharmaceutical composition can be drug administration by injection.Injection comprises intravenous injection, intramuscular injection, subcutaneous injection and intradermal injection etc.
Form of administration can be liquid dosage form, solid dosage forms.As liquid dosage form can be true solution class, colloidal type, particulate formulations, emulsion dosage form, mixed suspension form.Other dosage forms are tablet, capsule, drop pill, aerosol, pill, powder, solution, suspensoid, Emulsion, granule, suppository, lyophilized injectable powder etc. for example.
The compounds of this invention can be made ordinary preparation, also can be slow releasing preparation, controlled release preparation, targeting preparation and various particulate delivery system.
For the unit form of administration is made tablet, can be extensive use of various carrier well known in the art.Example about carrier is, for example diluent and absorbent are as starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, glucose, carbamide, calcium carbonate, kaolin, microcrystalline Cellulose, aluminium silicate etc.; Wetting agent and binding agent are as water, glycerol, Polyethylene Glycol, ethanol, propanol, starch slurry, dextrin, syrup, Mel, glucose solution, mucialga of arabic gummy, gelatine size, sodium carboxymethyl cellulose, lac, methylcellulose, potassium phosphate, polyvinylpyrrolidone etc.; Disintegrating agent, for example dry starch, alginate, agar powder, laminaran, sodium bicarbonate and citric acid, calcium carbonate, polyoxyethylene sorbitol fatty acid ester, dodecyl sodium sulfate, methylcellulose, ethyl cellulose etc.; Disintegrate inhibitor, for example sucrose, glyceryl tristearate, cocoa butter, hydrogenation wet goods; Absorption enhancer, for example quaternary ammonium salt, sodium lauryl sulphate etc.; Lubricant, for example Pulvis Talci, silicon dioxide, corn starch, stearate, boric acid, liquid paraffin, Polyethylene Glycol etc.Tablet further can also be made coated tablet, for example sugar coated tablet, thin membrane coated tablet, ECT, or double-layer tablet and multilayer tablet.
For example, can be extensive use of various carrier well known in the art for pill is made in the administration unit.Example about carrier is, for example diluent and absorbent are as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, polyvinylpyrrolidone, Gelucire, Kaolin, Pulvis Talci etc.; Binding agent is as arabic gum, Tragacanth, gelatin, ethanol, Mel, liquid sugar, rice paste or batter etc.; Disintegrating agent is as agar powder, dry starch, alginate, dodecyl sodium sulfate, methylcellulose, ethyl cellulose etc.
For example for capsule is made in the administration unit, the effective ingredient The compounds of this invention is mixed with above-mentioned various carriers, and the mixture that will obtain thus places hard gelatine capsule or soft capsule.Also the effective ingredient The compounds of this invention can be made microcapsule, be suspended in and form suspensoid in the aqueous medium, in the hard capsule of also can packing into or make injection and use.
For example, The compounds of this invention is made injection preparation, as solution, suspensoid solution, Emulsion, lyophilized injectable powder, this preparation can be moisture or non-water, can contain acceptable carrier, diluent, binding agent, lubricant, antiseptic, surfactant or dispersant on a kind of and/or multiple pharmacodynamics.Can be selected from water, ethanol, Polyethylene Glycol, 1 as diluent, the isooctadecanol of ammediol, ethoxylation, the isooctadecanol of polyoxyization, Polyoxyethylene Sorbitol Fatty Acid Esters etc.In addition, ooze injection, can in injection preparation, add proper amount of sodium chloride, glucose or glycerol, in addition, can also add conventional cosolvent, buffer agent, pH regulator agent etc. in order to prepare etc.These adjuvants are that this area is commonly used.
In addition, as needs, also can in pharmaceutical preparation, add coloring agent, antiseptic, spice, correctives, sweeting agent or other material.
For reaching the medication purpose, strengthen therapeutic effect, medicine of the present invention or pharmaceutical composition can be with any known medication administrations.
The dosage of The compounds of this invention, pharmaceutical composition depends on many factors, for example to prevent or treat the character and the order of severity of disease, the sex of patient or animal, age, body weight, personality and individual reaction, route of administration, administration number of times, therapeutic purposes, therefore therapeutic dose of the present invention can have large-scale variation.In general, the using dosage of Chinese materia medica composition of the present invention is well known to a person skilled in the art.Can be according to the actual drug quantity that is contained in the preparation last in the The compounds of this invention compositions, in addition suitable adjustment to reach the requirement of its treatment effective dose, is finished prevention of the present invention or therapeutic purposes.The consumption of the suitable dose scope chemical compound of the present invention of the every day of The compounds of this invention is the 0.001-150mg/kg body weight, is preferably the 0.01-100mg/kg body weight, and more preferably the 0.01-60mg/kg body weight most preferably is the 0.1-10mg/kg body weight.Above-mentioned dosage can the single dose form or be divided into several, for example two, three or four dosage form administrations this be subject to administration doctor's clinical experience and comprise the dosage regimen of using other treatment means.
Each treats that required accumulated dose can be divided into repeatedly or by the dose administration.Chemical compound of the present invention, compositions can be taken separately, or merge use and adjust dosage with other treatment medicine or symptomatic drugs.
The specific embodiment
The following examples are used for further specifying the present invention, but this and do not mean that any limitation of the invention.
Darkness avoidance test: belong to disposable training passive avoidance experiment, this method utilizes mice to have a liking for dark habit design.Experimental provision is divided into light and shade two Room, has a hole to connect, and bright chamber is the place of safety, does not have; The darkroom is the electric shock district, and the bottom is the copper grid, passes to 40 volts of alternating currents.Animal creeps into the darkroom and is promptly shocked by electricity, and flees back bright chamber and can hide noxious stimulation.Experiment is divided into to be carried out in two days, and first day is training, test after 24 hours.Acquisition that this promptly remembers and maintenance test, the number of times that the record mice is shocked by electricity is as the percentage rate (i.e. the number of elements of the mice that appearance is wrong accounts for the percentage rate of this group mice number of elements) of errors number and mistake in computation.Mice from counting begin to the time that enters for the first time the darkroom be incubation period.Mistake is few, long show memory well incubation period, and mistake is many, lack show poor memory incubation period.
Maze learning is a kind of identification learning of locus.Depth of water 10cm in the water maze, water temperature is controlled at about 25 ℃, has a cat ladder, animal to climb out of the water surface in the target area and obtains to have a rest.Experiment divides three phases to carry out.Phase I at the A place, makes animal begin training from A on the baffle plate retaining, and only as training usefulness, the 1-2 time, time and errors number do not take statistics at the A place.Prolong the swimming path of animal starting area to target area gradually, increase the cecum district simultaneously.Second stage at the B place, makes animal begin training, the 3-6 time from B on the baffle plate retaining.Phase III, at the C place, make animal begin training, the 7-9 time on the baffle plate retaining from C.See sketch map, 1,2,3,4 is cecum among the figure, and animal is swum into cecum and represents mistake.The time that arrives the ladder security platform from each training is the needed time of swimming.The number of times that enters cecum is few, and short expression of the time of swimming required learning and memory is good.Otherwise then poor, or be referred to as learning memory disorder.This method can detect the ability of animal spatial orientation and learning and memory.
Alzheimer disease is lost the most serious with the basal forebrain cholinergic neuron, cause the acetylcholine hyposecretion.Scopolamine is the M cholinergic receptor-blocking agent, can suppress the agonism of acetylcholine to m receptor, therefore can imitate the insufficient result of cholinergic function, is one of animal model of research alzheimer disease.
HDST: the abbreviation that is (+) hydrastine.
SCOP: the abbreviation of expression scopolamine.
NMDP: the abbreviation of nimodipine.
Tac: the abbreviation of tacrine.
PTB: the abbreviation of pentobarbital sodium.
The unit of all dosage is mg/kg.
Embodiment 1 (+) hydrastine causes the effect of memory acquisition disturbance (to keep away to scopolamine
Dark method)
50 of kunming mices are divided into 5 groups at random: the normal control group, scopolamine destroys memory models group, (+) hydrastine 0.075mg/kg, 0.15mg/kg, three dosage groups of 0.30mg/kg.Compare with the normal control group, behind the lumbar injection scopolamine 1.0mg/kg, make wrong percentage rate reach 60%, shortened 90 seconds incubation period, remarkable with the matched group comparing difference, the learning and memory that the prompting scopolamine can significantly destroy animal obtains.After the abdominal cavity awards (+) hydrastine in advance, train, the test of reforming after 24 hours the results are shown in Table 1
Table 1
Group dosage errors number incubation period (second) mistake %
Normal control group 0.0 ± 0.0 299.0 ± 0.0 0
SCOP 1.0 0.6±0.5
++?210.0±84.4
++?60
++
HDST+SCOP 0.075+1.0 0.4±0.5 231.2±93.0 40
HDST+SCOP 0.15+1.0 0.0±0.0 299±0.0
** 0
**
HDST+SCOP 0.30+1.0 0.4±0.7 262.7±62.4 30
N=10, X ± SD, ++ P＜0.01 vs matched group, * * P＜0.01 vs SCOP
Experimental result is presented in advance the abdominal cavity and awards behind (+) hydrastine 0.15mg/kg lumbar injection scopolamine 1.0mg/kg again, and the number of times of mistake is 0%.Incubation period is identical with the normal control group, returns to the level of normal group fully, illustrates to have reversed the detrimental effect that scopolamine obtains mouse memory fully.Illustrate that (+) hydrastine can effectively improve the learning and memory obstacle that the anticholinergic agent scopolamine causes.
Embodiment 2 (+) hydrastine causes the effect of memory acquisition disturbance (to keep away to pentobarbital sodium
Dark method)
60 of kunming mices are divided into 6 groups at random: the normal control group, pentobarbital sodium destroys memory models group, tacrine group, (+) hydrastine 0.075mg/kg, 0.15mg/kg, three dosage groups of 0.30mg/kg.Subcutaneous injection pentobarbital sodium 25mg/kg can destroy learning and memory in rats and mice significantly, and shortened to 65.9 second from 275.8 seconds incubation period, and the percentage rate of mistake is increased to 90% from 10%.The results are shown in Table 2
Table 2
Group dosage errors number incubation period (second) mistake %
Matched group 0.1 ± 0.3 275.8 ± 69.6 10
PTB 25 1.4±1.0
++?65.9±84.8
++ 90
++
Tac+PTB 1.5+25 1.3±0.7 57.5±52.9 100
HDST+PTB 0.075+25?1.1±0.8 89.2±113.5 70
HDST+PTB 0.15+25 0.4±0.5* 220.8±103.8** 40*
HDST+PTB 0.30+25 0.6±0.5* 178.0±108.0* 60
N=10, X ± SD, ++ P＜0.01 vs matched group, * P＜0.05 vs PTB, * * P＜0.01 vsPTB.
Lumbar injection (+) hydrastine 0.15mg/kg incubation period is 220.8 seconds, and the number of times of mistake is 40%, with model group P＜0.01 and＜0.05 relatively, significant difference.Tacrine 1.5mg/kg does not show any effect, and be 57.5 seconds incubation period, and the percentage rate of mistake is 100%.Illustrate that (+) hydrastine can effectively improve the learning and memory obstacle that pentobarbital sodium causes, and be better than tacrine.
The influence of the learning memory disorder that embodiment 3 (+) hydrastine causes pentobarbital sodium
(water maze test)
60 of kunming mices, be divided into 6 groups at random: the normal control group, pentobarbital sodium lumbar injection 15mg/kg destroys the memory models group, nimodipine (Nimodipine, NMDP) group, the oral 2.5mg/kg of (+) hydrastine, 1.25mg/kg, three dosage groups of 0.625mg/kg (be respectively median lethal dose(LD 50) 1/10,1/20,1/40).Experimental result shows that pentobarbital sodium 15mg/kg is broken to have encircled ability of learning and memory in mice, swims to compare with 12.2 seconds of matched group to have prolonged 1/3 to time of security platform, and be 18.0 seconds, significant difference (P＜0.05).The number of times of mistake is 2.4, and comparing to some extent than matched group (1.7 times) increases, but statistical discrepancy is not remarkable.The results are shown in Table 3
Table 3
Group dosage (mg/kg) errors number time (second)
Matched group 1.7 ± 0.6 12.2 ± 4.3
PTB 15 2.4±1.0 18.0±8.0+
NMDP+PTB 1.0+15 2.1±1.3 15.2±6.7
HDST+PTB 0.625+15 1.0±0.5** 8.7±2.4**
HDST+PTB 1.25+15 2.0±1.4 13.4±7.2
HDST+PTB 2.50+15 1.8±1.4 13.6±9.2
N=10, X ± SD ,+P＜0.05 vs matched group, * * P＜0.01vs PTB.
Oral 0.625mg/kg (+) hydrastine group is swum to the platform time and has only been spent 8.7 seconds, has not only shortened nearly 10 seconds than model group, and lacks than the normal control group and to have spent 3.5 seconds.Errors number 1.0 is also lacked 0.7 time than the normal control group.With model group ratio, difference highly significant, the P value all＜0.01.And oral 1mg/kg nimodipine group is swum to the not shortening of platform time, though errors number has minimizing, statistical disposition is all not remarkable.Illustrate that (+) hydrastine can effectively improve the learning and memory obstacle that pentobarbital sodium causes, and be better than nimodipine.
Embodiment 4 (+) hydrastine is to the influence (water maze test) of normal learning and memory of little mouse
50 of kunming mices are divided into 5 groups at random, 10 every group: normal control group, oral nimodipine 1mg/kg group, oral (+) hydrastine 0.625mg/kg, 1.25mg/kg, three dosage groups of 2.5mg/kg.Just allow for the 1st and the 2nd time animal be familiar with the condition training, do not note down.The results are shown in following table 4
Table 4 (+) hydrastine is to the influence of normal learning and memory of little mouse
The errors number of dosage B place test
Group (mg/kg) 3456
Matched group 3.9 ± 1.9 2.6 ± 1.4 2.3 ± 1.6 1.6 ± 0.8
NMDP 1 3.2±1.1 1.5±0.7** 1.6±1.5 0.8±0.7*
HDST 0.625 2.4±1.3 1.2±0.5** 0.8±6.4** 0.3±0.4**
HDST 1.25 2.2±0.8** 1.6±0.6** 1.2±0.8* 0.8±0.7*
HDST 2.50 2.5±0.8** 1.8±0.7* 1.0±0.6** 0.8±0.5**
N=10, X ± SD, * P＜0.05, * * P＜0.01 vs matched group.
The swimming time (second) of dosage B place test
Group (mg/kg) 3456
Matched group 24.3 ± 12.1 16.5 ± 13.1 13.1 ± 8.7 9.2 ± 3.9
NMDP 1 20.0±7.4 13.0±5.7 11.4±9.2 8.0±2.5
HDST 0.625 15.9±5.7* 9.5±1.6* 8.4±3.1* 6.9±2.1
HDST 1.25 12.6±3.2** 9.9±3.0* 9.6±2.7 8.2±2.0
HDST 2.50 20.0±11.4 13.6±7.4* 9.5±23.6 8.2±2.9
N=10, X ± SD, * P＜0.05, * * P＜0.01 vs matched group.
From the result of table 4 as can be seen (+) hydrastine show the improvement effect when the 3rd test.No matter be that errors number is few than normal group, swimming time is also short than normal group, demonstrates tangible nootropic effect.The nimodipine of 1mg/kg also has certain nootropic effect, but it is strong to be not so good as 0.625mg/kg (+) hydrastine.
Embodiment 5 (+) hydrastine and nimodipine, piracetam are to normal learning and memory of little mouse
The comparison (water maze test) of effect
40 of kunming mices are divided into 4 groups at random, 10 every group: normal control group, oral nimodipine 1mg/kg group, oral piracetam 400mg/kg group, oral (+) hydrastine 0.625mg/kg group.Just allow for the 1st and the 2nd time animal be familiar with the condition training, do not note down.The results are shown in following table
Table 5 (+) hydrastine and nimodipine, piracetam
Comparison to the effect of normal learning and memory of little mouse
The dosage errors number
Group mg/kg 345678
Matched group 5.56 ± 2.31 4.2 ± 2.63 1.9 ± 1.63 1.65 ± 1.18 1.58 ± 0.1 1.06 ± 0.5
HDST 0.625 3.24±1.09** 2.05±1.16* 1.79±0.89 0.6±0.39* 0.8±0.5* 0.61±0.46
NMDP 1 4.45±3.15 2.7±2.85 2.5±2.76 1.1±0.59 1.06±0.7 1.17±0.77
Piracetam 400 3.71 ± 2.49 2.12 ± 2.28 1.87 ± 1.08 1.06 ± 0.26 1.23 ± 0.6 1.37 ± 0.73
N=10, X ± SD, * P＜0.05, * * P＜0.01 vs matched group.
Dosage swimming time (second)
Group mg/kg 345678
Matched group 37.6 ± 14.86 38.4 ± 24.9 16.7 ± 10.9 15.27 ± 9.53 17.33 ± 8.6 10.5 ± 3.47
HDST 0.625 23.01±6.19** 14.9±4.04* 17.1±8.5 8±1.56* 8.73±2.01** 8.8±2.37
NMDP 1 28.9±17.67 18.49±14.85* 15.9±12.2 11.3±4.5* 10.37±3.95* 12.19±4.41
Piracetam 400 25.24 ± 12.31 17.76 ± 13.52* 15.6 ± 5.6 10.3 ± 2.38 11.54 ± 2.46 13.7 ± 4.35
N=10, X ± SD, * P＜0.05, * * P＜0.01 vs matched group.
Oral as can be seen 0.625mg/kg (+) hydrastine still shows fabulous nootropic effect from the result of table 5.The time of its wrong number of times and arrival security platform almost has only half of normal young matched group.Nimodipine also has certain effect, but it is obvious to can not show a candle to (+) hydrastine.The piracetam of oral 400mg/kg has the trend that strengthens ability of learning and memory, but statistical disposition difference does not have significance.Illustrate that (+) hydrastine is better than nimodipine, piracetam to the effect of normal learning and memory of little mouse.
Embodiment 6 (+) hydrastine is to the influence (water maze of male aged mouse learning and memory
Test)
Male aged mouse is planted a Mus for breeding old and feeble eliminating, and is continued to feed 4-6 month by the inventor.40 of male aged kunming mices, 10 of normal young mices are tested with water maze.Experimental result sees Table 6
Table 6 (+) hydrastine is to the influence of male aged mouse learning and memory
The errors number of dosage B place test
Group mg/kg 345678
Aged matched group 4.40 ± 2.06 2.50 ± 1.56 3.33 ± 2.67 2.60 ± 2.43 1.73 ± 1.40 0.89 ± 1.15
HDST 0.625 2.51±1.09* 1.07±0.59* 1.26±0.87* 0.56±0.33 0.92±0.82 0.56±0.44
HDST 1.25 2.10±0.73** 1.50±0.84 1.78±1.14 1.66±1.09 1.30±0.48 0.88±0.60
HDST 2.50 2.23±1.43 1.23±1.29 1.30±1.08 0.80±1.13 0.92±0.82 0.80±0.24
Young control: 2.65 ± 0.99 1.85 ± 0.66 2.80 ± 1.40 1.30 ± 1.02 1.51 ± 1.05 0.89 ± 0.74
N=10, X ± SD, * P＜0.05, * * P＜0.01 vs 01d (aged matched group).
The swimming time (second) of B place test
Group dosage 345678
Aged matched group 30.93 ± 14.29 23.70 ± 13.45 31.23 ± 20.58 23.04 ± 15.40 18.66 ± 14.72 15.56 ± 10.50
HDST 0.625 21.40±7.84 14.26±4.35 14.36±5.31* 11.03±2.18* 12.20±3.40 12.72±4.27
HDST 1.25 22.29±8.49 15.43±6.36 17.14±8.20 18.78±9.33 16.21±7.04 14.13±5.85
HDST 2.50 17.22±9.49 14.23±7.24 12.05±7.43 10.74±6.57 12.54±3.99 11.20±3.96
Young control: 18.93 ± 6.13* 18.00 ± 7.98 19.34 ± 8.44 13.31 ± 4.99 17.14 ± 8.45 12.06 ± 5.04
N=10, X ± SD, * P＜0.05, * * P＜0.01 vs 01d (aged matched group).
From table the result as can be seen, aged male mice is poorer than young learning and memory abilities in aging mice really, it is many and long that its errors number and trip reach all more young normal mouse of required time of security platform.But aged Mus its wrong number of times after taking (+) hydrastine 0.625mg/kg almost has only aged Mus half.The 6th time, its errors number is 1/5 (0.56 ratio 2.60 times) of aged Mus, and shows shorter and lack than young normal control group once more.
Embodiment 7 (+) hydrastine is to the influence (water maze of female aged mouse learning and memory
Test)
Female aged mouse is planted a Mus for breeding old and feeble eliminating, and is continued to feed 4-6 month by the inventor.40 of female aged kunming mices, 10 of normal young mices are tested with water maze.Experimental result sees Table 7
Table 7 (+) hydrastine is to the influence of female aged mouse learning and memory
The errors number of B place test
Group dosage 3456789
Aged matched group 3.41 ± 1.43 2.83 ± 1.29 1.97 ± 0.96 0.99 ± 0.87 1.43 ± 0.73 1.21 ± 0.81 0.75 ± 0.68
HDST 0.625 2.73±1.29 1.26±1.06** 1.12±0.71* 0.90±0.49 0.81±0.67 1.11±0.84 0.65±0.87
HDST 1.25 2.05±0.68 1.74±1.00 1.28±0.44 1.24±0.67 1.56±1.01 1.23±0.73 1.05±0.96
HDST 2.50 1.88±0.82 2.16±1.00 1.16±0.76 1.63±1.07 1.38±1.05 1.18±0.70 0.69±0.66
Young control: 2.20 ± 0.87 1.97 ± 0.81 2.19 ± 0.99 1.23 ± 0.73 1.38 ± 1.07 1.52 ± 0.68 0.85 ± 0.45
N=10, X ± SD, * P＜0.05, the aged matched group of * * P＜0.01 vs.
The swimming time (second) of B place test
Group dosage 3456789
Aged matched group 29.36 ± 10.95 24.95 ± 12.38 19.53 ± 10.14 14.07 ± 7.51 16.20 ± 6.62 12.98 ± 3.95 11.65 ± 2.92
HDST 0.625 21.13±10.45 13.70±7.51* 11.63±3.63* 10.60±3.62 10.63±3.05* 11.07±4.60 10.65±5.39
HDST 1.25 16.58±3.50** 19.34±6.50 14.09±5.30 14.26±4.39 14.37±5.55 12.11±2.79 12.25±4.53
HDST 2.50 18.89±7.00* 23.13±6.84 17.34±8.56 18.39±8.18 14.96±4.83 13.45±3.08 12.00±4.49
Young contrast 16.71 ± 6.31** 17.53 ± 5.37 16.27 ± 6.03 12.16 ± 5.99 13.56 ± 5.91 13.94 ± 3.68 10.95 ± 3.34
Group:
N=10, X ± SD, * P＜0.05, the aged matched group of * * P＜0.01 vs.
Table 7 experimental result shows similar substantially to aged male Mus, just a little less than the effect slightly.The result of consolidated statement 6 and table 7 can affirm that (+) hydrastine has the amnemonic effect of the aged animal learning of improvement.
Embodiment 8 (+) hydrastine oral administration is to the influence of mice hypoxia-bearing capability
40 of kunming mices are divided into 4 groups at random, 10 every group: normal control group, oral (+) hydrastine 0.625mg/kg, 1.25mg/kg, three dosage groups of 2.5mg/kg.Use 380ml ground transparent agent bottle, mice is put into bottle, cover tight bottle stopper and seal observation mice time-to-live in bottle with vaseline.Each administration group is carried out the t check with the normal control group respectively.
Oral administration of table 8a (+) hydrastine is to the influence of mice oxygen-resistant ability.
Group dosage body weight (gram) time-to-live (minute)
Matched group 23.0 ± 0.9 45.0 ± 6.4
Hydrastine 0.625 23.0 ± 0.8 47.8 ± 10.6
Hydrastine 1.25 22.3 ± 1.2 50.5 ± 5.3
*
Hydrastine 2.50 22.5 ± 0.8 54.0 ± 6.7
*
N=10, X ± SD, * P＜0.05, * * P＜0.01 vs matched group.
Continuous 30 days oral administrations of table 8b (+) hydrastine are to the influence of mice oxygen-resistant ability.
The group dosage time-to-live (minute)
Matched group 24.0 ± 3.4
Hydrastine 0.625 26.6 ± 1.7
Hydrastine 1.25 31.4 ± 3.1
*
Hydrastine 2.50 31.0 ± 3.9
*
N=10, X ± SD, * P＜0.05, * * P＜0.01 vs matched group.
Test explanation (+) hydrastine has tangible oxygen lack resistant function.No matter be an oral administration, or continuous oral administration 30 days, all can prolong the life span of Hypoxia and ischemia animal head, and demonstrate dose-effect relationship preferably.
Toxicity (the LD of embodiment 9 (+) hydrastine
50
)
Iv intravenous injection 0.27 (0.25-0.29) mg/kg
Ip lumbar injection 2.85 ± 0.39mg/kg
Po oral administration 25.8 ± 1.0mg/kg
Claims (6)
1, the application of (+) hydrastine shown in general formula (I) in the medicine of preparation prevention or treatment dementia:
2, the application of (+) hydrastine shown in general formula (I) in the preparation nootropics:
3, the application of (+) hydrastine shown in general formula (I) in the preparation anti-anoxic medicine:
According to the application of claim 1 or 2 or 3, it is characterized in that 4, described chemical compound comprises acceptable salt on stereoisomer and the pharmacodynamics.
5, a kind of pharmaceutical composition is characterized in that, contain medicine effective dose as the described arbitrary chemical compound of claim 1-3, and pharmaceutical carrier.
According to the pharmaceutical composition of claim 5, it is characterized in that 6, described pharmaceutical composition can be tablet, capsule, pill, injection, slow releasing preparation, controlled release preparation and various particulate delivery system.
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