CN1565441B - Use of levobutylphthalide in prevention and cure of dementia - Google Patents
Use of levobutylphthalide in prevention and cure of dementia Download PDFInfo
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Abstract
The invention discloses the use of levogyration n-butyl benzene phthaleins in preparing medicament for preventing and treating aphrenia, in particular Hammer disease and blood vessel aphrenia.
Description
Technical field
The present invention relates to the purposes of the L-NBP and the treatment dementia of the compositions that contains L-NBP.
Background technology
Alzheimer disease or claim Alzheimer (Alzheimer ' s disease, AD) be a kind of be the carrying out property degeneration neuropathy of feature with clinical and pathology.Its clinical manifestation is mainly memory (particularly near memory) goes down, and cognitive competence is low, bradyphrenia, spatial disorientation etc.Pathological manifestations is that beta amyloid peptide (A β) is formed neurofibrillary tangle in the extracellular is deposited as senile plaque and cell (neurofibrillarytangles, formation NFT) with other molecule, neuron and non-neurocyte.China's AD prevalence is between 0.2%～5.98%, and this disease mostly occurs the crowd more than 60 years old.Increase with the age, the existing AD patient of China is more than 3,600,000 people according to estimates.Investigate dull-witted sickness rate in the Beijing area and find that vascular dementia (VD) is more than AD.(Zhang Mingyuan etc.: the sickness rate of dementia and Alzheimer.China's psychiatric department magazine 1998; 31 (4): 195-196) because China has entered aging period, dementia patients increases year by year.And the cerebrovascular incidence rate is very high in elderly population, and dull-witted morbidity finally is about 9～30.8% after the apoplexy according to estimates, and long-term cerebral blood supply insufficiency also is the major reason that causes vascular dementia.In a word, dementia patients is not only very painful to me, and very big to the burden of family and society, and therefore seeking active drug is very important with the development that delays, controls the AD and the VD state of an illness.
Alzheimer (AD) is the main reason that carrying out property of old people's cognitive function goes down.Its main pathological change is to form with beta amyloid peptide (β-amyloid, A β) to be deposited as the senile plaque of core and nerve fiber around knot.Studies show that cholinergic system is relevant with people's learning and memory function in the brain.The ACh level descends in patient's AD brain, and the activity of the choline acetyltransterase (ChAT) of the synthetic ACh of catalysis is low, and its reduction degree and cognitive decrease are closely related.In addition, the cause of disease of oxidative stress and inflammatory reaction participation AD also more and more comes into one's own.A β is made up of 39-43 aminoacid, is the catabolite of β precursor protein (APP).Sedimentary scope of A β and nerve injury and cognitive function are damaged closely related.Previously studies confirm that: tricorn perfusion (i.c.v.) A β (1-40) or A β (1-42) can cause rat learning and memory damage (Nitts.et al. β-Amyloid protein-induced Alzheimer ' s disease animalmodel.Neurosci.Lett.1994 constantly; 170:63-66), the memory impairment that the A beta peptide aggregation is caused in the prompting brain can be simulated patient's AD symptom.After deliberation, L-NBP (L-NBP) can obviously improve mitochondrial function, improves brain microcirculation and energy metabolism; suppress neuronal apoptosis, anti-oxidative damage, inflammation-inhibiting reaction; antithrombotic reduces intracellular Ca2+, suppresses the cerebral protections such as release of glutamic acid.For this reason, can select for use lasting tricorn perfusion (i.c.v.) A β (1-40) as model.Detect that institute's chemical compound that try is closely remembered animal and locus memory function and with Morris water maze and biochemical method to the influence of oxidative damage.
Vascular dementia (VD) is owing to cerebrovascular disease causes the dementia that disordered brain function produces, most bigger cerebral arteries infraction or lacunar infarction or the low fillings of brain with pilosity.Cerebral blood flow reduces relevant (the Roman et al.Vascular dementia:diagnosticcriteria for research studies.Neurology 1993 with severity of dementia of degree; 43:250-260).The chronic progressive external cerebral blood supply insufficiency, make it to oxygen and glucose and other essential metabolite utilizations decline, its result causes oxidative damage, the biosynthesis of mitochondrial function and neurocyte is impaired, the synapse propagation function is obstructed, cause the neuro pathology to change at last, nervus retrogression promptly takes place change (Beal et al.Do defects in mitochondrial metabolism underlie the pathology of neurodegenerativedisease Trends Neurosci.1993; 16:125-131).It is damaged that patient VD mainly shows as nearly memory and spatial perception carrying out property decline and cognitive function.The information of the generation of vascular dementia and development and cholinergic nerve system is transmitted closely related, and also the oxidative damage with neurocyte is relevant, and patient's VD subcortical white is sparse on pathology.Studies show that in a large number ACh is considered to the important neurotransmitter of learning and memory.Patient's AD cholinergic access function reduces, show as neurotransmitter ACh level and descend, this is that its memory function is undermined one of major reason of cognitive impairment (Toghi et al.Cerebrospinal fluid acetylcholine and choline in vascular dementia ofBinswanger and multiple small infarct types as compared with Alzheimer-type dementia.J.Neural Transm.1996; 103:1211-1220).The chemical compound that tries has the raising effect to the ChAT activity, illustrates that it can make cholinergic nerve ACh level increase, and helps improving memory function.Over surplus in the of nearly ten year, a lot of laboratorys can reflect impaired and changes of function (the Richard Morris.Developments of a water-maze procedure for studying spatiallearning in the rat J.Neurosei Methods.1984 of animal central nervous system observantly with the memory of nearly memory of Morris determined with Morris water rat and locus; 11:47-60), and observe the effect of medicine to this model.Because dull-witted patient mainly shows as cognitive impairment, particularly to the carrying out property damage of nearly memory and spatial perception.Therefore to can yet be regarded as that a comparatively ideal observation medicine has presenile dementia (AD) and VD deny medicative model to this model.Can simulate the vascular dementia that blood supply insufficiency clinically causes and continue low filling, therefore can reflect effect (the Ni.J.W.et al.Neuronal damage anddecrease of central acetylcholine level following permanent occlusion bilateral commoncarotid arteries in rats.Brain Res.1995 of Drug therapy dementia with this law with rat bilateral common carotid arteries blocking-up (2-VO) model; 673:290-296).
1988 in the Butylphthalide (3-n-butylphthalide of timely rain core report; Ag-1) be synthetic raceme 3-n-butylphthalide; it causes rat learning and memory obstacle that the improvement effect is arranged to coriamyrtin; the rat hippocampus cell is had protective effect, and (in timely rain core etc.: Butylphthalide strengthens the effect Acta Pharmacologica Sinica 1988,9 (5) of learning and memory: 385-388).After this, have report think Herba Apii graveolentis extracting solution centering Aged Mice learning and memory have the improvement effect (Li Jing wait Herba Apii graveolentis extracting solution centering Aged Mice learning and memory influence Chinese herbal medicine 1996,27 (2): 104-105; Liu Luosheng etc.: quality standard research Shandong Medical University journal 2001,39 (6) of pacifying clear Cognex: 562-564), but do not see the report that optical stereo isomer-L-NBP (L-NBP) is treated alzheimer disease so far as yet.
Summary of the invention
In order to overcome the deficiencies in the prior art, the invention provides shown in general formula (I)
L-NBP (hereinafter to be referred as L-NBP) as the application of the medicine of dementia.
The used L-NBP of the present invention is through chemosynthesis, obtain racemization normal-butyl Phthalide earlier, after splitting, chemistry becomes left-handed rotation isomer normal-butyl Phthalide, pass through nuclear-magnetism, mass spectrum and spectrum analysis such as infrared, particularly use Hp 5890 gas chromatograpies, chirality gas chromatographic column (Chiraldex G-TA) is analyzed, proof optical purity of this product and chemical purity are single optical stereo isomer-L-NBP (specific rotatory power＞-66.49 °, optical purity＞98%, chemical purity＞98%), method for splitting is referring to Chinese patent " method for preparing the optical activity 3-n-butylphthalide ", application number 99109673.8, publication number CN1283621.The chemical structural formula of this product be with eat Herba Apii graveolentis and seed thereof in contained Butylphthalide structure identical.
The present invention promptly detects nearly memory of animal and spatial orientation power with the Morris water maze laboratory with the method for generally acknowledging in the world.
The present invention causes the lasting low model of irritating by setting up permanent blocking-up rat bilateral common carotid arteries (2-VO), detect the influence of L-NBP with Morris water maze method, detected L-NBP to some index of oxidative damage with to the neural influence of cholinergic nerve with biochemical method to nearly memory of animal and locus function.Activate in view of brain low filling causing behavior change is accompanied by the brain glial cell, white matter is thinning dredges.So this research pathology and immunohistochemical method, as index, having observed medicine influences it to use glia fiber acidic protein (GFAP) and K-B dyeing (pathological change of reflection neuron myelin).
Experiment of the present invention shows nearly memory and the locus dysfunction for the cerebral blood supply insufficiency rat, and L-NBP tool of the present invention improves significantly.The study of water maze test and reservation experiment are often used in the spatial memory ability that thinks poorly of the perfusion rat.Experimental result is presented in the water maze laboratory, and in training in first day, do not have significant difference incubation period between each group, illustrate all animals the mat woven of fine bamboo strips one day to this experimental implementation and be unfamiliar with.Through 5 days training, the search strategy of sham operated rats turned to trend formula and orthoscopic from marginal mode and random mode, and obviously shorten incubation period (12.6 ± 3.34 seconds), illustrated that animal via crosses training and had certain memory and spatial orientation power.And the search strategy of solvent control group does not significantly change, and still is marginal mode and random mode, and obviously do not shorten incubation period (47.6 ± 5.88 seconds), compares significant difference (P＜0.01) for two groups.The search strategy of L-NBP10mg/kg group turns to trend formula and orthoscopic from marginal mode and random mode, shorten incubation period (26.85 ± 5.98 seconds) obviously, with the solvent control group notable difference (P＜0.001 liang factor variance analysis) is arranged relatively, and relatively do not have significant difference with sham operated rats, illustrate that this dosage group is to memory and the effect of having clear improvement of spatial orientation power.Other medicines such as DL-NBP10 mg/kg, the improvement effect of DL-NBP30 mg/kg and D-NBP 30 mg/kg is all not obvious.
After 5 days learning trainings finish, carry out platform and explore experiment, safety island is removed with the test rat whether formed spatial memory to safety island.Desolventize outside the matched group, all rats time of staying of target quadrant all greater than 25%, show the memory that has all formed the relative position of safety island.The time of staying of sham operated rats is 17.73 ± 1.19 seconds, and the time of staying of group of solvents matched group (14.40 ± 0.73 seconds) obviously shortens.By the one factor analysis of variance statistics, notable difference (P＜0.05) is arranged between two groups.The L-NBP10mg/kg group obviously prolongs (17.62 ± 1.27 seconds) in the time of staying of platform place quadrant than the solvent control group, compares significance (P＜0.05) between two groups.DL-NBP group (10mg/kg and 30mg/kg) does not all have effect.In order to get rid of animal sports ability it is influenced, after measured, swimming rate zero difference between each group.More than explanation has only L-NBP that nearly memory and the locus functional impairment of cerebral blood supply insufficiency rat are had obvious effect, and racemization and dextrorotation normal-butyl Phthalide then do not have effect.
SOD is important antioxidase, and the activity of SOD is 100.07 ± 3.64 (NU/mg protein) in the normal control group cortical tissue; Activity in the hippocampal tissue is 57.90 ± 7.41 (U/mgprotein).Behind the permanent ligation bilateral common carotid arteries of rat, the activity of Hippocampus SOD is compared obvious rising (P＜0.05) with matched group, and this may be a kind of compensatory response.After L-NBP (10mg/kg) treatment, this enzymatic activity is obviously near normal level (P＜0.05).MDA is the sign of lipid peroxidation, can be reflected at the degree of intravital lipid peroxidation, reflects the degree of cell injury indirectly.In this experiment, the content of model group cortex MDA has raise 19.9%, compares with the normal control group to have significant difference (P＜0.001).After L-NBP (10mg/kg) treatment, the content of cortex MDA has obviously reduced by 20.7% (P＜0.001).Behind the permanent ligation bilateral common carotid arteries of rat, the active of cortex ChAT significantly reduces, compare with the normal control group, and 34.4% (P＜0.05) that descended, it is impaired to show that low perfusion can cause the cholinergic nerve function.And L-NBP (10mg/kg) successive administration can make the activity of ChAT in the cortical tissue improve 37.1% than model group after 16 days, had significant difference (P＜0.05).Can be drawn to draw a conclusion by the result: the L-NBP10mg/kg group can obviously be improved the dysmnesia of nearly memory of 2-VO animal and locus, and racemization butylphthalide and dextrorotation butylphthalide are all invalid to improving memory dysfunction.The present invention is the mat woven of fine bamboo strips 10 days beginning administration (always being administered to the 35th day) behind 2-VO, and purpose is to observe medicine to irritate the therapeutical effect that the neuron regression that causes becomes to brain is low, to get rid of the acute low filling influence of ischemic stage.
The present invention has the obvious treatment effect by the research explanation L-NBP of pathology and immunohistochemistry aspect to vascular dementia.Behind the permanent ligation bilateral common carotid arteries, the neuron in visible cortex of model group and Hippocampus CA1 district obviously reduces, cell shrinkage and neuron engrain, and can obviously improve the inductive neuronal damage of low perfusion after L-NBP (10mg/kg) treatment.The bibliographical information bilateral ligation can be induced Glial Activation in the brain, and thin with white matter.White matter is thin generally to be divided into 4 grades by its order of severity: 0 grade, normal; 1 grade, the nerve fiber staggered arrangement; 2 grades, obviously cavity forms; 3 grades, medullated fiber disappears.In our experiment, the normal matched group of the tractus opticus of model group shows that tangible white matter is thin, has a large amount of cavitys to occur, and can significantly improve this situation after L-NBP (10mg/kg) long term administration, and the cavity of tractus opticus obviously reduces.Immunohistochemical experiment finds, the male astrocyte of GFAP-is normal control group Hippocampus, tail nuclear, and positions such as corpus callosum seldom detect, but bilateral ligation is after 4 weeks, and the astrocyte of many GFAP-positive reactions and microglia occur.After L-NBP (10mg/kg) treatment, the male glial cell of GFAP-significantly reduces (seeing Fig. 3,4).In a word, L-NBP has the raising effect to the ChAT activity, and explanation can make cholinergic nerve ACh level increase, and helps improving memory function.Obviously inhibited oxidation damage of L-NBP in addition illustrates that L-NBP can reduce nerve cell damage.The low pathological characters of irritating of brain that is caused by 2-VO is that white matter is sparse, and cavity and glial cell increase (Narri.et al.Chronic cerebral hypoperfusion-indueed neuropathological changes in rats.Jpn.J.Psychopharmacol.1998; 18:181-188), and L-NBP all can improve these pathological changes.More than these mechanism of action L-NBP is improved the dysmnesia that the 2-VO rat causes foundation is provided.According to above result, L-NBP has the obvious treatment effect to vascular dementia.
Experimental result of the present invention shows rat memory and the pilot's vertigo that causes for beta amyloid peptide (1-40), and L-NBP tool of the present invention improves significantly.In the water maze laboratory behind the indoor continous perfusion A of rat brain β, in the training in first day, do not have significant difference an incubation period between each group.Through 5 days training, the search strategy of sham operated rats turned to trend formula and orthoscopic from marginal mode and random mode, and obviously shorten incubation period (13.02 ± 2.77 seconds).And the search strategy of model group does not significantly change, and still is marginal mode and random mode, and obviously do not shorten incubation period (30.18 ± 4.81 seconds), compares significant difference (P＜0.01) for two groups.After the L-NBP treatment, rat obviously shortens the incubation period in water maze test, wherein the search strategy of L-NBP10mg/kg group and 30mg/kg group turns to trend formula and orthoscopic from marginal mode and random mode, be respectively incubation period 27.28 ± 6.42 seconds and 25.88 ± 5.51 seconds, with model group notable difference (P＜0.05 liang factor variance analysis) is arranged relatively, and relatively do not have significant difference with sham operated rats, illustrate that the rat for the treatment of through 1-NBP near normal level, sees Fig. 4.In the working memory test, see Fig. 5 A, B the incubation period of experiment for the first time and the 2-5 time experiment.Though in experiment for the first time, do not have significant difference the incubation period of each group, afterwards in 4 experiments, be 9.15 ± 0.91 seconds the incubation period of sham operated rats, be 14.05 ± 1.88 seconds the incubation period of model group, and the latter obviously prolongs incubation period, and the two has significant difference (P＜0.01).L-NBP group can dose dependent the remarkable working memory ability (P＜0.01) of improving.
L-NBP can also increase the GSH-Px activity and reduce the content of MDA.GSH-Px is important antioxidase, and in our experiment, the activity of GSH-PX is 15.86 ± 0.91 (U/mg protein) in the sham operated rats cortical tissue; Activity in the hippocampal tissue is 16.19 ± 1.19 (U/mg protein).Behind rat A β (1-40) continous perfusion, the activity of GSH-Px is compared with sham operated rats at cortex and Hippocampus and has been reduced by 29.5% and 42.4% respectively, has significant difference (P＜0.01 and P＜0.001).After the L-NBP treatment, the 30mg/kg group obviously raises (P＜0.01) to this enzymatic activity, and L-NBP (10mg/kg) also has the active function of this enzyme that raises, but does not have statistical significance.MDA is the sign of lipid peroxidation, reacts the snperoxiaized degree of body lipid, reflects the degree of cell injury indirectly.In this experiment, the content of cortex and Hippocampus MDA has raise 25.7% and 23.6% respectively behind rat A β (1-40) continous perfusion, compares with sham operated rats to have significant difference (P＜0.05 and P＜0.01).After the L-NBP treatment, the content of cortex and Hippocampus MDA obviously reduces, and the 10mg/kg group has reduced by 28.4% and 24.3% (P＜0.05 and P＜0.01) respectively, and the effect of 30mg/kg is weaker than the 10mg/kg group, but compare with A β (1-40) model group, still have significant difference (P＜0.05).
Experiment of the present invention can draw as drawing a conclusion: it is the observation medicine of generally acknowledging models to the AD therapeutical effect that rat continues dysmnesia that tricorn perfusion A β (1-40) causes.By above result as seen, L-NBP not only causes blood supply insufficiency to cause that the model of vascular dementia has obvious effect to 2-VO, and to the dysmnesia that rat continues nearly memory that tricorn perfusion A β (1-40) causes and the locus effect that also has clear improvement.The effect that all has clear improvement of nearly memory that this explanation L-NBP causes different reasons and locus dysmnesia.In addition, L-NBP has the effect (improving the active and reduction MDA content of GSH-Px) of blocking oxide damage, and in conjunction with its tangible cerebral protection, prompting L-NBP has the effect of treatment alzheimer disease.
Generally speaking, the present invention's memory of nearly memory of Morris determined with Morris water rat and locus, continue low the filling simulating the vascular dementia that blood supply insufficiency clinically causes with rat 2-VO model, so this law can reflect the effect of Drug therapy dementia fully.Experimental result of the present invention shows that L-NBP10mg/kg organizes the dysmnesia that can obviously improve nearly memory of 2-VO animal and locus, and racemization butylphthalide and dextrorotation butylphthalide are all invalid to improving memory dysfunction.ACh is considered to the important neurotransmitter of learning and memory.Patient's AD cholinergic access function reduces, and shows as neurotransmitter ACh level and descends, and this is that its memory function is undermined one of major reason of cognitive impairment.And L-NBP has the raising effect to the ChAT activity, and explanation can make cholinergic nerve ACh level increase, and helps improving memory function.Obviously inhibited oxidation damage of L-NBP illustrates that L-NBP can reduce nerve cell damage.The low pathological characters of irritating of brain that is caused by 2-VO is that white matter is sparse, and cavity and glial cell increase, and L-NBP all can improve these pathological changes.Therefore, the chemical compound L-NBP shown in general formula (I) of the present invention prevents and therapeutical effect having of vascular dementia.
Tricorn perfusion A β (1-40) causes that the damage of rat learning and memory can simulate presenile dementia patient's symptom constantly.Memory function with nearly memory of Morris determined with Morris water rat and locus.L-NBP is to the effect that all has clear improvement of nearly memory and locus dysmnesia, and D-NBP and DL-NBP then do not have effect.GSH-Px is important antioxidase; MDA is the snperoxiaized degree of reaction body lipid, reflects the degree of brain cell damage indirectly.L-NBP can improve the GSH-Px activity and reduce the effect of MDA content, illustrates that L-NBP can damage by blocking oxide, and the effect of the brain injury of protection is arranged, and D-NBP and DL-NBP then do not have effect.Therefore, the chemical compound L-NBP shown in general formula (I) of the present invention prevents and therapeutical effect having of presenile dementia.In a word, L-NBP has prevention and the effect of treatment alzheimer disease, and racemization butylphthalide and dextrorotation butylphthalide all do not have effect.
Therefore the present invention also relates to and containing as the The compounds of this 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, The compounds of this 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.
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, intradermal injection and acupoint injection therapy 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, 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 suitable dose scope of the every day of The compounds of this invention is preferably the 0.1-100mg/kg body weight, more preferably 0.1-100mg/ days/people.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 or compositions can be taken separately, or merge use and adjust dosage with other treatment medicine or symptomatic drugs.
Term:
L-NBP: L-NBP
2-VO model: permanent bilateral ligation
Description of drawings
Fig. 1. water maze laboratory, the search pattern of the 5th day rat of 1A; The search pattern of rat during the 5th day platform of 1B explored and tested.
Fig. 2. oral L-NBP is to the influence of the spatial memory obstacle of rat in water maze laboratory after the permanent bilateral ligation.Fig. 2 A is illustrated in preclinical change of training stage;
The platform that Fig. 2 B represents to remove behind the platform is explored experiment, and in 60 seconds of rat free swimming, it is in time that platform place quadrant (Q4) stops.All numerical value are represented with mean ± standard error.Every group of 12-14 rat; Compare with sham-operation (sham) group #P＜0.05.
Compare with solvent control group (vehicle) P＜0.05.
Fig. 3. and bilateral ligation 5 week back rat hippocampus CA1 districts (A, B, C) and cortex (D, E, the visual change of painted microscopically of H-E F) (40 times).Sham operated rats (A, D); The solvent control group (B, E); L-NBP (10mg/kg) treatment group (C, F)
The microscopically image of 5 week of Fig. 4 .. bilateral ligation back rat tractus opticus K-B dyeing (C amplifies 40 times for A, B) and tail nuclear GFAP immunohistochemical staining (F amplifies 20 times for D, E) changes.Sham operated rats (A, D); The solvent control group (B, E); L-NBP (10mg/kg) treatment group (C, F)
Fig. 5 .L-NBP continues the amnemonic influence of tricorn perfusion A β (1-40) back in water maze laboratory to rat.Be illustrated as the change of training stage escape latency; All numerical value are represented with mean ± standard error.Every group of 10 rats.
Fig. 6 .L-NBP continues the amnemonic influence that tricorn perfusion A β (1-40) causes to rat.Working memory test (every day 5 times) was carried out behind A β (1-40) perfusion in 14-16 days.Fig. 5 A is illustrated in preclinical change in the experiment for the first time; Fig. 5 B represents preclinical change in back 4 experiments.All numerical value are represented with mean ± standard error.Every group of 10 rats.##P＜0.01 is compared with sham operated rats;
*P＜0.05 is compared with A β (1-40) model group.
Fig. 7. embodiment 1 mice began to gavage medicine or solvent on the 10th day from the back of performing the operation.Water maze laboratory carried out in 29-33 days after surgery, kept away dark experiment and carried out at 34-35 days.Animal was put to death at the 36th day, carried out biochemical measurement or pathological examination.In behavioristics's experiment, all in experiment administration in preceding 40 minutes.
Fig. 8. embodiment 2 mices began to gavage medicine and solvent on the 2nd day from the back of performing the operation.Water maze training test was carried out in 9-13 days after surgery, carried out the platform exploratory experiment, carried out working memory and test in 14-16 days in the 13rd day.Animal was put to death at the 17th day, and broken end is got brain and carried out biochemical measurement.In behavioristics's experiment, all in experiment administration in preceding 40 minutes.
The specific embodiment
1. a kind of to alzheimer disease of embodiment 1 L-NBP, the therapeutical effect of vascular dementia
Material and method
Reagent and medicine
L-, D-, DL-NBP is provided by the synthetic chamber of this institute, and optics and chemical purity＞98%, optical rotation are followed successively by-66.49 ,+66.88 and 0 degree.Prepare with vegetable oil.
Instrument
Morris water maze automatic monitoring instrument is kept away camera bellows by the chamber development of institute of Materia Medica,Chinese Academy of Medical Sciences instrument electricity
The 2-VO modelling
Male Wistar rat about body weight 280 grams, is placed in 1 cage for per 5 for 10 ages in week, and room temperature remains on 23 ℃, ad lib and diversion.Rat exposes with pentobarbital sodium anesthesia (40mg/kg), bilateral common carotid arteries, carefully separates Carotid peplos and vagus nerve.Low perfusion model group is used 5-0 silk thread ligation bilateral common carotid arteries.Sham operated rats is accepted identical operation except that not ligation bilateral common carotid arteries.Postoperative spreads a little sterilization crystallizing sulfanilamide powder, skin suture on wound.Perform the operation and carry out water maze laboratory after one month and keep away dark experiment.
Experiment grouping and design
Rat is divided into 8 groups at random, 10 every group.1) sham operated rats: remove not ligation bilateral common carotid arteries, all the other operations are all identical with low perfusion group; 2) solvent control group: orally taken plant oil only; 3) DL-NBP 10mg/kg group; 4) DL-NBP 30mg/kg group; 5) L-NBP10mg/kg group; 6) L-NBP 30mg/kg group; 7) D-NBP 30mg/kg group; The back began to gavage medicine or solvent on the 10th day from performing the operation.Water maze laboratory carried out in 29-33 days after surgery, kept away dark experiment and carried out at 34-35 days.Animal was put to death at the 36th day, carried out biochemical measurement or pathological examination.In behavioristics's experiment, all in experiment administration in preceding 40 minutes.
Water maze laboratory
The Morris water maze mainly is made up of a round metal cylindricality pond (the high 60cm in pond, diameter 120cm) and demonstration automatically, monitoring, recording equipment and safety island (platform of diameter 10cm).Inject clear water in advance in the pond, add the aqueous solution of the fresh milk powder that is dissolved with 1000g then, make Chi Shui become opaque milky, the water surface exceeds platform 15mm.Animal can not arrive platform by listening, look with olfactory sensation like this, so that detect the acuteness of animal to the locus.Water temperature keeps 23 ± 1 ℃, and the pond is divided into 4 quadrants (east, south, west, north), and platform places the center of Southwest Quadrant.The swimming activity of every rat is monitored by the TV instrument, is directly connected in computer and carries out Treatment Analysis.Water maze laboratory carried out 5 days continuously.Every rat was accepted 2 training in 1 day and seeks platform, and twice respectively from the mid point of Northeast Quadrant and Northwest Quadrant, and head is towards the pool wall entry, twice training 10 minutes at interval.Record finds the time (incubation period) of platform, and 2 experimental results are averaged.If rat was not found platform in 60 seconds, then calculated with 60 seconds incubation period.No matter whether found platform in 60 seconds, rat all stopped 10 seconds on platform.Before the experiment beginning for the first time rat being put into platform adapted to last 10 second.With the increase of frequency of training, each organizes shortening incubation period that rat seeks safety island.Explore experiment after the last training.Remove platform, 60 seconds searching platforms of rat free swimming, the record rat is in the time of each quadrant cost.Rat is long in the time that original platform place quadrant stops, and there is memory in the prompting rat to this extraterrestrial target.
We are divided into 4 classes with search strategy: (1) marginal mode, and rat moves along pool edge, does not have the motivation of searching; (2) random mode does not have specific direction during the rat search; (3) trend formula, rat has been remembered the Position Approximate of safety island, turning before finding safety island is less than 4 times; (4) orthoscopic, rat are clearly remembered the position of safety island, and directly trip is to safety island.It is that incubation period and search strategy are represented that experimental result finds the time of safety island with rat
Detection to CAT, antioxidase and MDA
The rat broken end is got brain, on ice bath, separate cortex and hippocampal tissue, place liquid nitrogen freezing stand-by after weighing rapidly.Sample adds the pH7.0 kaliumphosphate buffer 0.05mol L of pre-cooling
-1(include 0.5mol L
-1EDTA and 7% glycerol), ice bath is made 10% tissue homogenate, and protein quantification is with the Lowry colorimetric method for determining.
1. the mensuration of CAT (ChAT): add sodium phosphate buffer 0.5 mol L in the reaction system
-1, S-acetyl-coenzyme-A 0.0062 mol L
-1, choline chloride 1.0 mol L
-1, neostigmine methylsulfate 76 μ mol L
-1, NaCL3 mol L
-1And EDTA0.01 1mol L
-1, hydrochloric acid kreatinin 0.5 molL
-1Each 40 μ l, last each pipe adds distilled water to 0.8ml.After putting 37 ℃ of temperature bath 5min, each pipe adds 200 μ l tissue homogenates, with each pipe adding boiling water 2min, adds 2.5mmol L afterwards then
-1Natrium arsenicum 0.8ml, the centrifugal 3min of 15000 * g under the room temperature gets the 2.0ml supernatant and adds 40 μ l 3mmol L
-14-PDS puts after 25 ℃ of temperature bathe 15min, and (λ=324nm), calculating ChAT activity is represented with nmolCoA SH/mgprotein/hr to measure OD value.
2. superoxide dismutase (SOD), malonaldehyde (MDA), mensuration build up reagent company test kit description with reference to Nanjing and carry out.
Pathology and immunohistochemistry detect
Every group of picked at random 4-6 animal, after behavioristics's experiment, pentobarbital anesthesia (100mg/kgip), cut off skin successively, the thoracic cavity, fully expose heart, cut off the left side apex, insert towards the aorta direction with catheter needle, the hemostasis clamp closes, the infusion normal saline, cut off right atrium in the bottom, right auricle, normal saline perfusion 15-20min (200-300ml), it is clear that effluent becomes, change with 4% paraformaldehyde PBS liquid and continue perfusion 15-20min (150-200ml), the animal whole body is stiff, and till liver turned white, broken end was got brain then, cut anterior akrencephalon and rear portion cerebellum with blade, put into fixedly 48h (frozen section) of sucrose paraformaldehyde solution that 4% paraformaldehyde continues fixing 48h (paraffin section) or 20%.
Paraffin section is through fixing, embedding, and Hematoxylin-Eosin (HE) dyeing is used in the section back, and pathology detection is carried out in K-B (Kl ü ver-Barrera Luxol fast blue) dyeing, and the method for SABC detects the variation of GFAP content in cerebral tissue.
Statistical analysis
All results adopt mean ± standard error to express.Diversity ratio incubation period of each group adopts two factor variance analyses of replication in the water maze laboratory.Group difference adopts post hoc LSD or Turkey check.The water maze platform is explored experiment and is adopted one factor analysis of variance.Keep away dark experiment and adopt Kruskal-Wallis check and Mann-Whitney U check.Biochemical measurement adopts the analysis of single factor variance.P＜0.05 is for there being significant difference.
Experimental result
L-NBP to the influence of rat water maze learning and memory in water maze laboratory, study and keep experiment and be often used in the spatial memory ability that thinks poorly of the perfusion rat.In training in first day, there is not significant difference between each group.Through 5 days training, sham operated rats search strategy turn to trend formula and orthoscopic from marginal mode and random mode, obviously shorten incubation period (12.6 ± 3.34 seconds).And the search strategy of solvent control group does not significantly change, and still is marginal mode and random mode, and obviously do not shorten incubation period (47.6 ± 5.88 seconds), compares significant difference (P＜0.01) for two groups.The search strategy of L-NBP10mg/kg group turns to trend formula and orthoscopic from marginal mode and random mode, shorten incubation period (26.85 ± 5.98 seconds) obviously, with the solvent control group notable difference (P＜0.001 liang factor variance analysis) is arranged relatively, and relatively do not have significant difference with sham operated rats.Other medicines such as DL-NBP 10mg/kg, the improvement effect of DL-NBP30mg/kg and D-NBP 30mg/kg is all not obvious, sees Figure 1A, B and Fig. 2.After 5 days learning trainings finish, carry out platform and explore experiment, safety island is removed with the test rat whether formed spatial memory to safety island.Desolventize outside the matched group, all rats time of staying of target quadrant all greater than 25%, show the memory that has all formed the relative position of safety island.The time of staying of sham operated rats (17.73 ± 1.19 seconds) obviously is longer than solvent control group (14.40 ± 0.73 seconds), by the one factor analysis of variance statistics, has notable difference (P＜0.05) to see Fig. 3.L-NBP 10mg/kg group obviously prolongs (17.62 ± 1.27 seconds, P＜0.05) in the time of staying of platform place quadrant than the solvent control group.DL-NBP group (10mg/kg and 30 mg/kg) does not all have effect.In order to get rid of animal sports ability it is influenced, after measured, swimming rate zero difference between each group.More than explanation has only L-NBP that nearly memory and the locus functional impairment of cerebral blood supply insufficiency rat are had obvious effect, and racemization and dextrorotation normal-butyl Phthalide then do not have effect.
The SOD that influences to SOD, ChAT activity and MDA content is important antioxidase, and the activity of SOD is 100.07 ± 3.64 (NU/mg protein) in the normal control group cortical tissue; Activity in the hippocampal tissue is 57.90 ± 7.41 (U/mg protein).Behind the permanent ligation bilateral common carotid arteries of rat, the activity of Hippocampus SOD is compared obvious rising (P＜0.05) with matched group, and this may be a kind of compensatory response.After L-NBP (10mg/kg) treatment, this enzymatic activity is near normal level (P＜0.05), and MDA is the sign of lipid peroxidation, can be reflected at the degree of intravital lipid peroxidation, reflects the degree of cell injury indirectly.In this experiment, the content of model group cortex MDA has raise 19.9%, compares with the normal control group to have significant difference (P＜0.001).After L-NBP (10mg/kg) treatment, the content of cortex MDA has obviously reduced by 20.7% (P＜0.001).Behind the permanent ligation bilateral common carotid arteries of rat, the active of cortex ChAT significantly reduces, compare with the normal control group, and 34.4% (P＜0.05) that descended, it is impaired to show that low perfusion can cause the cholinergic nerve function.L-NBP (10mg/kg) successive administration is after 16 days, can make that the activity of ChAT has improved 37.1% than model group in the cortical tissue, has significant difference (P＜0.05).(seeing Table 1).
Table 1.L-NBP is to the influence (n=7-9) of SOD and ChAT activity and the MDA content of low perfusion rat layer and Hippocampus
#P＜0.05,
###P＜0.001 is compared with sham operated rats;
*P＜0.05,
* *P＜0.001 is compared with the solvent control group.
Behind pathology and the permanent ligation bilateral common carotid arteries of histochemical influence, the neuron in visible cortex of model group and Hippocampus CA1 district obviously reduces, cell shrinkage and neuron engrain, and can obviously improve the inductive neuronal damage of low perfusion after L-NBP (10mg/kg) treatment.The bibliographical information bilateral ligation can be induced the brain Glial Activation, and thin with white matter.White matter is thin generally to be divided into 4 grades by its order of severity: 0 grade, normal; 1 grade, the nerve fiber staggered arrangement; 2 grades, obviously cavity forms; 3 grades, medullated fiber disappears.In our experiment, the normal matched group of the tractus opticus of model group shows that tangible white matter is thin, has a large amount of cavitys to occur, and can significantly improve this situation after L-NBP (10mg/kg) long term administration, and the cavity of tractus opticus obviously reduces.Immunohistochemical experiment finds, the male astrocyte of GFAP-is normal control group Hippocampus, tail nuclear, and positions such as corpus callosum seldom detect, but bilateral ligation is after 4 weeks, and the astrocyte of many GFAP-positive reactions and microglia occur.After L-NBP (10mg/kg) treatment, the male glial cell of GFAP-significantly reduces (seeing Fig. 3,4).
Experiment conclusion
Can be drawn to draw a conclusion by the result: the L-NBP10mg/kg group can obviously be improved the dysmnesia of nearly memory of 2-VO animal and locus, and racemization butylphthalide and dextrorotation butylphthalide are all invalid to improving memory dysfunction.This research is the mat woven of fine bamboo strips 10 days beginning administration (always being administered to the 35th day) behind 2-VO, and purpose is to observe medicine to irritate the therapeutical effect that the neuron regression that causes becomes to brain is low, to get rid of the acute low filling influence of ischemic stage.
L-NBP has the raising effect to the ChAT activity, and explanation can make cholinergic nerve ACh level increase, and helps improving memory function.Obviously inhibited oxidation damage of L-NBP in addition illustrates that L-NBP can reduce nerve cell damage.The low pathological characters of irritating of brain that is caused by 2-VO is that white matter is sparse, and cavity and glial cell increase (Narri.et al.Chronic cerebralhypoperfusion-induced neuropathological changes in rats.Jpn.J.Psychopharmacol.1998; 18:181-188), and L-NBP all can improve these pathological changes.More than these mechanism of action L-NBP is improved the dysmnesia that the 2-VO rat causes foundation is provided.According to above result, prompting L-NBP has the possibility of obvious treatment and preventive effect to vascular dementia.
Embodiment 2 L-NBPs can obviously improve the alzheimer disease symptom that beta amyloid peptide (1-40) causes
Material and method
Reagent and medicine: L-NBP is provided by the synthetic chamber of this institute, prepares with vegetable oil.A β (1-40) is available from Sigma company.The little osmotic pumps perfusion device of Alzet brain is available from U.S. DURECT company.
Instrument: Morris water maze automatic monitoring instrument and experimental technique, referring to the low perfusion of above brain learning and memory in rats injury experiment
Modelling: male Wistar rat, in 10 ages in week, about body weight 280 grams, every cage is placed 1 animal, and room temperature remains on 23 ℃, ad lib and diversion.Rat is anaesthetized (40mg/kg) with pentobarbital sodium, ventral decubitus is fixed on the stereotaxic instrument, cut off the skin of head, the sleeve pipe that will be used for perfusion A β (1-40) is implanted ventriculus dexter cerebri, rat brain stereotaxic atlas according to Paxions and Watson, implant site is 0.3mm behind bregma, right 1.1mm, dark 4.0mm.Sleeve pipe is connected with a microdialysis pump.The microdialysis pump places the back of rat.A β (1-40) is dissolved in 35% acetonitrile/0.1 trifluoroacetic acid, and with 300pmol/ days lasting ventricles of the brain perfusions (i.c.v), matched group is perfusion solvent 35% acetonitrile/0.1% trifluoroacetic acid only.Previously experiment confirm is under this flow velocity, and solvent can not cause the change of rat behavior and neuro chemistry.
Experiment grouping and design: rat is divided into 4 groups at random, 10 every group.1) sham operated rats: the rat ventricles of the brain are perfusion 35% acetonitrile/0.1 trifluoroacetic acid+solvent only; 2) model group: A β (1-40)+solvent; 3) A β (1-40)+L-NBP10mg/kg group; 4) A β (1-40)+L-NBP30mg/kg group.The back began to gavage medicine and solvent on the 2nd day from performing the operation.Water maze training test was carried out in 9-13 days after surgery, carried out the platform exploratory experiment, carried out working memory and test in 14-16 days in the 13rd day.Animal was put to death at the 17th day, and broken end is got brain and carried out biochemical measurement.In behavioristics's experiment, all in experiment administration in preceding 40 minutes.(see figure 8)
Water maze laboratory: carried out water maze training test from icv A β (1-40) back in 9-13 days, carried out the platform exploratory experiment on the 13 day.Carried out working memory test (seeing last figure) in 14-16 days in icv A β (1-40) back, this test is that animal has obtained on certain memory basis after training test and platform exploratory experiment, the quick studying space memory ability of animal behind observation change platform and the quadrant.Except platform changes the position every day, experimentation is similar to the water maze training test of standard.5 experiments every day, rat is swum since 5 place of entry respectively.The experiment first time of every day is called demonstration test, and rat is allowed to swim on the platform that is in reposition, and stops for 10 seconds, four tests thereafter, and the position of platform remains unchanged, just the quadrant difference of place of entry.Get the 2nd meansigma methods to the 5th test the incubation period of working memory ability, the working memory ability of every rat is calculated by 3 days empirical average value.
Biochemical test: the mensuration of malonaldehyde (MDA) and glutathion peroxidase (GSH-Px) is with above experiment.
Statistical analysis: all results adopt mean ± standard error to express.Diversity ratio incubation period of each group adopts two factor variance analyses of replication in the water maze laboratory.Group difference adopts post hocLSD or Turkey check.The exploratory experiment of water maze platform, the working memory test, biochemical measurement adopts one factor analysis of variance.P＜0.05 is for there being significant difference.
Experimental result
L-NBP is to the influence of rat water maze learning and memory
In training in first day, there is not significant difference between each group.Through 5 days training, the search strategy of sham operated rats turned to trend formula and orthoscopic from marginal mode and random mode, and obviously shorten incubation period (13.02 ± 2.77 seconds).And the search strategy of model group does not significantly change, and still is marginal mode and random mode, and obviously do not shorten incubation period (30.18 ± 4.81 seconds), compares significant difference (P＜0.01) for two groups.After the L-NBP treatment, rat obviously shortens the incubation period in water maze test, wherein the search strategy of L-NBP10mg/kg group and 30mg/kg group turns to trend formula and orthoscopic from marginal mode and random mode, be respectively incubation period 27.28 ± 6.42 seconds and 25.88 ± 5.51 seconds, with model group notable difference (P＜0.05 liang factor variance analysis) is arranged relatively, and relatively do not have significant difference with sham operated rats, illustrate that the rat for the treatment of through L-NBP near normal level, sees Fig. 4.In the working memory test, see Fig. 5 A, B the incubation period of experiment for the first time and the 2-5 time experiment.Though in demonstration experiment for the first time, do not have significant difference the incubation period of each group, afterwards in 4 experiments, be 9.1 5 ± 0.91 second the incubation period of sham operated rats, be 14.05 ± 1.88 seconds the incubation period of model group, and the latter obviously prolongs incubation period, and the two has significant difference (P＜0.01).L-NBP group can dose dependent the remarkable working memory ability (P＜0.01) of improving.
L-NBP increases the GSH-Px activity and reduces the content of MDA
GSH-Px is important antioxidase, and in our experiment, the activity of GSH-PX is 15.86 ± 0.91 (U/mg protein) in the sham operated rats cortical tissue; Activity in the hippocampal tissue is 16.19 ± 1.19 (U/mg protein).Behind rat A β (1-40) continous perfusion, the activity of GSH-Px is compared with sham operated rats at cortex and Hippocampus and has been reduced by 29.5% and 42.4% respectively, has significant difference (P＜0.01 and P＜0.001).After the L-NBP treatment, the 30mg/kg group obviously raises (P＜0.01) to this enzymatic activity, and L-NBP (10mg/kg) also has the active function of this enzyme that raises, but does not have statistical significance.MDA is the sign of lipid peroxidation, reacts the snperoxiaized degree of body lipid, reflects the degree of cell injury indirectly.In this experiment, the content of cortex and Hippocampus MDA has raise 25.7% and 23.6% respectively behind rat A β (1-40) continous perfusion, compares with sham operated rats to have significant difference (P＜0.05 and P＜0.01).After the L-NBP treatment, the content of cortex and Hippocampus MDA obviously reduces, the 10mg/kg group has reduced by 28.4% and 24.3% (P＜0.05 and P＜0.01) respectively, the effect of 30mg/kg is weaker than the 10mg/kg group, but compare with A β (1-40) model group, still have significant difference (P＜0.05), see Table 2.
Table 2.L-NBP is to rat continous perfusion A β (1-40) back cortex and Hippocampus SOD is active and the influence (n=7) of MDA content
#P＜0.05,
##P＜0.01,
###Compare with sham operated rats P＜0.001;
*P＜0.05,
*Compare with model group P＜0.01.
Experiment is discussed:
It is the observation medicine of generally acknowledging models to the AD therapeutical effect that rat continues dysmnesia that tricorn perfusion A β (1-40) causes.By above result as seen, L-NBP not only causes blood supply insufficiency to cause that the model of vascular dementia has obvious effect to 2-VO, and to the dysmnesia that rat continues nearly memory that tricorn perfusion A β (1-40) causes and the locus effect that also has clear improvement.The effect that all has clear improvement of nearly memory that this explanation L-NBP causes different reasons and locus dysmnesia.In addition, L-NBP has the effect (improving the active and reduction MDA content of GSH-Px) of blocking oxide damage, and in conjunction with its tangible cerebral protection, prompting L-NBP has the effect of treatment and prevention alzheimer disease.
Claims (3)
1. the application in the medicine of preparation prevention or treatment dementia of L-NBP shown in general formula (I).
2. according to the application of claim 1, it is characterized in that described dementia is an Alzheimer.
3. according to the application of claim 1, it is characterized in that described dementia is a vascular dementia.
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| CN100471494C (en) * | 2005-12-24 | 2009-03-25 | 石药集团中奇制药技术（石家庄）有限公司 | Butylphthalide dripping pill and preparing method |
| ES2357261T3 (en) * | 2006-08-11 | 2011-04-20 | Dsm Ip Assets B.V. | DERIVATIVES OF LIGUSTILIDE FOR THE TREATMENT OF DISORDERS OF THE CENTRAL NERVOUS SYSTEM. |
| CN101579323B (en) * | 2008-05-16 | 2012-01-25 | 石药集团中奇制药技术（石家庄）有限公司 | Butylphenyl phthaleine sustained release tablet and preparation method thereof |
| CA2730154C (en) * | 2008-07-08 | 2015-01-06 | Institute Of Mataria Medica, Chinese Academy Of Medical Sciences | The application of potassium 2-(1-hydroxypentyl)-benzoate (d1-phpb) for the prevention and treatment of alzheimer's disease |
| CN101455661B (en) * | 2008-11-19 | 2012-10-10 | 中国科学院上海有机化学研究所 | Use of 3-substituted phthalide and the analogue |
| CN103417514B (en) * | 2012-05-24 | 2017-06-16 | 石药集团中奇制药技术（石家庄）有限公司 | A kind of butylphenyl phthaleine pharmaceutical composition of microencapsulation and its production and use |
| CN107595875B (en) * | 2016-07-12 | 2020-10-30 | 石药集团恩必普药业有限公司 | Composition containing butylphthalide and application thereof in drugs for treating cerebrovascular diseases |
| CN107595874B (en) * | 2016-07-12 | 2020-10-30 | 石药集团恩必普药业有限公司 | Pharmaceutical composition containing butylphthalide and application thereof in preparation of drugs treating cerebrovascular diseases |
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