CN1284790C - Cornus officinalis extract, extraction method thereof and application of extract in preparation of medicines and health-care products - Google Patents
Cornus officinalis extract, extraction method thereof and application of extract in preparation of medicines and health-care products Download PDFInfo
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- CN1284790C CN1284790C CN 200310121837 CN200310121837A CN1284790C CN 1284790 C CN1284790 C CN 1284790C CN 200310121837 CN200310121837 CN 200310121837 CN 200310121837 A CN200310121837 A CN 200310121837A CN 1284790 C CN1284790 C CN 1284790C
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Landscapes
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Abstract
The invention relates to a dogwood extract, an extraction method thereof, application thereof in preparing medicines and health products for preventing and treating nerve injury or nervous system diseases, and a medicinal composition thereof. Tests prove that the medicinal composition of the dogwood extract can obviously promote the expression of related proteins of the growth of nerves around wounds on various nerve injury animal models, is beneficial to the growth of axons, reduces the damage of free radicals in brain and the overload of neuronal calcium ions, improves the binding force of M-cholinergic receptors, enhances the activity of choline acetyltransferase, inhibits the activities of acetylcholinesterase, monoamine oxidase B and the like; can reduce the loss of neurons, improve the learning and memory functions and have good protective effect on various injuries of the neurons.
Description
Technical field
The present invention relates to Fructus Corni extract, its extracting method and its in preparation control nerve injury and the medicine of nervous system disorders and the purposes in the healthcare products, also relate to medicine and Halth-care composition by extracting method gained Fructus Corni extract preparation of the present invention.
Background technology
Nervous system disorders comprises that brain, spinal cord and peripheroneural function and textural anomaly change, the cerebral concussion that the cerebro-vascular diseases that common blood circulatory disorder causes, cerebral anoxia, mechanical injuries cause, cerebral edema, operation on nervous system damage, nerve compression syndrome or neural inflammation, and nerve degenerative diseases (degenerative disease), Alzheimer disease, Parkinson's disease, vascular dementia etc.The main pathomechanism of these diseases is that factors such as the interior free-radical generating of neural system is too much, intracellular calcium too high levels cause neurocyte oedema or dead pathologic process.Medicine at these mechanism development effectively preventing nervous system disorderss and symptom has crucial meaning.Therefore, the inventor shows tangible minimizing neurocyte and loses through discovering in a large number on the Fructus Corni extract animal model, strengthens neurotrophic factor expression, promotes the expression of wound circumference nerve growth associated protein, helps the growth of aixs cylinder; Alleviate damaged nerve tissue's oedema, reduce radical damage; Suppress calcium ion overload in the neurocyte; Suppress the monoamine oxidase-B activity, improve the injured nerve function, improve M-cholinergic receptor bonding force, strengthen choline acetyltransferase activity, the acetylcholine esterase inhibition isoreactivity; Improve learning and memory function; Neuronic various damages there is good protective action,, has realized the present invention based on this discovery.Particularly the Fructus Corni extract that obtains of the method for uniqueness of the present invention has improved morroniside and meliatin content, and has improved its effect aspect the treatment nervous system disorders greatly.
Summary of the invention
Therefore purpose of the present invention provides Fructus Corni extract and preparation method thereof and is preventing and treating nerve injury and the medicine of nervous system disorders and the purposes in the healthcare products.
Described nerve injury is meant that brain, spinal cord and peripheral nerve change being subjected to functions that factor caused such as blood circulatory disorder, mechanical injuries, interior originality radical damage, neurological sexually revise and textural anomaly.
Described nervous system disorders comprises that brain, spinal cord and peripheroneural function and textural anomaly change, the cerebral concussion that the cerebro-vascular diseases that common blood circulatory disorder causes, cerebral anoxia, mechanical injuries cause, cerebral edema, nervous system injury or surgical injury, nerve compression syndrome or neural inflammation, and nerve degenerative diseases (degenerative disease), Alzheimer disease, diseases such as Parkinson's disease, vascular dementia.
The present invention adopts unique resulting Fructus Corni extract of extracting method, by analysis, in the extract gross weight, contain morroniside 25-50wt%, meliatin 25-40wt%, the two total content accounts for the 50-90wt% of general extractive, is different from this extract of prior art fully.
The preparation method of Fructus Corni extract of the present invention may further comprise the steps:
(A) water is carried or water extract-alcohol precipitation;
(B) macroporous adsorbent resin separates; With
(C) refining.
Described water is carried and is preferably included skunk bush medicinal material water decoction 2-4 time, and amount of water 3-14 doubly time 1-4 hour, merges decoction liquor, concentrating under reduced pressure after filtering.
Described water extract-alcohol precipitation preferably includes skunk bush medicinal material water and decocts 2-4 time, and amount of water 3-14 times, time 1-4 hour, merge decoction liquor, filter the back concentrating under reduced pressure, adding ethanol, to transfer to determining alcohol be 50%-90%, refrigerate 12-48 hour, filter decompression filtrate recycling ethanol.
Described macroporous adsorbent resin separation preferably includes following steps: get spissated skunk bush water extraction or water extract-alcohol precipitation extracting solution, last macroporous adsorptive resins, make soup flow through full post, carry out gradient elution with deionized water, 5%-95% ethanol successively, concentrating under reduced pressure becomes fluid extract.
Described refining preferably including with Al on the isolating fluid extract of macroporous adsorbent resin
2O
3Chromatography column is used ethanol elution, and freeze-drying obtains solid product.
The measuring method of effective constituent: the said extracted Tetramune is used thin-layer chromatography carry out qualitative analysis.And the said extracted Tetramune is used high performance liquid chromatograph carry out quantitative analysis, chromatographic condition: the Lichrospher-C18 chromatographic column, mobile phase methanol-water (30: 70) detects wavelength 240nm, flow velocity 1.0ml/ minute.The check and analysis result: morroniside content accounts for 25-50%, meliatin content accounts for 25-40%, and the two total content accounts for 50-90%.
The invention provides Fructus Corni extract in the medicine of preparation treatment nervous system disorders or the purposes in the healthcare products, described nervous system disorders comprises nervous system injury and neural system degeneration, especially brain, spinal cord and peripheroneural function and textural anomaly change, the cerebral concussion that the cerebro-vascular diseases that common blood circulatory disorder causes, cerebral anoxia, mechanical injuries cause, cerebral edema, operation on nervous system damage, nerve compression syndrome or neural inflammation, and nerve degenerative diseases (degenerative disease), Alzheimer disease, Parkinson's disease, vascular dementia etc.
Relevant above-mentioned Fructus Corni extract is said extract in medicine for preparing the treatment nervous system disorders or the application in the healthcare products, both comprised with the resulting Fructus Corni extract of extracting method of the present invention, also comprised the Fructus Corni extract that utilizes any known technology in this area to be obtained.The one or more of technology that also comprise conventional extraction methods such as being selected from water extraction, organic solvent extraction, liquid chromatography technology, gas chromatographic technique, chromatographic technique in other words are in conjunction with the Fructus Corni extract that is obtained.
The present invention also provides pharmaceutical composition and the Halth-care composition that contains the said extracted thing.The pharmaceutical composition of the various nervous system disorderss of described treatment contains 10-100%, preferred 20-90%, and more preferably 50-90% Fructus Corni extract of the present invention also can contain 0-90% as required, preferred 10-80%, the more preferably conventional pharmaceutical carrier of 10-40%.And described Halth-care composition generally contains 5-80%, and preferred 10-50% Fructus Corni extract of the present invention also can contain 20-95% as required, conventional edible carrier of preferred 50-90% or additive.
The percentage ratio of mentioning among the present invention is weight percentage.
Morroniside (morroniside) in the described extract of the present invention, Ma Qiansu (loganin is a loganin) content are higher.In extract of the present invention, morroniside content accounts for 25-50%, meliatin content accounts for 25-40%, and the two total content accounts for 50-90%.But in extract of the present invention, except above composition, do not get rid of the existence that other activeconstituents is arranged, for example comprise in cornin (Cornin is venbenalin Verbenalin), methyl Morroniside (methylmorroniside), dehydrogenation Ma Qiansu (dehydrologanin), iridoid glycoside (iridoid glycosides), sweroside (sweroside), 5 hydroxymethyl furfural, the saponin etc. one or more, their content for example can be 0.1-20%.
Pharmaceutical composition of the present invention and Halth-care composition formulation can be tablet, pill, pulvis, capsule, oral liquid etc.The method for preparing these formulations is the ordinary method of this area, and this it is well known to those having skill in the art that, and is described in many documents.Its survival dose is according to patient's age, body weight, the character of disease, state of an illness weight, the decision of factors such as doctor's selection.As guidance, in extract enriching agent of the present invention, consumption is generally 1-500mg/ kg body weight day.
Embodiment
Below in conjunction with embodiment preparation method of extract of the present invention is described, it should be understood that these embodiment only are the preferable embodiment in the present invention's practice, they never constitute limitation of the scope of the invention.It will be apparent to those skilled in that, under situation without departing from the spirit and scope of the present invention, can make some variations and modification, these variations and modification are all forgiven in category of the present invention.
Embodiment 1
Water is carried: skunk bush medicinal material water decocts 3 times, 6 times of amount of water, and 2 hours time, merge 3 times decoction liquor, filter the back concentrating under reduced pressure, refrigerate standby.
Macroporous adsorbent resin separates: get spissated skunk bush water extract, last macroporous adsorptive resins makes soup flow through full post, carries out gradient elution with deionized water, 30% ethanol successively, and concentrating under reduced pressure becomes fluid extract.
Refining: with Al on the isolating fluid extract of macroporous adsorbent resin
2O
3Chromatography column is made with extra care with ethanol elution, and freeze-drying obtains solid product, yield 2.3%.Through the high performance liquid chromatograph analysis, morroniside content accounts for Fructus Corni extract 25-50% in the described product, meliatin content accounts for Fructus Corni extract 25-40%, and the two total content accounts for 50-90%.
Embodiment 2
Water extract-alcohol precipitation: skunk bush medicinal material water decocts 3 times, 6 times of amount of water, 2 hours time.Merge 3 times decoction liquor, filter the back concentrating under reduced pressure, adding ethanol, to transfer to determining alcohol be 70%, refrigerate 24 hours, and filtration behind the decompression filtrate recycling ethanol, refrigerates standby.
Macroporous adsorbent resin separates: get spissated skunk bush aqueous extract or water extract-alcohol precipitation extracting solution, last macroporous adsorptive resins makes soup flow through full post, carries out gradient elution with deionized water, 50% ethanol successively, and concentrating under reduced pressure becomes medicinal extract.
Refining: with Al on the isolating fluid extract of macroporous adsorbent resin
2O
3Chromatography column is made with extra care with ethanol elution, and freeze-drying obtains solid product, yield 2.5%.Through the high performance liquid chromatograph analysis, morroniside content accounts for Fructus Corni extract 25-50% in the described product, meliatin content accounts for Fructus Corni extract 25-40%, and the two total content accounts for 50-90%.
The preparation of embodiment 3 tablets
With the Fructus Corni extract 50mg of embodiment 2, lactose 70mg, W-Gum 350mg, Magnesium Stearate 5mg, polyvinylpyrrolidone 5mg makes tablet according to a conventional method.
The preparation of embodiment 4 oral liquids
The Fructus Corni extract 10g of embodiment 1, sucrose 90 grams, citric acid 8 grams, aspartame 3 grams, potassium sorbate 0.2 gram adds water to 1000 milliliters, and heating for dissolving adds essence, stirs, divide to install in 100 bottles of sterilization, every bottle of 10ml, packing gets final product.
Embodiment 5 capsular preparations
The Fructus Corni extract 100g of embodiment 2, talcum powder 4 grams, W-Gum 50g, lactose 50g mixes, and divides to install in the capsule, and packing is made 1000 capsules.
The preparation of embodiment 6 slow releasing tablets
The extract 100g of embodiment 1 adds 5%PVP, and 25% spirituous solution mixes, and softwood is granulated with 18 orders, and oven dry adds HPMC, the whole grain of Magnesium Stearate, compressing tablet, packing.
The preparation of embodiment 7 transfusions
The Fructus Corni extract 10g of embodiment 2 adds physiological saline and is settled to 1000 milliliters, and reheat dissolving, check, packing are gone in the bottle of sterilization, packing.
The pharmacodynamics test of extract of the present invention
One, Fructus Corni extract is to cutting off the influence that causes nerve injury and Model of Dementia rat every hippocampus arched roof umbrella
Senile dementia is a kind of chronic brain degenerative disease, and clinical is first symptom to be losing one's memory, and develops into gradually that memory completely loses, aphasis, dyskinesia.Discover that cholinergic neuron minimizing in senile dementia patient's brain cortex and the hippocampus, CAT and acetyl choline content reduce 40%-90%.Give light moderate senile dementia patient with the treatment of central cholinomimetic, can improve patient's cognitive function.Cut off rat and can cause the mechanicalness nerve injury every the psalterium umbrella, and blocking-up hippocampus cholinergic path, the animal model that both can be used as nerve injury, the animal model that can be used as senile dementia or cognitive impairment again, this research have been observed the curative effect of Fructus Corni extract in control nerve injury senile dementia and cognitive impairment.
(1) Fructus Corni extract improves the ability of learning and memory that cuts off rat model every hippocampus arched roof umbrella
1, experiment purpose: now proved every hippocampus cholinergic path and in learning and memory, brought into play important effect.This experiment causes the animal model of the blocking-up of cholinergic nerve path, cholinergic system hypofunction by cutting off rat every hippocampus arched roof umbrella, observes the curative effect of Fructus Corni extract in control nerve injury and senile dementia.
2, experimental technique: male SD rat, half an hour, gastric infusion began before art, to 6 weeks of postoperative, perfusion every day 1 time.With the positive contrast medicine of piracetam (La Xitan).
(1) cuts off the preparation of rat model every hippocampus arched roof umbrella: male SD rat, intraperitoneal anesthesia.The stereotaxic apparatus location, boring, adjusting blade and adjusting knob to front and back gauge point is 0.Move 2mm again, sidesway 1mm, 5mm downwards to the brain surface.Slowly take out cutter 4mm twice up and down, move 3mm outward then, slowly take out cutter twice more up and down, kept somewhere blade 2 minutes, withdraw from blade.Moving to offside operates equally.
(2) learning and memory testing method
Morris water maze test: begin the test of Morris water maze around the postoperative the.Each test continues 1 minute, about 1 minute of test interval.In 1 minute, can not find platform as mouse, guide it to reach platform, and it is placed on platform last 10 second of kind, survey altogether 6 days.
The test of channel-type water maze: 6 weeks of postoperative begin to survey the channel-type water maze.Make every rat swim upper mounting plate before the mensuration, begin to carry out the test of two cecums then, carry out the test of three cecums next day, carried out the test of four cecums since the 3rd day, tested altogether 6 days in the exit.Each test duration is decided to be 180 seconds.Can not find an exit as mouse, the guiding mouse arrives outlet.The record mouse is swum out of time and errors number, and rat whenever enters a blind area or oppositely swims and is decided to be once mistake.
3, experimental result: the test result of two kinds of water maze study of behaviour methods is found, Fructus Corni extract can obviously shorten (the table 1 of swimming out of the time of rat model, table 2), show that this medicine has the improvement effect to the learning and memory function of dementia rats model, show that simultaneously this medicine takes an evident turn for the better the function of nerve injury rat.
Table 1. Fructus Corni extract is swum out of the influence of time to rat model Morris water maze
| Group | Number of animals | Swim out of the time (second) |
| Normal control, (sham-operation) model model+piracetam, (positive control drug) Fructus Corni extract 1.5g/kg Fructus Corni extract 3g/kg Fructus Corni extract 6g/kg | 14 14 12 15 16 12 | 13.49±10.72 ** 45.60±14.54 35.70±14.53 * 32.78±18.29 ** 37.22±17.28 * 37.79±12.93 |
M ± SD;
*P＜0.05;
*Compare with model group p＜0.01.
Table 2. Fructus Corni extract is swum out of the influence of time to rat model channel-type water maze
| Group | Number of animals | Swim out of the time (second) |
| Normal control (sham-operation) model model+piracetam Fructus Corni extract 1.5g/kg Fructus Corni extract 3g/kg Fructus Corni extract 6g/kg | 14 14 11 15 14 9 | 2.19±2.17 ** 18.94±8.80 12.27±7.58 ** 14.46±8.60 ** 14.21±7.36 ** 15.31±8.26 |
M ± SD;
*P＜0.05;
*Compare with model group p＜0.01.
(2) Fructus Corni extract is to cutting off the neuronic provide protection of model rat brain every hippocampus arched roof umbrella
1, experiment purpose: one of important pathological characteristic of the nerve injury that nerve degenerative diseases such as senile dementia, Parkinson's disease and multiple reason cause is neuronic atrophy and loses.This research is observed Fructus Corni extract to the neuronic influence of rat model.
2, experimental technique: cutting off every hippocampus arched roof umbrella and gastric infusion after 6 weeks, every group is selected 4-7 rat to irritate to kill at random, and after fixing, frozen section behind Nissl's staining, is chosen same quantity picture number, carries out image analysis.Carry out the neurocyte numeration at medial septal nuclear and hippocampal dentate multiform layer respectively.
3, experimental result: in medial septal nuclear district and hippocampal dentate multiform layer, Fructus Corni extract can obviously reduce neuronic forfeiture (table 3), shows that Fructus Corni extract has the better protecting effect to cut off model rat brain neurone every hippocampus arched roof umbrella.
Table 3, Fructus Corni extract are to the neuronic influence of rat model hippocampal dentate multiform layer
| Group | N picture number | Neuronal quantity | |
| Normal control (sham-operation) model model+piracetam cornel extractive 1.5g/kg cornel extractive 3g/kg cornel extractive 6g/kg | 7 5 4 4 5 4 | 20 20 20 20 20 20 | 21.00±5.30 19.50±6.25 21.20±6.96 23.65±4.49 * 22.00±7.59 21.15±7.31 |
M ± SD;
*Compare with model group P＜0.05.
(3) Fructus Corni extract strengthens the expression of cutting off the model rat NGF every hippocampus arched roof umbrella
1. experiment purpose: when nervus centralis or peripheral nerve injury, nerve growth factor (NGF) plays an important role to neuronic survival and function.Nerve growth factor obviously reduces in nerve degenerative diseases such as senile dementia, the Parkinson's disease patient brain.The influence of Fructus Corni extract to the rat model nerve growth factor observed in this research.
2. experimental technique: male SD rat, cut off modeling, 6 weeks of gastric infusion, perfusion every day 1 time every hippocampus arched roof umbrella.In 6 weeks of postoperative, the method for usefulness immunohistochemical methods is measured the NGF content of brain tissue slice, the row image analysis of going forward side by side.
3. experimental result: Fructus Corni extract can obviously strengthen the expression (table 4) of rat model medial septal nuclear, hippocampal dentate multiform layer, entorhinal cortex/subiculum district NGF, shows that this medicine has neurotrophy and neuroprotective to multiple nervous system disorders.
Table 4. Fructus Corni extract is to the influence of rat model medial septal nuclear nerve growth factor
| Group | N picture number | Positive cell number | |
| Normal control (sham-operation) model model+piracetam cornel extractive 1.5g/kg cornel extractive 3g/kg cornel extractive 6g/kg | 7 5 4 4 5 4 | 10 10 10 10 10 10 | 67.1±49.4 50.2±48.6 212.0±01.9 ** 145.1±57.7 ** 161.3±08.2 ** 200.6±58.2 ** |
M ± SD;
*P＜0.05;
*Compare with model group p＜0.01.
Two, Fructus Corni extract causes the influence of dementia or memory impairment mouse model to Scopolamine
(1) Fructus Corni extract raising Scopolamine causes the model mice ability of learning and memory
1. experiment purpose: senile dementia is lost the most serious with the basal forebrain cholinergic neuron, cause the vagusstoff hyposecretion.Scopolamine is the m receptor blocker, and therefore the energy blockage of acetylcholine has imitated the result of vagusstoff hyposecretion to the agonism of m receptor, is one of animal model of senile dementia or memory impairment.The Morris water maze is the method for effectively evaluating rat behavior ability, and the influence of Fructus Corni extract to Scopolamine mouse model ability of learning and memory observed in this research.
2. experimental technique: male mouse of kunming, behind first day gastric infusion 30 minutes in abdominal injection scopolamine hydrobromide injection 1mg/kg, after 20 minutes animal is carried out the water maze test.Successive administration and test are 5 days altogether.
Morris water maze test (with experiment one).
3. experimental result: Fructus Corni extract can significantly reduce model mice swimming out of the time in the Morris water maze test, shortens swimming distance (table 5), shows that this medicine can improve the learning and memory function of Model of Dementia mouse.
Table 5. Fructus Corni extract is to the influence of Scopolamine model mice Morris water maze test
| Group | Swim out of the time (second) | The swimming distance (centimetre) |
| Contrast model model+piracetam Fructus Corni extract 1.7g/kg Fructus Corni extract 5g/kg Fructus Corni extract 15g/kg | 67.93±47.52 ** 99.32±38.10 63.58±48.26 ** 84.81±47.42 77.95±49.08 * 67.30±47.55 ** | 1146.3±836.1 ** 1808.8±869.4 1101.2±872.3 ** 1476.4±1028.1 1313.0±1036.0 * 1185.2±893.3 ** |
M ± SD;
*P＜0.05;
*Compare with model group p＜0.01.
(2) Fructus Corni extract improves Scopolamine mouse model cerebral tissue M-cholinergic receptor activity
1. experiment purpose: neurotransmitter acetylcholine needs and its function of receptors bind competence exertion, so cerebral tissue M-cholinergic receptor is the important factor that influences learning and memory.The influence of Fructus Corni extract to model mice cerebral tissue M-cholinergic receptor observed in this research.
2. experimental technique: male mouse of kunming, the continuously tested water maze was got cerebral tissue after 4 days in abdominal injection scopolamine hydrobromide injection 1mg/kg in 30 minutes behind first day gastric infusion, and preparation brain synaptic membrane press Lowry method mensuration membranin content.Carry out the receptors bind experiment: take out synaptic membrane from-70 ℃ of refrigerators, adjust protein concentration.Get 100 μ l diluents and add 200 μ l 50mMPB, every pipe adds 0.1 μ Ci
3H-QNB.Incubate at 25 ℃ and to bathe 60min, reaction finishes the 50mMPB 5ml of back with precooling, and suction filtration and divides 3 washings with the 50mMPB20ml of precooling on fibrous filter membrane.Filter membrane placed in the scintillating disc add Tritom toluene scintillation solution 5ml and on liquid glimmer instrument, measure the cpm value, calculate in conjunction with the synaptic membrane protein content
3The binding capacity of H-QNB is (with every milligram of albumen institute bonded
3The H-QNBfmol numerical table shows).
3. experimental result: Fructus Corni extract can significantly improve Scopolamine mouse model cerebral tissue M-cholinergic receptor activity (table 6).
Table 6. Fructus Corni extract is to the influence of Scopolamine model M-cholinergic receptor activity
| Group | Number of animals | 3H-QNB specificity binding capacity (fmol/mgprot) |
| Comparison model model+piracetam cornel extractive 1.7g/kg cornel extractive 5g/kg cornel extractive 15g/kg | 6 7 6 9 9 7 | 247.37±36.88 * 218.38±39.04 250.07±58.96 198.68±52.05 310.98±48.60 ** 282.25±46.55 ** |
M ± SD;
*P＜0.05;
*Compare with model group p＜0.01.
(3) Fructus Corni extract improves Scopolamine mouse model cerebral tissue choline acetyltransferase activity
1. experiment purpose: the activity of CAT (ChAT) descends and can cause neurotransmitter acetylcholine to generate reducing, cause learning and memory function to go down in the brain.This research is observed Fructus Corni extract to the active influence of ChAT in the model mice brain.
2. experimental technique: the mouse brain tissue is added 4 ℃ of 10mM EDTA solution in 1: 20 (w/v) ratio, and the protein concentration of homogenate is measured in homogenate under the ice bath, exempts from method mensuration ChAT with putting.Calculate: the mg number of the mole number/sample protein of ChAT activity=(the blank cpm of sample cpm-)/grand total cpm * every pipe aglucon.
3. experimental result: Fructus Corni extract can make the activity of CAT (ChAT) in the model mice brain significantly improve (table 7), makes that vagusstoff is synthetic to be increased, and helps improving learning and memory function.
Table 7. Fructus Corni extract is to the influence of Scopolamine mouse model cerebral tissue ChAT
| Group | Number of animals | ChAT activity (pmol/mg prot/min) |
| Contrast model model+Fructus Corni extract 1.7g/kg Fructus Corni extract 5g/kg Fructus Corni extract 15g/kg | 7 7 9 9 7 | 37.46±8.55 37.79±9.17 44.99±14.26 45.82±8.20 * 59.96±19.93 ** |
M ± SD;
*P＜0.05;
*Compare with model group p＜0.01.
Three, Fructus Corni extract is to the influence of nerve injury rat model
1, experiment purpose
Maincenter and peripheral nerve tissue edema are the typical case performances of neural tissue injury, and this experimentation is observed Fructus Corni extract, and nerve injury causes the influence of cerebral edema to mechanicalness.
2, experimental technique
The SD rat, body weight 200-250g, with Fructus Corni extract gastric infusion 7 days, imitative Feeney ' s freely falling body cortex was dampened model production method, and 10% Chloral Hydrate 0.4ml/kg body weight intraperitoneal anesthesia cuts off the top fur, iodophor disinfection.Cut scalp along top median line left side, separate periosteum, with bone drill 1mm behind coronal suture, the other 2mm in a median raphe left side bores the circular bone window that a diameter is 5mm.The one homemade percussion pad of moulding is firmly put into the bone window, with counterweight along grass tube in the vertical free falling of 30cm eminence on percussion pad, take counterweight away, sew up scalp.After 3 hours rapidly broken end get brain, separate and hinder side and each 100mg left and right sides cerebral tissue of strong side cortex, be placed in the phial of having weighed, put 110 ℃ of loft drier dryings 48 hours, weighing is taken out during to constant weight.Calculate water content with (weight in wet base-dry weight)/weight in wet base * 100%, and after proofreading and correct with each group right side (strong side) water content, between the work group relatively.
3, experimental result
Fructus Corni extract can effectively reduce nerve injury rat brain water content, illustrates that this medicine has good therapeutic action to nerve injury and nervous tissue edema.(table 8)
Table 8 drug intervention is to the influence (n=6) of nerve injury SD rat brain water content
| Group | The cortex percentage of moisture (%) |
| Normal control model (nerve injury) model+Fructus Corni extract 1.5g/kg Fructus Corni extract 3g/kg | 78.43±0.33 * 79.90±0.43 79.17±0.23 79.02±0.26 * |
M ± SD;
*Compare with the nerve injury model group P＜0.05
Four, Fructus Corni extract increases the influence of inductive nerve injury mouse model to Green Tea Extract
Experiment purpose: it is the important pathogenesis of multiple nervous system disorders (as cerebro-vascular diseases, nerve injury, neural inflammation, senile dementia, Parkinson's disease etc.) that free radical increases.Increased by oxyradical and to cause vascular endothelial cell damage, platelet aggregation forms thrombus, and causing the local organization ischemic necrosis is the common pathological change of ischemic angiocardiopathy and cerebrovascular disease and peripheral angiopathy.The modeling principle of photochemical induction acute cerebral infarction is that photoactive substance (rose-red) is injected mouse tail vein, cold light source irradiation mouse cranium portion with the 560nm wavelength, photochemical reaction takes place, generate a large amount of oxyradicals, cause vascular endothelial cell damage, platelet aggregation forms thrombus in irradiated region, local cortex ischemic necrosis.This research is intended to observe Fructus Corni extract increases the inductive nerve injury to free radical influence.
Experimental technique: give mouse gavaging various dose Fructus Corni extract, modeling after 15 days.Photoactive substance (rose-red) is injected mouse tail vein, with the cold light source irradiation mouse cranium portion of 560nm wavelength.After modeling, inject the Yi Wensilan dyestuff through the tongue vein in 3 hours, put to death animal after 1 hour.Get cerebral tissue after the execution and make homogenate, and with the optical density(OD) of the average cerebral tissue of colorimetric method for determining.The infraction severe patient, dyeing is dark, and optical density(OD) is big, and cerebral tissue ischemic half dark space area is big.
Experimental result: gavage the optical density(OD) that Fructus Corni extract can reduce photochemical induction acute cerebral infarction model mice cerebral tissue Yi Wensilan, and reduce the area (table 9) of model mice ischemic half dark space.Showing that Fructus Corni extract can alleviate owing to oxyradical increases causes blood vessel injury and thrombosis, helps preventing and treating the blood vessel injury and the tissue necrosis of ischemic vascular disease, and helps preventing and treating with free radical and increase relevant multiple disease.
Table 9 Fructus Corni extract is to the influence of photochemical induction cerebral infarction mouse model
| Group | Number of animals | Yi Wensilan (OD value) | Ischemic half blanking bar area |
| Model group model+Fructus Corni extract 0.167g/kg Fructus Corni extract 0.5g/kg Fructus Corni extract 1.5g/kg | 6 6 8 8 | 0.1333±0.0759 0.1097±0.0259 0.1072±0.0303 0.0547±0.0260 * | ++++ ++ + + |
M ± SD;
*P＜0.05 is compared with model group
Ischemic half blanking bar :+, ++, +++, ++ ++ represent area ascending successively.
Five, Fructus Corni extract antagonism neurocyte calcium overload damage
1. experiment purpose: calcium overload is the important pathogenesis of multiple nervous system disorders (as cerebro-vascular diseases, nerve injury, neural inflammation, senile dementia, Parkinson's disease etc.) in the neurocyte.It is the common pathological change of ischemic angiocardiopathy and cerebrovascular disease and peripheral angiopathy that the concentration of cytoplasm calcium ion that is caused by ischemic increases unusually, and calcium ion increases also can cause vasoconstriction or spasm.MCAO is the focal cerebral ischemia model of the simulation clinical disease used always.The imbalance of intracellular calcium stable state plays an important role in the cell ischemic damage.The concentration of cytoplasm calcium ion that is caused by ischemic increases unusually, can make the Phospholipid hydrolase that is subjected to regulation of calcium, proteolytic enzyme, endonuclease etc. be activated to cause membrane phospholipid to decompose and cytoskeleton destroys, and cell produces irreversible damage.This research be intended to observe Fructus Corni extract to ischemic after the influence of calcium ion concn in the neurocyte endochylema.
2. experimental technique:
(1) the middle cerebral artery occlusion rat model is made: experimental rat is in administration in the 14th day row intraperitoneal anesthesia after 30 minutes, the diagonal otch about in the of one in right external auditory canal and right outer canthus line mid point work, be separated to abundant exposure arteria cerebri media, be affixed on arteria cerebri media and anterior cerebral veins infall with the filter paper bar that is soaked with 50% iron trichloride, really block with the microscopic examination blood flow of middle cerebral artery after 30 minutes, remove filter paper, normal saline flushing, stitching.
(2) mensuration of calcium ion fluorescence intensity in the hippocampal cell: after the rat modeling 24 hours, broken end was got brain and is placed in the artificial cerebrospinal fluid, cuts the brain sheet of 300 micron thickness in the optic chiasma level.Add artificial cerebrospinal fluid 400 microlitres that contain 5uMFluo-3/AM, hatch laser confocal microscope mensuration hippocampus intracellular calcium fluorescence intensity after 1 hour.
3. experimental result: every group of right side is the ischemic side, and calcium ion concn increases than strong side (left side).Left and right sides brain calcium ion concn difference compares, and the interior calcium ion fluorescence intensity of model group hippocampal cell increases obvious than control group, and model is set up.Fructus Corni extract medication group reduces (table 10) than calcium ion concn in the model group hippocampal cell.Show that this medicine can reduce calcium ion concn in the neurocyte endochylema, help the neuroprotective tissue, improve cell survival rate, significant to the control of multiple nervous system disorders and ischemic vascular disease.
Table 10 Fructus Corni extract is to the influence of rat model hippocampal cell concentration of cytoplasm calcium ion
| Group | The calcium ion fluorescence intensity | ||
| The ischemic side | Strong side | (ischemic side-strong side) difference | |
| Normal control, (sham-operation) model model+hydergine, (contrast medicine) Fructus Corni extract 0.33g/kg Fructus Corni extract 1g/kg Fructus Corni extract 3g/kg | 47.99±26.28 105.27±41.30 86.02±35.10 99.20±13.52 89.57±15.67 95.22±29.42 | 36.72±6.93 60.31±32.34 56.15±27.30 58.33±19.10 54.57±17.75 64.40±23.44 | 11.27±22.38 * 44.96±12.44 29.88±29.13 40.86±18.23 34.60±3.92 30.82±17.39 |
M ± SD;
*P＜0.05 is compared with control group
Six, Fructus Corni extract causes the influence of nerve injury and dementia rats model to hypoxic-ischemic
(1) Fructus Corni extract improves the rat model learning and memory function
1. experiment purpose: the nervous tissue hypoxic-ischemic can cause dysfunction, learning and memory function to go down and be the important behaviour of brain tissue impairment.Long-term cerebral ischemia can cause vascular dementia, and the pathogeny of cerebral ischemia and senile dementia also has substantial connection.Fructus Corni extract causes nerve injury and dementia rats model learning memory function to bilateral ligation influence is observed in this research.
2. experimental technique:
(1) preparation of bilateral ligation rat model: the SD rat, intraperitoneal injection of anesthesia separates bilateral common carotid arteries, with No. 1 permanent ligation of silk thread, suture muscles skin.Prevention is irritated stomach and is given 2 weeks of Fructus Corni extract, 8 weeks of postoperative gastric infusion before the art.
(2) darkness avoidance test: detect the passive avoidance memory function.Adopt rat to keep away camera bellows, experimentize in the 8th week of postoperative, trained in first day, rat is put into bright chamber, make it enter the darkroom and shocked by electricity 2 times, test after 24 hours, the record rat enters the number of times and the latent period in darkroom, and classification.Two forelimbs enter the darkroom and are designated as 1 fen; Three forelimbs enter the darkroom and are designated as 2 fens; Four limbs enter the darkroom simultaneously and are designated as 3 fens.Compare between group as a result, carry out the t check.
(3) channel-type water maze method: in beginning training in the 8th week of postoperative.Experiment divides to be carried out in 4 days, and training 2 cecums were 2 times in the 1st day, and training 3 cecums were 2 times in the 2nd day; Training 4 cecums were 2 times in the 3rd day, the 4th day survey 4 cecums.Each training time is limited to 2min.Every number of times (mistake number) that the each training and testing of rat all writes down the time (time of arrival) of reaching home and enters cecum.As school grade, 4 time of arrival cecum testing period and wrong number be as the memory achievement with the average of 4 cecum time of arrival training period and wrong number, as a result between group relatively, carry out the t check.
(4) Morris water maze method: in beginning training in the 8th week of postoperative.Experiment divides to be carried out in 5 days, trained every day 2 times.Training in the 1st day 2 times, go into the position, pond by platform institute to quadrant and adjacent quadrant.In the quadrant limit 1/2 radian place with the rat head towards the pool wall entry.Training time is limited to 2min.The track of the time of swimming out of, distance, search platform is all write down in every each training of rat.Compare between group as a result, carry out the t check.
3. experimental result: the method for the long-term ligation of bilateral common carotid arteries can make rat produce learning memory disorder.Fructus Corni extract can improve the learning and memory function of rat, shows time of swimming out of that can shorten in the water maze test and distance, reduces errors number (table 11-13), can prolong latent period in keeping away dark test, reduces errors number (table 14).
Table 11. Fructus Corni extract is swum out of the time influence of (second) to rat model Morris water maze
| Group | The example number | Second day | The 3rd day | The 4th day |
| Normal control model model+Fructus Corni extract 3g/kg | 14 12 9 | 25.78±23.36 46.38±34.56 32.85±22.56 | 12.82±15.22 * 35.36±24.17 10.52±7.04 ** | 9.50±5.73 * 25.75±20.20 16.55±10.98 |
X ± SD, compare with model group:
*P＜0.05,
*P＜0.01
Table 12. Fructus Corni extract to rat model Morris water maze swim out of the distance (centimetre) influence
| Group | The example number | Second day | The 3rd day | The 4th day |
| Normal control model model+Fructus Corni extract 3g/kg | 14 12 9 | 532.51±485.17 934.25±759.87 710.44±457.20 | 307.46±382.49 * 746.41±540.72 227.11±134.18 * | 190.06±108.84 * 612.66±505.56 366.78±251.87 |
X ± SD, compare with model group:
*P＜0.05,
*P＜001
Table 13 Fructus Corni extract is to the influence of rat model channel-type water maze learning and memory
| Group | School grade (4 cecum) | Memory achievement (4 cecum) | ||
| Swimming time (s) | Errors number | Swimming time (s) | Errors number | |
| Normal model model+Fructus Corni extract 3g/kg | 59.43±16.19 74.41±31.02 63.22±36.83 | 1.19±0.61 ** 2.92±1.83 2.78±2.38 | 28.64±20.55 ** 66.33±28.85 35.33±24.47 * | 0.39±0.77 * 1.83±2.02 0.61±0.82 * |
X ± SD, compare with model group:
*P＜0.05,
*P＜0.01
Table 14. Fructus Corni extract is kept away the influence of dark experiment to rat model
| Group | The example number | Latent period (second) | Errors number | Classification |
| Normal control model model+Fructus Corni extract 3g/kg | 14 12 9 | 234.644±20.04 * 169.75±99.34 211.25±58.42 | 0.07±0.27 * 0.92±1.31 0.25±0.46 | 0.07±0.27 * 1.17±1.59 0.38±0.74 |
X ± SD, compare with the mold crack group:
*P＜0.05,
*P＜0.01
(2) Fructus Corni extract suppresses rat model pallium acetylcholine esterase active
1. experiment purpose: acetylcholinesterase (AchE) is the enzyme of hydrolysis neurotransmitter acetylcholine in the brain.The AchE inhibitor can slow down the katabolism of vagusstoff, improves ability of learning and memory.This research is observed Fructus Corni extract bilateral ligation is caused the active influence of rat model pallium AchE.
2. the preparation of bilateral ligation rat model: the SD rat, intraperitoneal injection of anesthesia separates bilateral common carotid arteries, with No. 1 permanent ligation of silk thread, suture muscles skin.Prevention is irritated stomach and is given 2 weeks of Fructus Corni extract, 8 weeks of postoperative gastric infusion before the art.After big rat brain tissue homogenate is centrifugal, gets supernatant liquor and measure the AchE activity with biochemical method.
3. experimental result: Fructus Corni extract can obviously suppress bilateral ligation rat model pallium AchE activity (table 15), and the decomposition that may slow down vagusstoff helps improving learning and memory function.
Table 15. Fructus Corni extract is to the active influence of bilateral ligation rat model pallium AchE
| Group | The example number | AchE (umol/mg albumen) |
| Normal control model Fructus Corni extract 3g/kg | 12 8 6 | 0.430±0.073 * 0.623±0.189 0.329±0.077 ** |
X ± SD, compare with model group:
*P＜0.05,
*P＜0.01
(3) Fructus Corni extract suppresses rat model pallium monoamine oxidase-B activity
1. experiment purpose: multiple patient with nervous system disease monoamine oxidase-B (MAO-B) activity such as neural aging, the cerebrovascular, senile dementia, vascular dementia, Parkinson's disease, dysthymia disorders, neural inflammation increase, the MAO-B inhibitor can be used for treating multiple nervous system disorders, and this research is observed Fructus Corni extract to the active influence of bilateral ligation rat model nervous tissue MAO-B.
2. experimental technique: bilateral ligation model and medication are the same, after big rat brain tissue homogenate is centrifugal, gets supernatant liquor and measure the MAO-B activity with biochemical method.
3. experimental result: Fructus Corni extract can obviously suppress bilateral ligation and cause Model of Dementia rat cerebral cortex MAO-B activity (table 16).
Table 16. Fructus Corni extract is to the active influence of rat model pallium MAO-B
| Group | The example number | MAO-B(U/mg/h) |
| Normal control model Fructus Corni extract 3g/kg | 12 8 6 | 899.2±190.4 * 1214.0±230.1 851.3±263.5 * |
X ± SD, compare with model group:
*P＜0.05
Conclusion:
Fructus Corni extract shows tangible minimizing neurocyte and loses on multiple nerve injury and nervous system disorders animal model, strengthen neurotrophic factor expression, promotes the expression of wound circumference nerve growth associated protein, helps the growth of aixs cylinder; Alleviate damaged nerve tissue's oedema, reduce radical damage; Suppress calcium ion overload in the neurocyte; Suppress the monoamine oxidase-B activity, improve the injured nerve function, improve M-cholinergic receptor bonding force, strengthen choline acetyltransferase activity, the acetylcholine esterase inhibition isoreactivity; Improve learning and memory function; Neuronic various damages there is good protective action.Show that this drug regimen has the control nerve injury that causes of various factors and the purposes of multiple nervous system disorders.
Claims (7)
1, the purposes of Fructus Corni extract in preparation control nerve injury, Alzheimer ' s disease, Parkinson's disease or vascular dementia medicine and healthcare products; Wherein said Fructus Corni extract contains morroniside 25-50wt%, meliatin 25-40wt% by the gross weight of Fructus Corni extract, and the two total content accounts for 50-90%.
2, Fructus Corni extract is prevented and treated purposes in nervous system disorders medicine and the healthcare products in preparation; Wherein said Fructus Corni extract contains morroniside 25-50wt%, meliatin 25-40wt% by the gross weight of Fructus Corni extract, and the two total content accounts for 50-90%.
3, according to the purposes of claim 1 or 2, wherein said nerve injury or nervous system disorders are selected from the neural encephalopathic of cerebro-vascular diseases, cerebral anoxia, cerebral concussion, cerebral edema, nervous system injury or surgical injury, brain or tumor of spinal cord, compressive myelopathy, nutrition and metabolic, Wernicke encephalopathic, epilepsy, nervus centralis radiation injury, nerve degenerative diseases or Cognitive function damage.
4, according to the purposes of claim 1 or 2, it is characterized in that, by the gross weight of Fructus Corni extract, described Fructus Corni extract also contains one or more compositions in cornin, methyl Morroniside, dehydrogenation Ma Qiansu, sweroside or the 5 hydroxymethyl furfural of being selected from of 0.1-50%.
The pharmaceutical composition of 5, a kind of treatment nerve injury, Alzheimer ' s disease, Parkinson's disease or vascular dementia is characterized in that, contains the Fructus Corni extract of 5-100wt%, also contains the conventional pharmaceutical carrier of 0-95wt%; In the described Fructus Corni extract, morroniside content accounts for 25-50%, meliatin content accounts for 25-40%, and the two total content accounts for 50-90%.
6, according to the pharmaceutical composition of claim 5, it is characterized in that, contain the Fructus Corni extract of 50-90wt%, contain the conventional pharmaceutical carrier of 10-50wt%.
The Halth-care composition of 7, a kind of control nerve injury, Alzheimer ' s disease, Parkinson's disease or vascular dementia is characterized in that, contains the Fructus Corni extract of 5-80%, also contains conventional edible carrier and the foodstuff additive of 20-95%; In the described Fructus Corni extract, morroniside content accounts for 25-50%, meliatin content accounts for 25-40%, and the two total content accounts for 50-90%.
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| CN102329353A (en) * | 2007-09-13 | 2012-01-25 | 山东绿叶天然药物研究开发有限公司 | Method for preparing morroniside |
| CN101810335B (en) * | 2010-04-30 | 2012-07-25 | 西南大学 | Method for preparing health-care foods with different activities by comprehensively using dogwoods |
| CN102614243B (en) * | 2012-04-26 | 2013-10-30 | 西北大学 | Method for extracting common macrocarpium fruit total glycoside and application of common macrocarpium fruit total glycoside to preparation of hypoxia tolerant medicines |
| CN103360443A (en) * | 2013-07-30 | 2013-10-23 | 天津科丝美特生物科技有限公司 | Method for extraction and purification of four iridoid glycosides in cornus officinalis |
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