CN101254185A - Use of cyclic enol ether terpenoid for producing promotive neurocyte proliferate and differentiation medicament - Google Patents
Use of cyclic enol ether terpenoid for producing promotive neurocyte proliferate and differentiation medicament Download PDFInfo
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- CN101254185A CN101254185A CNA2007100844325A CN200710084432A CN101254185A CN 101254185 A CN101254185 A CN 101254185A CN A2007100844325 A CNA2007100844325 A CN A2007100844325A CN 200710084432 A CN200710084432 A CN 200710084432A CN 101254185 A CN101254185 A CN 101254185A
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
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- A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
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- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
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- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A—HUMAN NECESSITIES
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Abstract
The invention discloses an application of iridoids in preparing drugs for promoting nerve cell proliferation and/or differentiation and a method for treating diseases related to nerve cell proliferation and/or differentiation by using the same.
Description
Technical field
The present invention relates to purposes and the drug prepared compositions of iridoid in the medicine of preparation promotion neurocyte proliferation and/or differentiation.The present invention also relates to method with described chemical compound or medicine composite for curing or prevention and promotion neurocyte proliferation and/or differentiation diseases associated or disease.
Technical background
(neural stem cell NSC) is meant to have the self renewal ability among the central nervous system and can break up the pluripotent cell that produces ripe brain cell (comprising neuron, astrocyte and oligodendrocyte) to neural stem cell.Neural stem cell has self renewal ability, high proliferation potential and many differentiation potentials, can be divided into neuron, oligodendrocyte and astrocyte etc., the daughter cell that neural stem cell produces to central nervous system's growth, keep and implement the cell replacement treatment and have important function.The discovery of NSC and In vitro culture success are for the cell replacement therapy of central nervous system's disease has been widened road.As treat nervous system degenerative disease, as parkinson disease (PD), Alzheimer (AD) and Huntington Chorea (HD), can obviously improve symptom.Simultaneously, a large amount of external and in the verified adult brain of body experiment, have NSC really, lost the stimulation of active factors after just reaching maturity.These cells as brain tissue impairment, ischemia, factors stimulated growth etc., can breed, move and break up under certain conditions, the alternative certain function of neurocyte performance of losing of newborn neuron.Therefore, research promotes that effectively the method for cell proliferation of nerve cord and/or differentiation has important meaning.
Iridoid (Iridoids) is the special monoterpene of a class, and its parent nucleus is a ring-type all, has ethylene linkage and ehter bond.Get her ant lactone first in the defence secretions of nineteen twenty-five by her ant, O.Halpern in 1958 and H.Schmid to determining of plumieride structure the basic framework of iridoid.Iridoid in the plant kingdom is to generate smelly ant dialdehyde (iridodial) by geranyl pyrophosphate (GPP) through biosynthesis pathway, and acetal is derived and formed its basic framework such as following structural formula again.
1. the basic framework of iridoid
In the iridoid molecule, C
1-OH is very active, easily combines with sugared, and naturally occurring iridoid mostly is glycosides, and mostly is the D-glucoside.Comprise but not only have:
(1) common iridoid glycoside: 1. C-8 iridoid glycoside.2. C-9 iridoid glycoside (the 9th C is connected on the C-4).3. C-9 iridoid glycoside (the 9th C is connected on the C-8).4. C-10 iridoid glycoside.As 6 '-acetyl asperuloside, morroniside, meliatin, jasminoidin, catalpol, allamdin, allamandin, asperuloside, aucubin, catalposide, deoxidation loganin, genipin, plumericin, verbenalin, kingiside.
(2) secoiridoid glycosides: as gentiopicrin, the bitter ester glycosides of Radix Gentianae, Secologanin, Herba Swertiae bimaculatae bitter principle etc.
(3) Valeriana type iridoid, as 7,10,2 '-3 acetyl patrinosides and 10-acetyl patrinoside.
(4) Plumeria type iridoid: as poncirin A.
(5) 3,10 interdigits form the iridoid of oxo bridge, form the iridoid glycoside crescent glycosides B of oxo bridge as 3,10 interdigits.
(6) Schizonepetin correlation type iridoid has purple glycosides.
(7) Bian Xing class iridoid, crescent glycosides A for example, B, 8 poncirin B that ternary oxygen spirane structure is arranged.
(8) directly be formed by connecting by several iridoids through ester bond or by terpenoid, phenols.As acevaltratum, 10-deacetyl asperulosidic thuja acid methyl ester etc.
The inventor finds that iridoids has good short propagation and/or short differentiation to neural stem cell, thereby has finished the present invention by the research to meliatin and morroniside.
Summary of the invention
One aspect of the present invention provides iridoid for example meliatin and/or the purposes of morroniside in the medicine of preparation promotion cell proliferation of nerve cord and/or differentiation.The present invention also provides the pharmaceutical composition that contains iridoid and on the other hand with the method for described chemical compound or combination treatment and neurocyte proliferation and/or differentiation diseases related.
Along with the rapid renewal progress of modern molecular biology, the mankind might develop growing the propagation and the differentiation technique of perfect adult neurocyte.Based on short propagation and the differentiation of iridoid to neural stem cell, iridoid also has short propagation and differentiation to the adult neurocyte, and then the treatment a variety of causes causes is the nervous system disease of feature with the neuron loss.
The above method of iridoid and purposes can be to use separately to impel stem cells hyperplasia and the differentiation that remains in the sacred disease patient nervous system, or externally derived stem cells is transplanted to and is bred in the sacred disease patient nervous system and differentiation reaches treatment or prevention nervous system disease purpose.
Morroniside of the present invention, meliatin all have the basic framework of iridoid, can extract according to known method from Fructus Corni, or obtain from city's mid-sales.
Meliatin (loganin) morroniside (morroniside)
Chemical compound of the present invention also can be synthesized according to method known to those skilled in the art.
The present invention also plans to contain the homologue and the analog of this compounds except above-listed chemical compound.In this case, homologue is the molecule with substantive structural similarity of above-claimed cpd, and analog is the molecule with the substantive biological similarity that has nothing to do with structural similarity.
Pharmaceutical composition is also contained in the present invention, described compositions comprises iridoid and organic and pharmaceutically acceptable salt mineral acid, acid-addition salts for example, acid for example can be hydrochloric acid, sulphuric acid, methanesulfonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid etc.Pharmaceutically acceptable salt can also be by the processing of inorganic base and organic base and is prepared, and inorganic base is the hydroxide of sodium, potassium, ammonium, calcium or ferrum for example, and organic base is 2-aminopropane., trimethylamine, 2-ethylaminoethanol, histidine, procaine etc. for example.
Pharmaceutical composition is also contained in the present invention, and described compositions comprises the hydrate of iridoid.Term " hydrate " includes but not limited to semihydrate, monohydrate, dihydrate, trihydrate etc.
Pharmaceutical composition is also contained in the present invention, and described compositions comprises any solid or the liquid physical form of iridoid.For example, iridoid can be a crystal form, amorphous, and has particle diameter arbitrarily.The iridoid particle can be by micronization, perhaps can be coalescent microgranular granule, powder, oil, oil suspension or other solids or liquid physical form arbitrarily.
Pharmaceutical composition
The compounds of this invention and derivant thereof, fragment, analog, homologue, pharmaceutically acceptable salt or hydrate can be made with pharmaceutically acceptable carrier or excipient and be suitable for pharmaceutical composition for oral administration.This based composition comprises any above-claimed cpd and the pharmaceutically acceptable carrier for the treatment of effective dose usually.Preferably, effective dose is to promote the amount of neurocyte proliferation and/or differentiation effectively and less than causing the toxic amount of patient.
In preparation of the present invention, can use the inert excipient that generally is used as carrier or diluent arbitrarily, for example natural gum, starch, sugar, cellulosic material, acrylate or its mixture.Preferable absorbent is a microcrystalline Cellulose.Compositions can further comprise disintegrating agent (for example cross-linking sodium carboxymethyl cellulose) and lubricant (for example magnesium stearate), one or more additives be can comprise in addition, binding agent, buffer agent, protease inhibitor, surfactant, solubilizing agent, plasticizer, emulsifying agent, stabilizing agent, viscosity increasing agent, sweeting agent, film former or its combination in any are selected from.In addition, the present composition can be the form of controlled release preparation or IR formulation.
A kind of embodiment is the oral administration pharmaceutical composition, comprises iridoid or its pharmaceutically acceptable salt or hydrate, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose and magnesium stearate.Another kind of embodiment comprises iridoid or its pharmaceutically acceptable salt or hydrate, the microcrystalline Cellulose of 20-40 weight %, the cross-linking sodium carboxymethyl cellulose of 5-15 weight % and the magnesium stearate of 0.1-5 weight % of 50-70 weight %.Another kind of embodiment comprises the iridoid of about 50-200mg.
In one embodiment, pharmaceutical composition is an oral administration, thereby is formulated into the form that is suitable for oral administration, just solid or liquid prepared product.The solid orally ingestible that is fit to comprises tablet, capsule, pill, granule, piller etc.The liquid oral medicine that is fit to comprises solution, suspension, dispersion, Emulsion, oil preparation etc.In a kind of embodiment of the present invention, compositions is formulated into capsule.In this embodiment, the present composition also comprises hard gelatin capsule except iridoid reactive compound and inert carrier or diluent.
" pharmaceutically acceptable carrier " used herein plans to comprise arbitrarily and all solvent, disperse medium, coating, antibacterium and antifungal, isotonic agent and absorption delay agent etc. that they and pharmacy administration are compatible, for example aseptic pyrogen-free water.The carrier that is fit to is described among the latest edition Remington ' s Pharmaceutical Sciences, and it is the canonical reference book of this area, is incorporated herein by reference.The preferred embodiment of this class carrier or diluent includes but not limited to water, saline, Ringer's mixture, glucose solution and 5% human serum albumin.Can also use liposome and non-aqueous carrier, for example fixing oil.It is well known in the art that this class medium and reagent are applied to pharmaceutically active substances.Unless any conventional media or reagent and reactive compound are not compatible, in its purposes in compositions all is encompassed in.Can also mix the complementarity reactive compound to compositions.
Solid carrier/diluent includes but not limited to natural gum, starch (for example corn starch, pregelatinized starch), sugar (for example lactose, mannitol, sucrose, glucose), cellulosic material (for example microcrystalline Cellulose), acrylate (for example polymethacrylates), calcium carbonate, magnesium oxide, Talcum or its mixture.
With regard to liquid preparation, pharmaceutically acceptable carrier can be aqueous or non-aqueous solution, suspension, Emulsion or oil.The example of non-aqueous solvent has propylene glycol, Polyethylene Glycol and injectable organic ester, for example ethyl oleate.Aqueous carrier comprises water, alcohol/aqueous solution, emulsion or suspension, comprises saline and the buffered medium of process.The example of oil has those of oil, animal, plant or synthetic source, for example Oleum Arachidis hypogaeae semen, soybean oil, mineral oil, olive oil, sunflower oil and cod-liver oil.Solution or suspension can also comprise following component: sterile diluent, for example water for injection, saline solution, fixing oil, Polyethylene Glycol, glycerol, propylene glycol or other synthetics; Antibacterial, for example benzyl alcohol or methyl parahydroxybenzoate; Antioxidant, for example ascorbic acid or sodium sulfite; Chelating agen, for example ethylenediaminetetraacetic acid (EDTA); Buffer agent, for example acetate, citrate or phosphate; With the reagent of regulating opening property, for example sodium chloride or glucose.PH can regulate with acid or alkali, for example hydrochloric acid or sodium hydroxide.
In addition, compositions can further comprise binding agent (arabic gum for example, corn starch, gelatin, carbomer, ethyl cellulose, guar gum, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, polyvidone), disintegrating agent (corn starch for example, potato starch, alginic acid, silicon dioxide, cross-linking sodium carboxymethyl cellulose, polyvinylpolypyrrolidone, guar gum, primojel, Primogel), the buffer agent of different pH and ionic strength (Tris-HCl for example, acetate, phosphate), prevent the additive (for example albumin or gelatin) that the surface absorbs, detergent (polysorbas20 for example, Tween 80, Pluronic F68, bile salt), protease inhibitor, surfactant (for example sodium lauryl sulfate), penetration enhancers, solubilizing agent (glycerol for example, polyethylene glycerol), fluidizer (for example silica sol), antioxidant (ascorbic acid for example, sodium metabisulfite, butylatedhydroxyanisole), stabilizing agent (hydroxypropyl cellulose for example, hydroxypropyl emthylcellulose), viscosifier (carbomer for example, silica sol, ethyl cellulose, guar gum), sweeting agent (sucrose for example, aspartame, citric acid), correctives (Herba Menthae for example, methyl salicylate or orange flavoring), antiseptic (thimerosal for example, benzyl alcohol, p-Hydroxybenzoate), lubricant (stearic acid for example, magnesium stearate, Polyethylene Glycol, sodium lauryl sulfate), flow promortor (for example silica sol), plasticizer (diethyl phthalate for example, triethyl citrate), emulsifying agent (carbomer for example, hydroxypropyl cellulose, sodium lauryl sulfate), polymer coating (for example poloxamer or poloxamine), coating and film former (ethyl cellulose for example, acrylate, polymethacrylates) and/or auxiliary agent.
In one embodiment, will protect chemical compound to prevent to eliminate rapidly from body with the carrier that reactive compound is prepared, controlled release preparation for example comprises the delivery system of implant and microencapsulation.Can use polymer biodegradable, bio-compatible, for example ethylene vinyl acetate, polyanhydride, polyglycolic acid, collagen, poe and polylactic acid.The preparation method of this class preparation will be conspicuous to those skilled in the art.Material can also be commercial from Alza Corporation and Nova Pharmaceuticals, and Inc obtains.Can also use liposome suspension (comprising the liposome that is oriented to infection cell and the monoclonal antibody of virus antigen) as pharmaceutically acceptable carrier.These can be prepared according to method known to those skilled in the art, and for example U.S. Patent No. 4,522, and 811 is described.
The Orally administered composition of preparation dosage unit form is particularly advantageous in light administration and dosage concordance.Dosage unit form used herein is represented physically discrete unit, is suitable as curee's unit dose; Each unit contains and the associating scheduled volume reactive compound of required pharmaceutical carrier, produces required therapeutic effect according to calculating.The specification of dosage unit form of the present invention depends on and directly depends on the specific characteristic of reactive compound and the particular treatment effect that will reach, and this area is around the inherent restriction with regard to individual treatment of a kind of like this reactive compound.
Pharmaceutical composition can instruct with administration and be included in container, packing or the dispenser.
The compounds of this invention or compositions can repeat administration every day continuously and reach a couple of days to the several years.Oral medication can continue thoughtful patient's life-span.Preferably, administration reaches continuous five days, then can evaluate patient need to determine whether further administration.Administration can be successive or intermittently, treatment was succeeded by the rest period in just continuous several days.
The preparation of drug combination that contains active component is well known in the art, for example mixing, pelletize or tabletting process.Often with active treatment composition and mixed with excipients pharmaceutically acceptable and can be compatible with active component.With regard to oral administration, active agent is mixed with the additive that is customarily used in this purpose, for example carrier, stabilizing agent or inert diluent, relend the dosage form that helps conventional process to be converted into to be suitable for administration, for example tablet, coated tablet, hard or Gelseal, water, alcohol or oil solution etc., as mentioned above.
The The compounds of this invention oral administration total every day dosage 25 to 4000mg/m
2Between, for example about 25 to 1000mg, 50-1000mg, 100mg, 200mg, 300mg, 400mg, 600mg, 800mg, 1000mg etc.Usually, when the patient is administered to many 400mg, with chemical compound as the single dose administration.(just greater than 400mg) is divided into a plurality of dosage with total amount with regard to higher accumulated dose, for example twice of every day, every day three inferior, time that in the same day, equated at interval preferably.For example, can at interval give two doses in 12 hours, each 500mg for example, one day accumulated dose reaches 1000mg.
In a kind of presently preferred embodiments, iridoid is 200mg to accumulated dose every day of patient's administration.In another kind of presently preferred embodiments, iridoid is 400mg to accumulated dose every day of patient's administration.In another kind of presently preferred embodiments, iridoid is 600mg to accumulated dose every day of patient's administration.
Chemical compound to the amount of patient's administration less than causing toxic amount to the patient.In some embodiments, chemical compound equals or exceeds the amount of toxicity of compound level less than the concentration that causes chemical compound in patient's blood plasma to the amount of patient's administration.Preferably, the concentration of chemical compound in patient's blood plasma maintains about 10nM.In another embodiment, the concentration of chemical compound in patient's blood plasma maintains about 25nM.In another embodiment, the concentration of chemical compound in patient's blood plasma maintains about 50nM.In another embodiment, the concentration of chemical compound in patient's blood plasma maintains about 100nM.In another embodiment, the concentration of chemical compound in patient's blood plasma maintains about 500nM.In another embodiment, the concentration of chemical compound in patient's blood plasma maintains about 1000nM.In another embodiment, the concentration of chemical compound in patient's blood plasma maintains about 2500nM.In another embodiment, the concentration of chemical compound in patient's blood plasma maintains about 5000nM.In enforcement of the present invention, chemical compound should will depend on employed specific compound and sanatory type to the optimised quantity of patient's administration.
In current preferred embodiment of the present invention, pharmaceutical composition comprises common iridoid glycoside; Microcrystalline Cellulose is as carrier or diluent; Cross-linking sodium carboxymethyl cellulose is as disintegrating agent; With magnesium stearate as lubricant.In particularly preferred embodiments, iridoid is morroniside or meliatin.
Active component and the percentage ratio of various excipient in preparation can have nothing in common with each other.For example, compositions can comprise the common iridoid glycoside of 20 to 90 weight %, preferred 50-70 weight %.In addition, compositions can comprise the microcrystalline Cellulose of 10 to 70 weight %, preferred 20-40 weight % as carrier or diluent.In addition, compositions can comprise the cross-linking sodium carboxymethyl cellulose of 1 to 30 weight %, preferred 5-15 weight % as disintegrating agent.In addition, compositions can comprise the magnesium stearate of 0.1-5 weight % as lubricant.In another preferred embodiment, compositions comprises the iridoid (for example iridoid of 50mg, 100mg and 200mg) of about 50-200mg.In particularly preferred embodiments, compositions is the form of tablet or gelatine capsule agent.
Current preferred embodiment of the present invention is the solid preparation of iridoid and microcrystalline Cellulose NF (Avicel Ph 101), cross-linking sodium carboxymethyl cellulose NF (AC-Di-Sol) and magnesium stearate NF, is included in the gelatine capsule.Further preferred embodiment is 200mg solid SAHA and 89.5mg microcrystalline Cellulose, 9mg cross-linking sodium carboxymethyl cellulose and 1.5mg magnesium stearate, is included in the gelatine capsule.
Pharmaceutical composition of the present invention not only can be used for promoting the propagation and the differentiation of neurocyte, and should it is evident that to those skilled in the art, and these compositionss can be used for treating the multiple disease that has been found that iridoid is useful.
For example, have been found that iridoid, can be used for treating the disease of the appearance neuron loss that a variety of causes causes, comprise central nervous system injury, comprise but not only in ischemic, traumatic and ethanol brain or spinal cord injury; The systemic wasting disease of the system that affects the nerves, Basal ganglia degenerative disease, myodystonia, idiopathic extrapyramidal disease; And nervous system degeneration disease.Ischemia injury comprises cerebral ischemia (for example as wound, epilepsy, hemorrhage or apoplexy result's brain injury, they all can cause neural degeneration); Amyotrophic lateral sclerosis (ALS); Multiple sclerosis; Myopathy, for example muscle protein metabolic disease.
For example, have been found that iridoid can be used for treating multiple neurodegenerative disease, its non exhaustive property tabulation has:
I. be the obstacle of feature, for example Alzheimer with the progressive dementia that does not have other outstanding neurological's symptom to exist; Senile Alzheimer type dementia; And Pick's disease (circumscribed atrophy of brain).
II. be associated with the outstanding unusual syndrome of neurological of progressive dementia and other, for example A) be mainly seen in adult's syndrome (for example Huntington's disease, be associated with dull-witted and ataxic multiple system atrophy and/or parkinsonian performance, progressive supranuclear plasy (Steel-Richardson-Olszewski), diffusibility sharp dimension corpusculum disease and corticodentatonigral degeneration); And B) is mainly seen in child or young syndrome (for example hallervorden-Spatz disease and progressive familial myoclonic epilepsy).
III. position with the motion gradual unusual syndrome, for example Parkinsonism (parkinson), striatonigral degeneration, progressive supranuclear plasy, torsion dystonia (torsion spasm; Dystonia musculorum deformans), spasmodic torticollis and other dyskinesia, familial tremor and Tourette's syndrome.
IV. carrying out property ataxic syndrome, for example cerebellar degeneration (for example cortex of cerebellum degeneration and olivopontocerebellar atrophy (OPCA)) and spinocerebellar degeneration (friedreich's ataxia and associated disorders).
V. the syndrome of maincenter autonomic nervous system depletion (Shy-Drager syndrome).
VI. do not feel the muscle that changes is weak and become thin syndrome (motor neuron disease, for example amyotrophic lateral sclerosis, spinal muscular atrophy (for example baby's spinal muscular atrophy (Werdnig-Hoffman), teenager spinal muscular atrophy (Wohlfart-Kugelberg-Welander) and other forms of familial spinal muscular atrophy), primary lateral sclerosis and hereditary spastic paraplegia.
VII. be associated with syndrome (the carrying out property neuromuscular atrophy that muscle is weak and become thin and feel to change; Chronic familial polyneuropathy), for example A. calf amyotrophy (Charcot-Marie-Tooth), the various forms of chronic progressive external neuropathys of matter polyneuropathy (Dejerine-Sottas) and C. between the B. hypertrophy.
VIII. the syndrome of carrying out property visual deprivation, for example pigmentary retinal dystrophy (retinitis pigmentosa) and hereditary optic atrophy (leber's disease).
Embodiment in the following experimental detail part further sets forth the present invention.This part helps to understand invention, but the invention of not planning, also should not being interpreted as limiting following claims by any way and being limited.
Description of drawings:
Fig. 1. iridoid meliatin and morroniside are to the influence of cell proliferation of nerve cord.
A. matched group: cultivated 6 days most cell deaths (* 200) with the DMEM/F12 culture fluid that does not add somatomedin; B. do not add and add meliatin 50 μ g/ml in the DMEM/F12 culture fluid of somatomedin, cultivated neural stem cell sphere volume increase (* 200) 6 days; C. do not add and add meliatin 25 μ g/ml in the DMEM/F12 culture fluid of somatomedin, cultivated 14 days, the neural stem cell volume further increases (* 200); D. do not add and add morroniside 25 μ g/ml in the DMEM/F12 culture fluid of somatomedin, cultivated visible neural stem cell sphere volume increase (* 200) 6 days; E. do not add and add morroniside 25 μ g/ml in the DMEM/F12 culture fluid of somatomedin, cultivated 14 days, the neural stem cell volume further increases (* 200).
Fig. 2. iridoid meliatin and morroniside promote the cell differentiation of nerve cord effect.
A matched group: with the DMEM/F12 culture fluid induced nerve stem cells differentiation that contains 1% hyclone (FBS) 7 days, unicellularly move out from cell ball periphery, the form of cell of moving out is broadly divided into two kinds: 1. fraction cell cell space form is near oval, 2～3 elongated projections are arranged, be similar to neuronic form; 2. the out-of-shape of most of cell, projection is more, through the immunocytochemistry interpretation, is respectively neuron, glial cell and astrocyte (* 200).B induces differentiation 7 days with the DMEM/F12 culture fluid (no FBS) that contains meliatin 50ug/ml, and the cell ball is almost completely adherent, good differentiation, the cell of moving out radial arrangement heterogeneous, but interconnection reticulating (* 200) between the cell.C induces differentiation 7 days with the DMEM/F12 culture fluid (no FBS) that contains morroniside 50ug/ml, and the cell ball is almost completely adherent, and good differentiation, the projection of the cell of moving out join end to end " beading " (* 200).
Fig. 3. cell proliferation of nerve cord effect behind the iridoids pharmaceutical composition promotion brain injury.
A normal rat hippocampus dentate gyrus has the Brdu positive neurons stem cell of the distribution of being dispersed in, and the positive cell karyon is painted, and majority is oval; There is the Brdu positive neurons stem cell of the distribution of being dispersed in B normal rat ventricles of the brain lower floor, and the positive cell karyon is painted, and majority is oval; C. the Brdu positive neurons stem cell of cerebral ischemic model group rat hippocampus dentate gyrus significantly increases than normal group; D. the Brdu positive neurons stem cell of cerebral ischemic model group rat ventricles of the brain lower floor significantly increases than normal group; E gives the iridoids pharmaceutical composition, and (meliatin: the cerebral ischemic model group rat hippocampus dentate gyrus Brdu positive neurons stem cell number morroniside compositions=1: 1) significantly increases than normal group and model group; F gives the iridoids pharmaceutical composition, and (meliatin: the cerebral ischemic model group rat ependyma Brdu positive neurons stem cell number morroniside compositions=1: 1) significantly increases than normal group and model group.
Embodiment 1
Meliatin and morroniside promote neural stem cell survival proliferation function
One, experiment purpose
Observe the influence of meliatin and morroniside to neural stem cell survival proliferation function.
Two, experimental technique
Get newborn 1 day SD rat, get brain under the aseptic condition, separate Hippocampus, place the culture dish that fills the sugared DMEM/F12 of a small amount of height; Divest meninges and vascular tissue, will organize as far as possible to shred, add cell culture fluid 5ml, blow and beat gently with the Pasteur suction pipe of flame polish and make cell suspension, 400 eye mesh screens filter, and tire is expected the ratio of blue dyeing counting living cells, behind the cell counting with 2 * 10
6The density of individual cell/ml is inoculated into the culture bottle of 25ml.Adopt basic culture solution DMEM/F12 (1: 1) and B27 (2%), and add meliatin and the morroniside that final concentration is respectively 10,50,100,200,400 μ g/ml respectively, to cultivate in 37 ℃ of culture plate immigrations, 5%CO2, the 95% air balance humidity incubator, inverted microscope observation of cell upgrowth situation, little chi is measured the cell bulb diameter.
Neural stem cell is identified, get above-mentioned cell ball, removal contains the culture fluid of somatomedin EGF and bFGF, add the DMEM/F12 that contains 10%FBS, plant in 24 well culture plates that are covered with poly-D-lysine, row nestin and doublecortin (DCX) immunocytochemical stain in the time of 16 hours, cell almost is the nestin and the doublecortin positive, illustrates that the cultured cells ball is neural ancestral cells.
Three, experimental result
As can be seen from Figure 1, cultivated 6 days with the DMEM/F12 culture fluid that does not add somatomedin, most cell deaths, cell is disperse state.Do not add and add meliatin 25～200ug/ml in the DMEM/F12 culture fluid of somatomedin, cultivated 6 days, the neural stem cell sphere volume increases, and the effective range of breeding for short stem cell survival is with 50～100ug/ml the best; Morroniside 25～100ug/ml, the neural stem cell sphere volume increases, for the effective range of short cell survival propagation, with 25～50ug/ml the best.Illustrate that meliatin and morroniside can effectively promote neural stem cell survival propagation.
Embodiment 2
Meliatin and morroniside promote the cell differentiation of nerve cord effect
One, experiment purpose
Observe the influence of meliatin and morroniside to the cell differentiation of nerve cord effect
Two, experimental technique
Get second filial generation neural stem cell ball, remove the culture fluid that culture bottle contains somatomedin, the cell ball is divided into 2 groups at random, 1. hyclone (FBS) matched group: culture fluid is DMEM/F12+10%FBS; 2. drug treating group: add meliatin or the morroniside that final concentration is 10,50,100 μ g/ml among the no FBS culture fluid DMEM/F12 respectively, above-mentioned two groups of cell kinds are in 24 well culture plates that are covered with poly-D-lysine, row immunofluorescence dyeing after 7 days, observation is taken pictures.
Three, experimental result
Hyclone cellular control unit ball is adherent fully, unicellularly moves out from cell ball periphery, and the form of the cell of moving out is broadly divided into two kinds: 1. fraction cell cell space form has 2～3 elongated projections near oval; 2. the cell space of most of cell is bigger, out-of-shape, and projection is more, through the immunocytochemistry interpretation, is respectively neuron, glial cell and astrocyte.
Add respectively in the Tissue Culture Plate of meliatin and morroniside among the no FBS culture fluid DMEM/F12,10, two groups of cell balls of 50 μ g/ml are almost completely adherent, good differentiation, the move out radial arrangement of cell of cell, but interconnection reticulating between the cell, or the projection of several cells joins end to end " beading "; The result of 100 μ g/ml group is basic identical.The result shows that meliatin and morroniside have good short differentiation (Fig. 2) to neural stem cell.
Embodiment 3
Cell proliferation of nerve cord effect behind the compositions promotion brain injury of meliatin and morroniside
One, experiment purpose
Observe meliatin and morroniside compositions to the neurogenetic influence of apoplexy rat model
Two, experimental technique
The SD rat, the filling stomach gives meliatin and morroniside compositions (1: 1) (heavy dose of 180mg/kg, middle dosage 60mg/kg, low dose of 20mg/kg) was made the focal cerebral ischemia rat model with line bolt legal system after 7 days, after the modeling in 4～7 days continuously lumbar injection give Brdu (10mg/ml, 50mg/kg/ time, 2 times/d) labelling endogenous proliferating cells, perfusion in the 8th day, fix, get brain, continuous frozen section, the thick 30～40um of sheet, row immunofluorescence dyeing.
Three, experimental result
There are the Brdu positive cell of the distribution of being dispersed in normal rat hippocampus dentate gyrus (DG) and ventricles of the brain lower floor (SVZ), and the positive cell karyon is painted, and majority is oval; The positive cell of model group rat DG and SVZ significantly increases than normal group; The positive cell of the heavy dose of group of meliatin and morroniside compositions rat increases than normal group and model group.Illustrate that meliatin and morroniside compositions can promote cell proliferation of nerve cord (Fig. 3) behind the brain injury.
Claims (10)
1. iridoid promotes purposes in the medicine of neurocyte proliferation and/or differentiation in preparation.
2. according to the purposes of claim 1, wherein said iridoid is common iridoid glycoside.
3. according to the purposes of claim 2, wherein said iridoid glycoside is morroniside or its homologue or analog.
4. according to the purposes of claim 2, wherein said iridoid glycoside is meliatin or its homologue or analog.
5. according to each purposes of claim 1-4, wherein said promotion neurocyte proliferation and/or differentiation are the diseases that is used for the treatment of the appearance neuron loss that a variety of causes causes.
6. according to each purposes of claim 1-4, wherein said promotion neurocyte proliferation and/or differentiation are to be used for the treatment of the nervous system degeneration disease.
7. according to the purposes of claim 5 or 6, wherein said disease is systemic wasting disease, Basal ganglia degenerative disease, myodystonia, idiopathic extrapyramidal disease or the multiple sclerosis of parkinson disease, Alzheimer, Huntington Chorea, amyotrophic lateral sclerosis, movement disorder disease, the property amyotrophy of spinal cord source and relevant disease, the system that affects the nerves.
8. according to each purposes of claim 1-4, wherein said promotion neurocyte proliferation and/or differentiation are to be used for the treatment of central nervous system injury.
9. according to the purposes of claim 8, wherein said central nervous system injury is ischemic, traumatic and ethanol brain or spinal cord injury.
10. according to the purposes of claim 9, wherein said central nervous system injury is a traumatic brain injury.
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| CN2007100844325A CN101254185B (en) | 2007-03-02 | 2007-03-02 | Use of cyclic enol ether terpenoid for producing promotive neurocyte proliferate and differentiation medicament |
| PCT/CN2008/000427 WO2008106863A1 (en) | 2007-03-02 | 2008-03-03 | The use of iridoids in the manufacture of the medicine for promoting nerve cell proliferation and differentiation |
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| CN2007100844325A CN101254185B (en) | 2007-03-02 | 2007-03-02 | Use of cyclic enol ether terpenoid for producing promotive neurocyte proliferate and differentiation medicament |
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| WO2008106863A1 (en) | 2008-09-12 |
| CN101254185B (en) | 2012-05-30 |
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