WO2008106863A1 - Utilisation d'iridoïdes pour la fabrication de médicaments promouvant la prolifération et-ou la différenciation de cellules nerveuses - Google Patents

Utilisation d'iridoïdes pour la fabrication de médicaments promouvant la prolifération et-ou la différenciation de cellules nerveuses Download PDF

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WO2008106863A1
WO2008106863A1 PCT/CN2008/000427 CN2008000427W WO2008106863A1 WO 2008106863 A1 WO2008106863 A1 WO 2008106863A1 CN 2008000427 W CN2008000427 W CN 2008000427W WO 2008106863 A1 WO2008106863 A1 WO 2008106863A1
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Prior art keywords
differentiation
disease
use according
iridoid
proliferation
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PCT/CN2008/000427
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English (en)
Chinese (zh)
Inventor
Lin Li
Wen Wang
Haifeng Wei
Ruiqin Yao
Xiaoli Li
Ruyi Zhang
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Xuanwu Hospital Of Capital Medical University
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Publication of WO2008106863A1 publication Critical patent/WO2008106863A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to the use of an iridoid compound for the preparation of a medicament for promoting proliferation and/or differentiation of nerve cells and a pharmaceutical composition prepared.
  • the invention also relates to a method of treating or preventing a disease or condition associated with promoting proliferation and/or differentiation of nerve cells with said compound or pharmaceutical composition.
  • Neural stem cells are pluripotent cells that are self-renewing in the central nervous system and capable of differentiating to produce mature brain cells, including neurons, astrocytes, and oligodendrocyte. Neural stem cells have the ability of self-renewal, high proliferative potential and multi-differentiation, and can differentiate into neurons, oligodendrocytes and astrocytes. The development and maintenance of the central nervous system by the daughter cells produced by the neural cells And the implementation of cell replacement therapy plays an important role. The discovery of NSC and successful in vitro culture have broadened the path for cell replacement therapy for central nervous system diseases.
  • Neurodegenerative diseases such as Parkinson's disease (PD), Alzheimer's disease (AD), and Huntington's disease (HD) can significantly improve symptoms.
  • PD Parkinson's disease
  • AD Alzheimer's disease
  • HD Huntington's disease
  • a large number of in vitro and in vivo experiments have confirmed the existence of NSC in the adult brain, but the stimulation of the active factor is lost after development.
  • These cells can undergo proliferation, migration and differentiation under certain conditions, such as brain tissue damage, ischemia, growth factor stimulation, etc. Newborn neurons can replace the lost nerve cells to perform certain functions. Therefore, it is important to study effective methods for promoting proliferation and/or differentiation of neural stem cells.
  • Iridoids are a special class of monoterpene compounds in which the mother nucleus is cyclic and has an olefinic bond and an ether bond.
  • the iridoids in the plant kingdom are derived from aldehyde aryl phthalate (GPP) by biosynthetic route to form ir idodia, which is derived from the acetal.
  • the basic skeleton is as follows.
  • C-guang 0H The basic skeleton of iridoids In the cyclomethine oxime molecule, C-guang 0H is very active and easily binds to sugar.
  • the naturally occurring iridoids are mostly glycosides, and most of them are D-glucosides. Contains but not only:
  • Valeriana-type iridoids such as 7,10, 2, -3 acetyl sulfonate, and 10-acetyl sulphate sauce.
  • Plumer ia type quinone ether such as glucoside A.
  • iridoids have a good pro-proliferation and/or differentiation-promoting action on neural stem cells by studying horse physin and morroniside, and thus completed the present invention. Summary of the invention
  • the invention provides the use of an iridoid compound such as cycline and/or morroniside in the manufacture of a medicament for promoting proliferation and/or differentiation of neural stem cells.
  • an iridoid compound such as cycline and/or morroniside
  • Another aspect of the invention also provides a pharmaceutical composition comprising an iridoid compound and a method of treating a disease associated with proliferation and/or differentiation of nerve cells with the compound or composition.
  • cyclohexene compounds may also promote proliferation and differentiation of adult nerve cells, and thus treat various causes of neuronal loss. Nervous system disease.
  • the above described methods and uses of the iridoids may be used alone to promote proliferation and differentiation of stem cells remaining in the nervous system of a neurological patient, or Exogenous stem cells are transplanted into the nervous system of patients with neurological diseases for proliferation and differentiation to achieve the purpose of treating or preventing neurological diseases.
  • the morroniside and the loganin of the present invention each have a basic skeleton of an iridoid, which can be extracted from hawthorn according to a known method, or obtained from a commercially available product.
  • the present invention is intended to encompass homologs and analogs of such compounds in addition to the above listed compounds.
  • the homologue is a molecule having substantial structural similarity to the above compounds
  • the analog is a molecule having substantial biological similarity irrespective of structural similarity.
  • the present invention also encompasses pharmaceutical compositions comprising a pharmaceutically acceptable salt of an iridoid compound and an organic and inorganic acid, such as an acid addition salt, the acid being, for example, hydrochloric acid, sulfuric acid, methanesulfonic acid, Fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid, and the like.
  • the pharmaceutically acceptable salts can also be prepared by treatment with inorganic bases such as sodium, potassium, ammonium, calcium or iron hydroxides, organic hydrazines such as isopropylamine, tridecylamine, 2-ethylamino. Ethanol, histidine, procaine, etc.
  • the invention also encompasses pharmaceutical compositions comprising a hydrate of an iridoid compound.
  • hydrate includes, but is not limited to, hemihydrate, monohydrate, dihydrate, trihydrate, and the like.
  • the invention also encompasses pharmaceutical compositions comprising any solid or liquid physical form of the iridoid compound.
  • the iridoid compound may be in a crystalline form, amorphous, and have an arbitrary particle size.
  • the iridoid quinone particles may be micronized, or may be coalesced particulate granules, powders, oils, oil suspensions or any other solid or liquid physical form.
  • compositions suitable for oral administration may be combined with a pharmaceutically acceptable carrier or excipient to produce a pharmaceutical composition suitable for oral administration.
  • a pharmaceutically acceptable carrier or excipient typically comprise a therapeutically effective amount of any of the above compounds and a pharmaceutically acceptable carrier.
  • the effective amount is an amount effective to promote proliferation and/or differentiation of nerve cells and less than an amount that causes toxicity to the patient.
  • compositions of the invention may be employed in the formulations of the present invention.
  • a preferred diluent is microcrystalline cellulose.
  • the composition may further comprise a disintegrant (such as croscarmellose sodium) and a lubricant (such as magnesium stearate), and may additionally comprise one or more additives selected from the group consisting of a binder, a buffer, and a protease.
  • the compositions of the invention may be in the form of a controlled release formulation or an immediate release formulation.
  • One embodiment is a pharmaceutical composition for oral administration comprising an iridoid compound or a pharmaceutically acceptable salt or hydrate thereof, microcrystalline cellulose, croscarmellose sodium and magnesium stearate .
  • Another embodiment comprises 50 to 70% by weight of an iridoid compound or a pharmaceutically acceptable salt or hydrate thereof, 20 to 40% by weight of microcrystalline cellulose, and 5 to 15% by weight of a crosslinked carboxy group.
  • Another embodiment comprises about 50 to 200 mg of the iridoids Compound.
  • the pharmaceutical composition is administered orally and is thus formulated in a form suitable for oral administration, i.e., a solid or liquid preparation.
  • Suitable solid oral preparations include tablets, capsules, pills, granules, pellets and the like.
  • Suitable liquid oral preparations include solutions, suspensions, dispersions, emulsions, oils and the like.
  • the composition is formulated as a capsule.
  • the composition of the present invention comprises a hard gelatin capsule in addition to the iridoid active compound and the inert carrier or diluent.
  • pharmaceutically acceptable carrier is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, etc., which are compatible with pharmaceutical administration.
  • sterile pyrogen-free water Suitable carriers are described in the latest edition of Remington's Pharmaceutica l Sciences, which is a standard reference in the art, which is incorporated herein by reference.
  • Preferred examples of such carriers or diluents include, but are not limited to, water, saline, Ringer's solution, dextrose solution, and 5% human serum albumin.
  • Liposomes and non-aqueous carriers such as fixed oils can also be used.
  • the use of such intermediaries and reagents for pharmaceutically active substances is well known in the art. Unless any conventional media or agent is incompatible with the active compound, its use in the conjugate is covered. Supplementary active compounds can also be incorporated into the compositions.
  • Solid carriers/diluents include, but are not limited to, starch (eg, corn starch, pregelatinized starch), sugars (eg, lactose, mannitol, sucrose, glucose), cellulosic materials (eg, microcrystalline cellulose), acrylic acid An ester such as polymethacrylate, calcium carbonate, magnesium oxide, talc or a mixture thereof.
  • starch eg, corn starch, pregelatinized starch
  • sugars eg, lactose, mannitol, sucrose, glucose
  • cellulosic materials eg, microcrystalline cellulose
  • acrylic acid An ester such as polymethacrylate, calcium carbonate, magnesium oxide, talc or a mixture thereof.
  • the pharmaceutically acceptable carrier can be an aqueous or nonaqueous solution, suspension, emulsion or oil.
  • non-aqueous solvents are propylene glycol, polyethylene glycol, and injectable organic esters such as ethyl oleate.
  • Aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media.
  • oil are oil, moving Those of vegetable, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, olive oil, sunflower oil and cod liver oil.
  • the solution or suspension may also include the following components: sterile diluents such as water for injection, saline solution, fixed oil, polyethylene glycol, glycerol, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or p-hydroxybenzoic acid a methyl ester; an antioxidant such as ascorbic acid or sodium hydrogen sulfite; a chelating agent such as ethylenediaminetetraacetic acid (EDTA); a buffering agent such as acetate, citrate or phosphate; and an agent for regulating the elongation, for example Sodium chloride or glucose.
  • sterile diluents such as water for injection, saline solution, fixed oil, polyethylene glycol, glycerol, propylene glycol or other synthetic solvents
  • antibacterial agents such as benzyl alcohol or p-hydroxybenzoic acid a methyl ester
  • an antioxidant such as ascorbic acid or sodium hydrogen sulfite
  • composition may further comprise a binder (eg, gum arabic, corn starch, gelatin, carbomer, ethyl cellulose, guar gum, hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone) ), disintegrating agents (such as corn starch, potato starch, alginic acid, silica, croscarmellose sodium, crospovidone, guar gum, sodium starch glycolate, Pr imogel), different pH And ionic strength buffers (such as Tr i s-HC1, acetate, phosphate), additives to prevent surface absorption (such as albumin or gelatin), detergents (such as Tween 20, Tween 80, Pluronic F68, Bile acid salts), protease inhibitors, surface agents (such as sodium lauryl sulfate), penetration enhancers, solubilizers (eg glycerol, polyethylene glycerol), glidants (eg colloidal silica), antioxidants (
  • the carrier formulated with the active compound will protect the compound from rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems.
  • a controlled release formulation including implants and microencapsulated delivery systems.
  • Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acids. Methods of preparing such formulations will be apparent to those skilled in the art. Materials are also commercially available from Alza Corporation and Nova Pharmaceuticas, Inc. Liposomal suspensions (including monoclonal antibodies directed against liposomes and viral antigens that infect cells) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Patent No. 4,522,811.
  • Dosage unit form denotes physically discrete units suitable as unitary dosages of the subject; each unit contains a predetermined amount of active compound associated with the desired pharmaceutical carrier, which yields the desired therapeutic effect.
  • the specifications of the dosage unit form of the present invention depend on and depend directly on the unique characteristics of the active compound and the particular therapeutic effect to be achieved, as well as the limitations inherent in such art in the context of such an active compound.
  • the pharmaceutical composition can be included in a container, package or dispenser together with instructions for administration.
  • the compound or composition of the present invention can be continuously administered daily for several days to several years. Oral treatment can last for a week to the life of the patient. Preferably, the administration is for up to five consecutive days and the patient can then be evaluated to determine if further administration is desired. Administration can be continuous or intermittent, i.e., treatment for several consecutive days followed by a rest period.
  • compositions containing the active ingredient is well known in the art, such as mixing Combine, granulate or tablet.
  • the active therapeutic ingredient is often combined with excipients which are pharmaceutically acceptable and compatible with the active ingredient.
  • the active agent is mixed with an additive conventionally used for this purpose, such as a carrier, a stabilizer or an inert diluent, and converted into a dosage form suitable for administration by a conventional method, such as a tablet, a coated tablet, Hard or soft gelatin capsules, water, alcohol or oil solutions, etc., as described above.
  • the total daily dose of the compound of the present invention for oral administration is between 25 and 4000 mg/m 2 , such as about 25 to 1000 mg, 50 - l OOO mg, 100 mg, 200 mg, 300 mg, 400 mg, 600 mg, 800 mg, l OOOmg, and the like.
  • the compound is administered as a single dose.
  • the total amount is divided into multiple doses, such as twice daily, three times daily, etc., preferably at equal intervals within the day.
  • two doses, for example 500 mg each can be administered at intervals of 12 hours, with a total dose of 1000 mg per day.
  • the total daily dose of the iridoid compound to the patient is 200 mg. In another presently preferred embodiment, the total daily dose of the iridoid compound administered to the patient is 400 mg. In another presently preferred embodiment, the total daily dose of the iridoid compound to the patient is 600 mg.
  • the amount of the compound administered to the patient is less than the amount that will cause toxicity to the patient. In certain embodiments, the amount of the compound administered to the patient is less than the amount that causes the concentration of the compound in the patient's plasma to equal or exceed the level of toxicity of the compound.
  • the concentration of the compound in the patient's plasma is maintained at about 10 nM. In another embodiment, the concentration of the compound in the patient's plasma is maintained at about 25 nM. In another embodiment, the concentration of the compound in the patient's plasma is maintained at about 50 nM. In another embodiment, the concentration of the compound in the patient's plasma is maintained at about 100 nM. In another embodiment, the concentration of the compound in the patient's plasma is maintained at about 500 nM.
  • the concentration of the compound in the patient's plasma is maintained at about 1000 nM. In another implementation In the mode, the concentration of the compound in the patient's plasma is maintained at about 2500 nM. In another embodiment, the concentration of the compound in the patient's plasma is maintained at about 5 000nM. In the practice of the invention, the optimal amount of the compound that should be administered to the patient will depend on the particular compound employed and the type of condition being treated.
  • the pharmaceutical composition comprises a common iridoid glycoside; microcrystalline cellulose as a carrier or a drier; croscarmellose sodium as a disintegrant; and magnesium stearate As a lubricant.
  • the iridoid compound is morroniside or loganin.
  • the percentage of active ingredient to various excipients in the formulation may vary.
  • the composition may comprise from 20 to 90% by weight, preferably from 50 to 70% by weight, of the general iridoid glycoside.
  • the composition may comprise from 10 to 70% by weight, preferably from 20 to 40% by weight, of microcrystalline cellulose as a carrier or diluent.
  • the composition may comprise from 1 to 30% by weight, preferably from 5 to 15% by weight. /.
  • the croscarmellose sodium is used as a disintegrant.
  • the composition may contain from 0.1 to 5% by weight of magnesium stearate as a lubricant.
  • the composition comprises from about 50 to 200 mg of an iridoid compound (e.g., 50 rag, 100 mg, and 200 mg of an iridoid compound).
  • the composition is in the form of a tablet or gelatin capsule.
  • Presently preferred embodiments of the invention are solids of an iridoid compound with microcrystalline cellulose NF (Avicel Ph 101), croscarmellose sodium NF (AC-Di-Sol) and magnesium stearate NF.
  • the preparation is contained in gelatin capsules.
  • a further preferred embodiment is 200 mg of solid SAHA and 89. 5 mg of microcrystalline cellulose, 9 mg of croscarmellose sodium and 1.5 mg of magnesium stearate, which are contained in gelatin capsules.
  • compositions of the present invention are useful not only for promoting proliferation and differentiation of nerve cells, but it should also be apparent to those skilled in the art that these compositions are useful for treating a variety of diseases in which iridoids have been found to be useful.
  • iridoids have been found to be useful in the treatment of various causes.
  • Diseases in which neuronal loss occurs including central nervous system damage, including but not only ischemic, traumatic, and alcoholic brain or spinal cord injury; systemic atrophy affecting the nervous system, basal ganglia degenerative disease, muscle tone Obstruction, primary extrapyramidal disease; and neurodegenerative diseases.
  • Ischemic injury including cerebral ischemia (eg, brain damage as a result of trauma, epilepsy, hemorrhage, or stroke, which can cause neurodegeneration); amyotrophic lateral sclerosis (ALS); multiple sclerosis; myopathy, eg Muscle protein metabolism disease.
  • iridoids have been found to be useful in the treatment of a variety of neurodegenerative diseases, a non-exhaustive list of which are:
  • Syndrome with progressive dementia and other prominent neurological abnormalities such as A) mainly found in adult syndromes (eg Huntington's disease, multiple system atrophy with dementia and ataxia, and/or Parkinson's Disease manifestations, progressive supranuclear palsy (Stee ⁇ Richardson-Ol szewski), genital Levi's small body disease and cort icodentatonigral degeneration); and B) syndromes mainly found in children or youth (eg Ha-S Second disease and progressive familial myoclonic epilepsy).
  • A mainly found in adult syndromes (eg Huntington's disease, multiple system atrophy with dementia and ataxia, and/or Parkinson's Disease manifestations, progressive supranuclear palsy (Stee ⁇ Richardson-Ol szewski), genital Levi's small body disease and cort icodentatonigral degeneration); and B) syndromes mainly found in children or youth (eg Ha-S Second disease and progressive familial myoclonic epilepsy).
  • cerebellar degeneration eg, cerebellar degeneration and olivopontocerebellar atrophy (0PCA)
  • PCA olivopontocerebellar atrophy
  • spinocerebellar degeneration Fried Hearing Ataxia and related disorders
  • V. Syndrome of central autonomic nervous system failure (Shy-Drager syndrome).
  • VI. Muscle weakness and weight loss syndrome without sensory changes motor neuron diseases such as amyotrophic lateral sclerosis, spinal muscular atrophy (eg, infant spinal atrophy (Werdnig-Hoffman), adolescent spinal muscular atrophy (Wohlfart-Kugelberg) - elander) and other forms of familial spinal muscular atrophy), primary lateral sclerosis and hereditary spastic paraplegia.
  • Figure 1 Effect of iridoids, logomycin and morroniside on proliferation of neural stem cells.
  • a control group The differentiation of neural stem cells was induced by DMEM/F12 medium containing 1% fetal bovine serum (FBS) for 7 days.
  • the single cells migrated from the periphery of the cell sphere.
  • the morphology of the migrated cells can be roughly divided into two types: 1 small Some cell bodies are nearly elliptical in shape, with 2 to 3 elongated protrusions, similar to the morphology of neurons. 2 Most of the cells are irregular in shape and have many protrusions.
  • the results of immunocytochemistry are neuron. , gel shield cells and astrocytes (X 200).
  • B induced differentiation with DMEM/F12 medium (without FBS) containing 50 ug/ml of procyanidin for 7 days.
  • the cell spheres were almost completely adherent, and the differentiation was better.
  • the migrated cells were arranged in a non-uniform radial pattern, but the cells were Interconnected into a mesh (X 200 ).
  • C Differentiation was induced for 7 days with DMEM/F12 medium (without FBS) containing 50 ⁇ g/ml of morroniside.
  • the cell spheres were almost completely adherent and differentiated well.
  • the protrusions of the migrated cells were connected end to end in a "beaded shape" (X 200).
  • SD rats were taken for 1 day, and the brain was taken under aseptic conditions.
  • the hippocampus was isolated and placed in a culture medium containing a small amount of high-dose DMEM/F12.
  • the meninges and vascular tissues were removed, and the tissues were cut as much as possible.
  • the basic culture medium DMEM/F12 (1:1) and B27 (2%) were used and added separately.
  • the final concentration was 10, 50., 100, 200, 400 g / ral of loganin and morroniside, the culture plate was transferred to a 37 ° C, 5% CO 2, 95% air balance humidity incubator, inverted microscope The cell growth was observed and the microsphere was used to measure the cell diameter.
  • neural stem cells taking the spheroid cells, removing the culture medium containing growth factors EGF and bFGF, adding DMEM/F12 containing 10% FBS, and planting in a 24-well culture plate with polylysine for 16 hours.
  • nestin and doublecortin (DCX) immunocytochemical staining the cells were almost positive for nestin and doublecortin, indicating that the cultured cell sphere is a neural stem/progenitor cell.
  • the cells were cultured for 6 days in DMEM/F12 medium without growth factors, and most of the cells died, and the cells were dispersed.
  • the volume of the neural stem cell sphere increased, which is the effective range for promoting stem cell survival and proliferation, preferably 50 ⁇ 100ug/ml;
  • the morronium 25 ⁇ 100ug/ml the volume of the neural stem cell sphere is increased, which is the effective range for promoting cell survival and proliferation, and is optimal at 25 ⁇ 50ug/ml. It is indicated that strychnine and morroniside can effectively promote the survival and proliferation of neural stem cells.
  • the second generation neural stem cell sphere was taken, and the culture medium containing the growth factor in the culture flask was removed.
  • the cell spheres were randomly divided into 2 groups, 1 fetal bovine serum (PBS) control group: the culture medium was DMEM/F12 + 10% FBS; Drug treatment group: No FBS medium EM/F12 was added to the final concentration of 10, 50, 100 ⁇ 8 / ⁇ 1 of loganin or morroniside, on The two groups of cells were cultured in a 24-well culture plate with polylysine. After 7 days, immunofluorescence staining was performed to observe the photograph.
  • PBS fetal bovine serum
  • the fetal bovine serum control group cells are completely adherent, and the single cells migrate from the periphery of the cell sphere.
  • the morphology of the migrated cells can be roughly divided into two types: 1 small cell morphology is close to elliptical, with 2 to 3 elongated Protrusion; 2 Most of the cells have larger cell bodies, irregular shapes and more protrusions.
  • the results of immunocytochemistry experiments are neurons, glial cells and astrocytes.
  • a rat model of focal cerebral ischemia was made by suture method.
  • the composition of logomycin and morroniside was administered intragastrically 3 hours after model establishment (1:1) (large dose 180 mg/kg, medium dose) 60mg/kg, low dose 20mg/kg) once a day.
  • Continuous intraperitoneal injection of Brdu (10rag/ml, 50mg/kg/time, 2 times/day) within 4-7 days after model establishment The proliferating cells were perfused at 7, 14 and 28 days after ischemia, fixed, taken, and serially frozen, sliced to a thickness of 40 ⁇ m, and immunofluorescent staining. The effect of CIG on neurogenesis in rats was observed.
  • Figure 3 shows the semi-quantitative analysis of the number of Brdu-positive cells (Figure 3-G) and nestin-positive cell density (Figure 3-H) of SVZ in groups of animals at 7, 14, and 28 days after cerebral ischemia.
  • Figure 3 shows the semi-quantitative analysis of the number of Brdu-positive cells (Figure 3-G) and nestin-positive cell density (Figure 3-H) of SVZ in groups of animals at 7, 14, and 28 days after cerebral ischemia.
  • the combination of loganin and morroniside significantly promoted the proliferation of neural stem cells in cerebral ischemia rats (P ⁇ 0.01).
  • the iridoid composition promotes proliferation of neural stem cells after brain injury.
  • Iridoid compound composition promotes differentiation of neural stem cells after brain injury

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Abstract

L'invention porte sur l'utilisation de composés d'iridoïdes, et particulièrement sur le morroniside ou la loganine, pour la fabrication de médicaments promouvant la prolifération et-ou la différenciation de cellules nerveuses, et sur des préparations pharmaceutiques les contenant. Lesdits médicaments peuvent servir à traiter la délétion des neurones, ou des maladies dégénératives du système nerveux telles que les de Parkinson, d'Alzheimer ou de Huntington, et à traiter des lésions du SNC telles que des lésions ischémiques, traumatiques et alcooliques du cerveau, ou des lésions spinales.
PCT/CN2008/000427 2007-03-02 2008-03-03 Utilisation d'iridoïdes pour la fabrication de médicaments promouvant la prolifération et-ou la différenciation de cellules nerveuses WO2008106863A1 (fr)

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CN2007100844325A CN101254185B (zh) 2007-03-02 2007-03-02 环烯醚萜类化合物在制备促进神经细胞增殖和分化药物中的用途
CN200710084432.5 2007-03-02

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CN113214784A (zh) * 2021-06-07 2021-08-06 长春中科应化特种材料有限公司 一种莫诺苷接枝聚乙烯共聚聚乙烯醇缩甲乙醛热熔胶的制备

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