CN103860575A - Application of geniposide used as acetylcholin esterase inhibitor - Google Patents
Application of geniposide used as acetylcholin esterase inhibitor Download PDFInfo
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- CN103860575A CN103860575A CN201410132806.6A CN201410132806A CN103860575A CN 103860575 A CN103860575 A CN 103860575A CN 201410132806 A CN201410132806 A CN 201410132806A CN 103860575 A CN103860575 A CN 103860575A
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Abstract
The invention discloses an application of geniposide which is used as an acetylcholin esterase inhibitor in a medicament for treating and preventing diseases with acetylcholin esterase activity abnormity. The invention relates to geniposide which directly inhibits activity of the acetylcholin esterase, inhibits activity of acetylcholin esterase in a cultured nerve cell, and inhibits activity of the acetylcholin esterase in a transgenic animal brain with Alzheimer's disease. The geniposide can bring inhibition effect on the activity of the acetylcholin esterase into play by virtue of the way, but is not limited to the way, and the geniposide possibly has a potential treatment value on the Alzheimer's disease by inhibiting the acetylcholin esterase.
Description
Technical field
The present invention relates to the new purposes of geniposide, relate in particular to the application of geniposide as an acetylcholinesteraseinhibitors inhibitors.
Background technology
Alzheimer (Alzheimer ' s disease, AD) be a kind of neurodegenerative diseases common, occurred frequently.Along with living condition's improvement, AD sickness rate increases just year by year, has become the fourth-largest cause of disease that causes old people's death after tumor, heart disease and cerebrovascular.Clinical symptoms shows as persistence cognitive function and learning disorder.Because the pathological characters of AD comprises β sample starch albumen (β-amyloid, A β) polymerization, formation of deposits senile plaque and Protein tau transition phosphorylation form neurofibrillary tangles, another one typical case pathological characters is acetylcholine (Acetylcholine, Ach) level reduces, therefore one of therapeutic strategy of AD is the consumption that reduces acetylcholine with acetylcholinesterase (Acetylcholinesterase, AChE) inhibitor.
Conventionally the most of region of AChE activity in patient's AD brain all reduces, and experiment is found, near AChE activity senile plaque obviously raises on the contrary.Someone thinks that the activity of AChE extremely may be relevant with the toxicity of this A β.And AChE also may accelerate A β deposition, and be combined with A β and form complex, the toxicity of two complex is larger than the toxicity of A β self, has accelerated the apoptosis of neurocyte.People suppress AChE activity by the method for translation nucleic acid, and discovery can obviously reduce the beta induced neuronal apoptosis of A.This will go for the new AD treatment of development the thinking that provides new.
Because acetylcholinesteraseinhibitors inhibitors can, by reducing the degraded of synaptic space acetylcholine, increase the utilization of acetylcholine between synapse, therefore people are devoted to find acetylcholinesteraseinhibitors inhibitors, and exploitation becomes the medicine for the treatment of AD.People have found that some have strong active acetylcholinesteraseinhibitors inhibitors from the compound library of Chinese herbal medicine, microbial metabolic products and chemosynthesis at present.Comprising tacrine (Tacrine), donepezil 9donepezil), this bright (Rivastigmine), galantamine (Galantamine), huperzine A (Huperzine) etc. of profit, although these compounds have certain effect to the cognitive function that improves early stage and moderate AD patients, but owing to there being various untoward reaction, as low in hepatotoxicity, gastrointestinal dysfunction and oral administration biaavailability etc., therefore its clinical practice is subject to great restriction.
People are just being devoted at present screening from natural product, are finding and obtaining the novel acetylcholinesteraseinhibitors inhibitors that toxic and side effects is little.
Fructus Gardeniae: another name Yellow Fructus Gardeniae, Fructus Gardeniae, white toad are the fruits of Maguireothamnus speciosus Fructus Gardeniae.At present, the fruit of Fructus Gardeniae is Chinese medicine, and the l that belongs to Ministry of Public Health promulgation criticizes medicine-food two-purpose resource, has the effects such as hepatoprotective, function of gallbladder promoting, blood pressure lowering, calmness, hemostasis, detumescence.Be usually used in treating the diseases such as icterohepatitis, bruise, hypertension, diabetes at tcm clinical practice.
Geniposide (structure as shown in Figure 1) is a kind of iridoid glucoside, soluble in water, is the main pharmacodynamics composition of Fructus Gardeniae, the existing lot of documents report of its extracting method and product application.Geniposide all has significant curative effect to digestive system, the cardiovascular system central nervous system disease of unifying, and in addition, geniposide also has the effect of certain antiinflammatory and treatment soft tissue injury.But about geniposide have not been reported the inhibitory action of acetylcholinesterase.
In early-stage Study, we apply GLP-1 receptor agonism agent high flux screening (the High throughput screen) model taking Luciferase as reporter gene, find to have glucagon 1 (Glucago-like peptide 1 in Chinese medicine Fructus Gardeniae extract, GLP-1) receptor stimulating agent, confirm through separation and purification with standard control, geniposide (Geniposide) is a kind of new GLP-1 receptor stimulating agent.Geniposide can, by activating GLP-1 receptor, discharge cAMP, and by the differentiation of mapk kinase approach induction PC12 cellular neural sample, demonstrates neurotrophic effect; We are further research discovery also; geniposide can pass through the expression of PI3K, MAPK and PKA signal path adjusting anti-apoptotic proteins Bcl-2; the PC12 apoptosis of inhibited oxidation stress-induced, improves cell viability, shows that geniposide has certain neuroprotective.
Summary of the invention
The present invention has found the new purposes of geniposide aspect medical, and geniposide is acetylcholine esterase inhibition activity in vivo and in vitro, be a kind of new acetylcholinesteraseinhibitors inhibitors.
The present invention proposes geniposide as acetylcholinesteraseinhibitors inhibitors, the application in the medicine for the treatment of and the abnormal disease of prevention acetylcholine esterase active.
The present invention further proposes geniposide as acetylcholinesteraseinhibitors inhibitors, the application in the medicine for the treatment of and prevention Alzheimer, Down's syndrome.
The present invention also proposes the acetylcholinesteraseinhibitors inhibitors of a kind for the treatment of and prevention acetylcholine esterase active abnormal diseases, described inhibitor comprises active component geniposide and the pharmaceutically acceptable carrier for the treatment of effective dose, and the percentage by weight of described active component geniposide is 0.01%-99.99%; Described preparation comprises tablet, capsule, injection etc.
" carrier that pharmacy is accepted " of the present invention refers to the excipient or the adjuvant that in pharmacy, use.
The term " treatment effective dose " that the present invention uses refers to the effective dose of the active component for realizing its therapeutical effect, and this dosage normally and the characteristic of patient's symptom, age, body weight, sex, medication, administration time and interval and pharmaceutical preparation etc. and changing.It is appreciated for those skilled in the art that and aspect dosage, do not have individual restriction, the dosage of active component is about each patient 16-128 mg/ days every day under normal circumstances, be preferably 32-96 mg/ days, more preferably 40-80 mg/ days, is generally 1 administration.Or in most cases, the effective dosage ranges of every day is 0.4-1.6 mg/Kg body weight, is preferably 0.8-1.2 mg/Kg body weight.But, in some cases, be necessary to use the dosage outside above restriction, determined by doctor's prescription.
The present invention relates to geniposide to comprising the direct inhibition of acetylcholine esterase active, to the inhibition of acetylcholine esterase active and the inhibition to acetylcholine esterase active in AD transgenic animal brain in the neurocyte of cultivating.Geniposide can, by above-mentioned approach, be brought into play the inhibitory action to acetylcholine esterase active but be not limited to above-mentioned approach.
Because AD patient's senile plaque around exists the obvious acetylcholine esterase active phenomenon that extremely raises, and more existing acetylcholinesteraseinhibitors inhibitors have obvious effect to the cognitive function that improves AD with the learning capacity that improves AD patient, therefore, geniposide may have potential therapeutic value to AD by acetylcholine esterase inhibition.
Brief description of the drawings
fig. 1. the chemical structural formula of geniposide;
fig. 2. the dose-effect relationship of geniposide acetylcholine esterase inhibition activity;
fig. 3.the impact of the geniposide of various dose on AChE activity in the neurocyte of cultivating;
fig. 4.the difference of acetylcholine esterase active in neurocyte after geniposide processing different time;
fig. 5.the impact of geniposide on acetylcholine esterase active in Alzheimer mouse model animal brain.
Detailed description of the invention
Essence for a better understanding of the present invention, we in vitro, analyzed the inhibitory action of geniposide to acetylcholine esterase active in three different levels such as cellular level and whole animal level,
experiment material
APP/PSN transgenic AD mice: Nanjing University's model animal institute
PC12 cell: purchased from the biochemical institute in Chinese Academy of Sciences Shanghai cell bank
Serum, culture medium: RPMI1640, Gibco company
Geniposide: Nat'l Pharmaceutical & Biological Products Control Institute
Acetylcholinesterase, 2-(Dimethylamino)ethyl acetate methiodide and DTNB:Sigma company
Other chemical reagent: Sigma company
instrument and equipment
Carbon dioxide incubator: Heraeus company
Inverted microscope: Japanese Nikon
Microplate reader: U.S. thermoelectricity Varioskan
Autoclave sterilization pot: TOMYAUOCLAVESS325, Gene company
Centrifuge: Superfuge, Heraeus company
Pure water instrument: Millipore company of the U.S.
Low speed centrifuge: Ependof company
experimental technique
1, PC12 cell culture
P of Rats C12 neurocyte is at 37 ° of C, 5%CO
2incubator in cultivate, culture medium is that DMEM adds 5% hyclone and 10% horse serum, 100 U/mL penicillins, 100 μ g/mL streptomycins, change culture fluid for 2-3 days one time, in the time that cell density reaches 80 left and right, go down to posterity.When passage, first use up the culture medium in bottle, add 0.25% appropriate trypsin/0.02%EDTA digestion, piping and druming gently, to dispel cell mass, the cell of the trophophase of taking the logarithm is tested.
2, AChE activity analysis
In order to investigate the direct effect of geniposide to AChE activity, we select the inhibitory action of the external investigation geniposide of classical Ellman spectrophotography to people's enzyme acetylcholine, and use blank group, and this bright positive matched group of profit is tested.Configuration Tris pH of buffer is 7.2, substrate 2-(Dimethylamino)ethyl acetate methiodide (Acetylcholineiodide, ACTI) concentration 0.02 mol/L, developer dithio-nitrobenzene formic acid (5,5-dithiobis-(2-nitrobenzoic acid, DTNB) concentration 0.03 mol/L, AChE total amount 0.035 Units, geniposide concentration 0,0.01,0.1,1.0,10 and 100 μ mol/L.
Get Tris buffer 30 μ L, AChE 20 μ L, the inhibitor 10 μ L of various concentration are in 96 orifice plates, at 37 DEG C, be incubated after 10 minutes, add 15 μ L substrate A CTI, 15 μ L developer DTNB, read every hole absorbance by microplate reader at 412 nm places within 10 minutes.Blank group replaces respectively substrate and inhibitor with l5 μ Ls buffer, and criterion group replaces inhibitor with 15 μ L Tris buffer.
Suppression ratio computing formula I=100 × (A
surveyone A
empty)/(A
mark-A
empty) %
Each experiment at least in triplicate, is established 3 multiple holes at every turn and is averaged and represent Gates's experimental result.
3, the impact of geniposide on AChE activity in cultured cell
In order to investigate the impact of geniposide on AChE activity in the neurocyte of cultivating, we process cell 0,12,24,48 hours with 10 μ M geniposides respectively, or process cell 24 hours with 0,0.1,1.0,10 and 100 μ M geniposides, collect subsequently and cell lysis, after treating protein quantification, measure the activity of AChE in each group of cell.Concrete step is: get 40 μ L cell pyrolysis liquids, 40 μ L 2-(Dimethylamino)ethyl acetate methiodide (6.7 mM, configure with distilled water), 20 μ L Ellman solution (0.15 mM DTNB, with the PBS of 0.1 M, pH 7.4 configures), after mix homogeneously, within 10 minutes, measure light absorption value by microplate reader at 412 nm places, calculate the inhibitory action of geniposide to AChE activity.
4, the impact of geniposide on AChE activity in AD transgenic rat brain
experiment grouping:matched group (7)---mark " contrast (C) "
Low dose group (7) 10 mg/Kg geniposides---mark " low "
Middle dosage group (7) 20 mg/Kg geniposides---mark " in "
High dose group (7) 40 mg/Kg geniposides---mark " height "
administering mode:tested medicine (gavage)
dosage:tested medicine: each 200 microlitre gavages
administration time:4 weeks, every day 1 time,
After administration finishes, anesthetized animal sacrificed by decapitation, gets full brain, after homogenate, measures protein concentration wherein, and protein concentration is adjusted to same concentrations.Measure the activity of AChE in each group of homogenate.Concrete step is: get 40 μ L brain tissue homogenate liquid, 40 μ L acetylcholine (6.7 mM, configure with distilled water), 20 μ L Ellman solution (0.15 mM DTNB, with the PBS of 0.1 M, pH 7.4 configures), after mix homogeneously, within 10 minutes, measure light absorption value by microplate reader at 412 nm places, calculate the inhibitory action of geniposide to AChE activity.
experimental result
1, the direct repression of geniposide to AChE activity
We have analyzed the direct repression of geniposide to AChE by classical Ellman method, found that, geniposide can dose-dependent inhibition AChE activity, through curve fitting, and its IC
50be approximately 120 nmol/L. experimental results as shown in Figure 2.
2, the impact of geniposide on AChE activity in neurocyte
?in order to investigate the impact of geniposide on AChE activity in the PC12 neurocyte of cultivating, we have measured and have used variable concentrations geniposide to process neurocyte 24 hours and the activity with AChE in neurocyte after geniposide processing neurocyte different time, experimental result shows, geniposide can dosage and time dependent inhibition neurocyte in AChE activity, experimental result is as shown in accompanying drawing 3 and accompanying drawing 4.
3, the inhibition of geniposide to AChE activity in AD transgenic rat cerebral tissue
In order to investigate geniposide impact on AChE activity in whole animal level, we have investigated the impact of geniposide on AChE activity on APP/PSN transgenic AD mice, after with the continuous gastric infusion of geniposide 4 weeks, under narcotism, put to death animal, get full brain homogenate, after measuring protein concentration, the difference of the geniposide of mensuration various dose to AChE activity in AD model mice brain, result shows, high dose group geniposide can obviously suppress the AChE activity in AD model mice brain, show that geniposide also has certain inhibitory action to the AChE on whole animal model.Experimental result is as being shown in as shown in accompanying drawing 5.
In the following embodiment of the present invention, the medicine of following amount and other component combine with standard pharmaceutical technology.Gained preparation is fallen into capsule housing to employing standard pharmaceutical technology or compacting is in blocks.
embodiment 1:
Capsule preparation method thereof: geniposide and sodium starch glycol are mixed, carry out wet granulation after then adding lauryl sodium sulfate aqueous solution.Then this wet stock is dry in fluid bed, basin or other suitable exsiccator.Then can, by dry particle grinding, to reach suitable particle size distribution, mix with other component afterwards.Then this mixture is packed in two hard gelatin capsule housings.
component
content in every
Sodium lauryl sulphate 5 mg
Lactose hydrous 71 mg
Magnesium stearate 4 mg
Sodium starch glycol 80 mg
Capsule gross weight 200 mg.
embodiment 2:
Capsule preparation method thereof: geniposide and starch glycol sodium are granulated by lauryl sodium sulfate aqueous solution, subsequently that this wet feed is dry in fluid bed, basin or other suitable exsiccator, then dried particles is milled, to reach suitable particle size distribution, mix with other component afterwards, finally incapsulate by weight in shell.
component
content in every
Sodium lauryl sulphate 5 mg
Lactose hydrous 63 mg
Talcum 4 mg
Colloidal silica 4 mg
Magnesium stearate 4 mg
Sodium starch glycol 80 mg
Capsule gross weight 200 mg.
embodiment 3:
Method for preparing tablet thereof: geniposide, starch glycol sodium and microcrystalline Cellulose are granulated by lauryl sodium sulfate aqueous solution, subsequently that this wet feed is dry in fluid bed, basin or other suitable exsiccator, then dried particles is milled, to reach suitable particle size distribution, by this mixture compacting in flakes, if needed, and by these tablet coatings.
component
every middle content
Sodium lauryl sulphate 6 mg
Starch glycol sodium 60 mg
Lactose hydrous 49 mg
Magnesium stearate 5 mg
Tablet total weight amount 200 mg.
Claims (5)
1. geniposide is as the application of acetylcholinesteraseinhibitors inhibitors.
2. geniposide is as acetylcholinesteraseinhibitors inhibitors, the application in the medicine for the treatment of and the abnormal disease of prevention acetylcholine esterase active.
3. geniposide is as acetylcholinesteraseinhibitors inhibitors, the application in the medicine for the treatment of and prevention Alzheimer, Down's syndrome.
4. the acetylcholinesteraseinhibitors inhibitors for the treatment of and prevention acetylcholine esterase active abnormal diseases, described inhibitor comprises treats the active component geniposide of effective dose and the carrier that pharmacy is accepted, and the percentage by weight of described active component geniposide is 0.01%-99.99%.
5. acetylcholinesteraseinhibitors inhibitors according to claim 4, is characterized in that, described preparation comprises tablet, capsule or injection.
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| CN201410132806.6A CN103860575A (en) | 2014-04-03 | 2014-04-03 | Application of geniposide used as acetylcholin esterase inhibitor |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108464986A (en) * | 2018-03-20 | 2018-08-31 | 江南大学 | Application of the geniposide in alleviating skeletal muscle fibre |
| CN108685934A (en) * | 2018-08-22 | 2018-10-23 | 江南大学 | Application of the geniposide in promoting skeletal muscle fast muscle to generate |
| CN110960522A (en) * | 2019-12-30 | 2020-04-07 | 深圳大学 | Application of genipin in preparation of drugs for preventing and treating Tau protein abnormality |
| CN113336811A (en) * | 2021-06-01 | 2021-09-03 | 浙江大学 | Iridoid glycoside compounds, preparation and application thereof |
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| CN101548980A (en) * | 2008-04-02 | 2009-10-07 | 山东靶点药物研究有限公司 | Application of geniposide, derivative and analog thereof in preparing anxiolytic medicine for preventing and/or treating depression |
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| CN1839870A (en) * | 2006-01-18 | 2006-10-04 | 刘建辉 | Use of geniposide as glicetin 1 acceptor excitomotor |
| CN101548980A (en) * | 2008-04-02 | 2009-10-07 | 山东靶点药物研究有限公司 | Application of geniposide, derivative and analog thereof in preparing anxiolytic medicine for preventing and/or treating depression |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108464986A (en) * | 2018-03-20 | 2018-08-31 | 江南大学 | Application of the geniposide in alleviating skeletal muscle fibre |
| CN108464986B (en) * | 2018-03-20 | 2020-01-07 | 江南大学 | Application of geniposide in relieving skeletal muscle fibrosis |
| CN108685934A (en) * | 2018-08-22 | 2018-10-23 | 江南大学 | Application of the geniposide in promoting skeletal muscle fast muscle to generate |
| CN108685934B (en) * | 2018-08-22 | 2020-01-07 | 江南大学 | Application of geniposide in promoting generation of skeletal muscle fast muscle |
| WO2020037895A1 (en) * | 2018-08-22 | 2020-02-27 | 江南大学 | Application of geniposide in promoting formation of skeletal muscle fast muscle |
| CN110960522A (en) * | 2019-12-30 | 2020-04-07 | 深圳大学 | Application of genipin in preparation of drugs for preventing and treating Tau protein abnormality |
| CN113336811A (en) * | 2021-06-01 | 2021-09-03 | 浙江大学 | Iridoid glycoside compounds, preparation and application thereof |
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Inventor after: Liu Jianhui Inventor after: Yin Fei Inventor before: Zhang Yonglan Inventor before: Liu Jianhui Inventor before: Yin Fei |
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Application publication date: 20140618 |