CN1839870A - Use of geniposide as glicetin 1 acceptor excitomotor - Google Patents
Use of geniposide as glicetin 1 acceptor excitomotor Download PDFInfo
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- CN1839870A CN1839870A CN 200610054042 CN200610054042A CN1839870A CN 1839870 A CN1839870 A CN 1839870A CN 200610054042 CN200610054042 CN 200610054042 CN 200610054042 A CN200610054042 A CN 200610054042A CN 1839870 A CN1839870 A CN 1839870A
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Abstract
The invention discloses the use of geniposide as receptor agonist of glucagon-like peptide-1, which can induce PC12 cell differentiation by means of Mitogen-activated protein kinase (MAPK) to be antagonistic to oxidation injury induced by A beta 25-35. Geniposide can be used for treating nerve retrogression diseases such as AD caused by oxidation injury.
Description
Technical field the present invention relates to a kind of application of geniposide, and particularly geniposide is as the application of glucagon-like peptide 1 receptor stimulating agent.
(Alzheimer ' s disease AD) is a kind of nervous system degenerative disease to background technology Alzheimer disease, mainly shows as cognitive and memory ability decline, aphasis and individual character variation etc.Along with the aging of population, the sickness rate of AD is more and more higher, brings serious burden for society and patient family.Because the pathogenetic complexity of AD, people are also very unclear to the mechanism of the formation and development of AD, also do not have satisfied Therapeutic Method.But great deal of research results shows, oxidative stress and it and cell antioxidant system unbalance has important effect in the pathogenesis of AD.Therefore, screen and find that some can have important effect for treatment and prevention AD to the medicine of anti-oxidation stress, raising cell oxidation resistance.
Glucagon-like peptide 1 (Glucagon like peptide-1, GLP-1) be a kind of endogenous insulin nutrition peptide hormone, can be by combining with the G protein coupling receptor (GLP-1 receptor) of surface of cell membrane, regulate the insulin that glucose relies on and discharge, so the GLP-1 receptor is considered to treat the medicine target of the tool future of hyperglycemia (type ii diabetes) that glucose relies on.Owing to a large amount of GLP-1 expression of receptor is all arranged in rodent and human brain, shows that GLP-1 may have important function in brain function.The GLP-1 receptor mainly is expressed in nucleus hypothalamicus, and the major function of prompting GLP-1 receptor is relevant with feed.Yet the GLP-1 receptor also is expressed in the GLP-1 expression of receptor is arranged all in thalamus, brain stem, barrier film, cortex, Hippocampus and the cerebellum, show that it is movable relevant with learning and memory etc.People discover that GLP-1 is not only a kind of hormone, and are a kind of somatomedin, can regulate cell mitogen, growth, differentiation and apoptosis.They discover simultaneously, GLP-1 can by with the GLP-1 receptors bind, discharge secondary messagers such as cAMP, the neurocyte differentiation of inducing culture, irritability death of antagonism neurocyte and oxidative damage.GLP-1 and agonist Extendin-4 thereof can reduce the APP level in interior endogenous amyloid beta (β-amyloid, A β) level of mouse brain and the neuron.Owing in the brain a large amount of GLP-1 expression of receptor is arranged, therefore, activates the GLP-1 receptor a kind of new strategy may be provided for the treatment of AD.
Geniposide (geniposide) is a pale yellow crystals, is soluble in hot water, methanol, ethanol and the sig water, is insoluble in cold water, ether, chloroform and benzene equal solvent, and light resistance is poor.Geniposide has function of gallbladder promoting, eases pain, protects the liver, blood fat reducing, blood sugar lowering, effect such as anticancer.Also do not have relevant geniposide to have neural activity and antioxidative report at present, and geniposide is as the application of glucagon-like peptide 1 receptor stimulating agent.
Summary of the invention purpose of the present invention just provides the application of a kind of geniposide as the glucagon-like peptide 1 receptor stimulating agent, can treat the nervous system degenerative disease that oxidative damage causes, also can be used as the medicine of treatment senile dementia.
People discover in recent years: environment or gene mutation cause amyloid precursor protein (β-amyloidprecursor protein, the Developmental and Metabolic Disorder of β-APP), outside neuronal cell, produce amyloid beta (β-amyloid protein, A β) deposition, form the center of presenile speckle, and cause neuronal damage, and the appearance of a large amount of senile plaques is important neuropathological features of AD.Therefore, the formation main method that is considered to treat AD of regulation and control β.Present Therapeutic Method mainly is that (Nerve growthfFactor, replenishing NGF) still, because NGF is a kind of protein, is difficult to pass blood brain barrier to nerve growth factor, limited its application in clinical.People are seeking the micromolecular compound that some have neurotrophic activity at present, and they not only have the similar physiological function of NGF, and pass blood brain barrier easily, have broad application prospects.
We use modern molecular biology and cytobiology technology to set up the high flux screening model that can screen the GLP-1 receptor stimulating agent, through a large amount of screenings, find that the Fructus Gardeniae ethanol extraction can activate the GLP-1 receptor, compare through initial gross separation with standard substance, find that geniposide is its main active, it can activate the GLP-1 receptor, has the similar function of GLP-1.It not only can induce the PC12 cell differentiation, demonstrates nerve nutrition factor active, and can resist the inductive oxidative damage of A β 25-35, demonstrates stronger oxidation resistance, can be used as the medicine of a kind of novel treatment AD.
The structural formula of geniposide is:
Geniposide (geniposide) is a pale yellow crystals, is soluble in hot water, methanol, ethanol and the sig water, is insoluble in cold water, ether, chloroform and benzene equal solvent, and light resistance is poor.Geniposide has function of gallbladder promoting, eases pain, protects the liver, blood fat reducing, blood sugar lowering, effect such as anticancer.
The present invention is for having found the new purposes of known compound geniposide, it can pass through the activated protein kinase approach of mitogen (Mitogen-activated protein kinase, MAPK) induce the PC12 cell differentiation, the inductive oxidative damage of antagonism A β 25-35, improve the survival rate of cell, reduce the DNA damage in the neurocyte; And can regulate the oxidation resistance of oxidative damage type class AD rat, reduce A β and produce, therefore, geniposide can be treated the neurodegenerative diseases such as AD that oxidative damage causes, also can be used as the medicine of a kind of new treatment AD.
Geniposide can with suitable medicine carrier coupling.Such compositions contains geniposide for the treatment of effective dose and carrier or the excipient of pharmaceutically approving.Described carrier includes but not limited to; Saline, buffer salt solution, glucose, water, glycerol, lactose, phosphate, mannitol, arginine, trehalose, and their combination.Such preparation must adapt with administering mode, and is easy to be determined by those skilled in the art.
A kind of geniposide of the present invention can be treated the nervous system degenerative disease that oxidative damage causes as the application of glucagon-like peptide 1 receptor stimulating agent, also can be used as the medicine of treatment senile dementia.
Description of drawings
Fig. 1 is that geniposide of the present invention induces the PC12 cell to extend projection (A: matched group; B: geniposide group; The C:NGF group), microscopically observing effect figure;
Fig. 2 is the dose relationship (mg/L) that geniposide of the present invention and PC12 cell process extend, and shows that geniposide has the design sketch of neurotrophic effect;
Fig. 3 geniposide of the present invention and NGF induce the relation of PC12 cell differentiation and MAPK path, the design sketch of geniposide neurotrophic effect mechanism;
Fig. 4 geniposide of the present invention is to the protective effect of the beta induced PC12 cellular oxidation damage of A, the design sketch of geniposide antioxidation mechanism;
Fig. 5 geniposide of the present invention is to the influence (1: matched group of the beta induced PC12 cell DNA fragmentation of A; 2:A β group; The 3:NGF group; 4: the geniposide group), the design sketch of geniposide neurotrophic effect;
The influence that Fig. 6 geniposide of the present invention is expressed Bax and Bcl-2 in the PC12 cell of A β processing, the design sketch of geniposide antioxidation mechanism;
The present invention is further illustrated below in conjunction with accompanying drawing for the specific embodiment:
In order to understand the present invention better, measure the neurotrophic activity and the anti-oxidation function of geniposide below by modern biotechnology.Concrete grammar is as follows:
Experiment material
Geniposide: Japanese Wako company (No.070-03123);
NGF (nerve growth factor): Gibco company
Newborn hyclone, horse serum, DMEM:Gibco company
Cell cultures such as phenol red, Sodium Pyruvate: Huamei Bio-Engrg Co.,
Sistomycocin, streptomycin, trypsin: Beijing ancient cooking vessel state bio tech ltd
Acrylamide monomer: USB company
Bovine serum albumin: BM company
Other reagent are homemade analytical reagent.
Rat pheochromocytoma PC12 cell: Shanghai cell institute of Chinese Academy of Sciences cell bank
The SD male rat: Medical University Of Chongqing's Experimental Animal Center provides
Experimental facilities
Inverted microscope: Japanese Nikon
Uv-spectrophotometric instrument: UV-2450, the Japan company of falling Tianjin
Centrifuge: Super T21, U.S. Suo Fu company
Pure water instrument: U.S. Millipore company
Carbon dioxide incubator: Heraeus company
Electro-heating standing-temperature cultivator: HH-B110 type, the Shanghai medical apparatus and instruments factory of making a leapleap forward
Constant temperature shaking table: THZ-95 type, Taicang medical apparatus and instruments factory
Low speed centrifuge: Ependof
Electrophoresis and commentaries on classics film device: Bio-Red
Experimental technique
PC12 cell culture and projection elongation are analyzed
Rat is had a liking for chromium neuroma PC12 cell and cultivates in 37 ℃, the incubator of 5%CO2, and culture medium is that DMEM (Dulbeccops modified eagles medium) adds 10% deactivation horse serum and 5% inactivated fetal bovine serum.In order to investigate the influence to the PC12 cell of NGF and geniposide, the PC12 cell inoculation is in 24 well culture plates, and cell density is 2 * 10
4/ cm
2Behind the cell attachment, culture medium changes the test media of adding 2% deactivation horse serum and 1% inactivated fetal bovine serum into.When the cytoplasmic process of running business into particular one played the elongation analysis, 3 or 4 visuals field were selected in each hole at random, and statistical length surpasses the cell process of 1.5 times of cell dias, 100 cells of each hole statistics, and each data point repeats 3 times at least.Analyze projection elongation situation then, and do statistical analysis.
Detect the influence of geniposide to associated kinase
The method that employing Sano etc. introduces detects the expression of MAPK and phospho-MAPK, with 10% polyacrylamide gel electrophoresis isolated cell lysate, (polyvinylidene difluoride membranes is PVDF) on the film to polyvinylidene fluoride with the protein band trace to change the film instrument with Bio-Red then.Before changeing film, pvdf membrane is immersed in 1min in the methanol, in changeing the film buffer, soaks 5min then; Film behind the trace resists 4 ℃ with special MAPK or phospho-MAPK one then and hatched 2 hours with TBS (20mol/LTris-HCl buffer, pH7.5,150mol/L NaCl) the sealing 1h (room temperature) that contains 5% horse serum.Wash film three times with the TBS that adds 0.1%Tween-20, each 5min; Then hatch 1h, wash behind the film, film is scanned and carries out quantitative analysis with ECL method control colour developing with the IgG of horseradish peroxidase-labeled.
The dna fragmentation fractional analysis
Dna fragmentation adopts the method for introductions such as Pratice, analyzes with agarose gel electrophoresis.Collecting cell, rinsing uses the Tris-HCl buffer (pH8.0 is comprising 1mmol/L EDTA, 0.25%Nonidet P-40 and 0.1%RNase A) of 0.5ml 50mmol/L to handle 30min at 37 ℃ then, add 10G/L E.C. 3.4.21.64 50 μ l subsequently, then hatch 30min.Get 5 μ g DNA and carry out electrophoresis on 1.5% agarose gel, uviol lamp is observed electrophoresis result down and is taken pictures.
Geniposide is to the antioxidation of oxidative damage class AD rat
40 SD male rats, body weight (200 ± 10) g is provided by Medical University Of Chongqing's Experimental Animal Center.Rat is set up 5 groups at random separately: normal control group (being called for short normal group, 10), operative control group (10), AD model group (being called for short model group, 10), model add geniposide group (being called for short the administration group, 10).The administration group by 1 all administrations before the modeling, is irritated stomach every day 1 time, continuous 3 weeks with 200mg/kg administration every day.Rat freely ingests and drinks water during this time.
Rat is with 2% pentobarbital sodium (40mg/kg body weight) intraperitoneal injection of anesthesia, the stereotactic apparatus fixing head, cut off scalp, expose skull, (P019, L114, H319) trocar sheath of the about 0.8mm of embedding internal diameter in the ventriculus sinister cerebri position, fix with tooth shedding and 502 glue, the rustless steel steel wire is made the kink inner core sealing mouth of pipe.During administration, pull out inner core, with the constant speed boost pump through trocar sheath to intracerebral ventricle injection.From operation day, model group and medication therapy groups are respectively injected DHF (2.4mmol/L)-FeCl
3(43nmol/L)-and ADP (1.56 μ mol/L) 5 μ l/ time, every injection on the two 1 time, totally 3 times.Operative control group is injected with the equivalent normal saline.
Experimental result
Geniposide is to the oxicity analysis of PC12 cell
Collect the PC12 cell of exponential phase, then with 2 * 10
4/ cm
2Density be seeded in 24 orifice plates.After treating cell attachment, culture medium is replaced by test media (DMEM replenishes 1% hyclone and 2% horse serum).In the geniposide function cells after 24 hours, the metabolite lactic acid dehydrogenase by detecting the PC12 cell (lactate dehydrogenase, LDH) investigate geniposide whether the PC12 cell had toxic and side effects by activity.Experimental result proves that in the 0-200mg/L scope, geniposide does not have obvious cytotoxicity to the PC12 cell, sees Table 1.
Table 1. geniposide is to the toxicity of PC12 cell
| Light absorption value | |
| Geniposide (mg/L) 0 10 25 50 100 200 Control Total cell lysate NGF (100 μ g/L) | 0.138±0.05 0.172±0.06 * 0.198±0.07 0.215±0.05 * O.219±0.04 * 0.321±0.11 2.656±0.09 0.224±0.05 * |
Geniposide induces the elongation of PC12 cell process to analyze
Referring to Fig. 1, Fig. 2, when doing cell aixs cylinder elongation analysis, the PC12 cell is with 2 * 10
4The density of individual/mL is seeded in 24 orifice plates that scribble poly-D-lysine in advance, after treating cell attachment, culture medium is replaced by the test media that DMEM adds 2%HS, 1%FBS and 2mM glucose, adds the geniposide (0-100mg/L) of NGF and variable concentrations subsequently.Add 100 μ g/L NGF after four days in adherent PC12 cell, cell grows a large amount of projections, shows neural sample differentiating characteristic (Fig. 1 C); In negative control hole (equal-volume DMSO processing), seldom there is cell to extend aixs cylinder (Figure 1A); In the culture hole of handling with the 50mg/L geniposide, the cell cell space tightens, and extends a large amount of aixs cylinders (Figure 1B), and with the increase of geniposide concentration, the PC12 cell proportion that extends aixs cylinder also improves (Fig.2) gradually.
Geniposide is induced the associated kinase approach of PC12 cell differentiation
Referring to Fig. 3, induce the signal transduction pathway of PC12 cell differentiation in order to study geniposide, we collect the PC12 cell of NGF and geniposide processing 20min, analyze NGF and geniposide is expressed MAPK and the influence of phosphorylation with Western blotting (Western blots), the result as shown in Figure 3.Simultaneously, we use NGF and geniposide effect PC12 cell then with the special inhibitor PD98059 of mapk kinase pretreatment PC12 cell.Experiment finds that after with the PD98059 pretreatment cell, inductive p44 of NGF and p42MAPK phosphorylation have descended 5216% and 20% respectively; When handling the PC12 cell with geniposide, MAPK1/2 is activated, and can keep about 1h, and the phosphorylation level of p44 and p42MAPK increases by 1290% and 310% respectively.But after the PD98059 pretreatment, the phosphorylation of MAPK obviously is suppressed (Fig. 3), descended 4615% and 2910% respectively, and the development length of cell process shortens obviously.The explanation of above-mentioned experiment conclusion is being induced aspect PC12 cell differentiation and the MAPK phosphorylation, and geniposide has similar effect to NGF.
Geniposide is to the apoptotic influence of the beta induced PC12 of A
Referring to Fig. 4, Fig. 5, experiment finds that A β can induce PC12 cellular oxidation damage.But after adding the geniposide of debita spissitudo (0-50mg/L) in the cultivating system, the low concentration geniposide can rely on the survival rate (Fig. 4) that ground improves cell by dosage.In order to confirm the protective effect of geniposide to A beta-oxidation damage, we have investigated the influence of geniposide to DNA damage in the PC12 cell., agarose gel electrophoresis shows, A β effect 72 hours, examines the interior a large amount of fragmentations of DNA; Add geniposide (50mg/L) and can suppress the dna fragmentationization (Fig. 5) that A β causes significantly, these presentation of results, geniposide has the certain protection effect to the PC12 cell injury that A β causes.
Geniposide is to the adjusting of the PC12 cellular oxidation reducing condition of A β processing
SOD and GSH are important antioxidants in the cell, and their active size or content have reflected the oxidation resistance of cell.MDA is the product of lipid peroxidation, so people are through using it always as one of standard of estimating lipid peroxidation.In control experiment, not with SOD, the GSH of A β processing and vigor difference 9.8 ± 3.2U/ (mg protein), 211 ± 14mg/L and 6.5 ± 1.3 μ mol/L (protein) of MDA, but after 2 hours, SOD, GSH and MDA are respectively 4.8 ± 1.1U/ (mg protein), 108 ± 9mg/L and 12.7 ± 2.0 μ mol/ (L protein) with A β effect.Experimental result shows, geniposide can be alleviated the oxidative pressure of the PC12 cell that A β causes significantly, reduces cell injury, and the ratio that increases survivaling cell improves the oxidation resistance of cell, sees Table 2.
The influence that table 2 geniposide changes SOD, GSH, MDA in the beta induced PC12 cell of A
| Handle | GSH(mg/L) | SOD(U/mg protein -1) | MDA(μmol/L protein -1) | ||
| Total SOD | MnSOD | CuZnSOD | |||
| Control group geniposide (mg/L) 025 10 20 50 positive controls (100g/L) NGF | 211±14 * 108±9 112±13 159±15 * 178±9 202±10 ** 195±11 198±15 * | 9.8±3.2 4.8±1.1 4.4±1.6 6.5±2.0 ** 7.8±2.2 9.4±2.1 ** 9.1±2.3 9.2±3.3 | 2.4±0.9 ** 2.2±1.2 2.1±1.1 * 2.4±1.3 2.5±1.0 ** 2.4±1.4 2.5±1.0 2.5±1.2 ** | 7.4±1.6 2.6±0.5 2.3±2.0 * 4.1±2.5 * 5.3±2.5 7.0±1.3 6.6±2.5 * 7.2±3.5 | 6.5±1.3 * 12.7±2.0 10.8±2.3 ** 8.0±2.8 * 7.4±2.1 * 6.6±1.8 7.0±1.7 6.7±1.4 * |
In the PC12 cell that geniposide is handled A β apoptosis-related protein influence
Referring to Fig. 6, experiment showed, that the ratio of apoptotic cell obviously reduces when reuse A β handles after 2 hours with the geniposide incubated cell in advance.Western blot testing result finds, geniposide can improve the level of anti-apoptotic proteins Bcl-2 in the PC12 cell that A β handles, reduces the expression of pro apoptotic protein Bax.
Geniposide is to the sedimentary influence of A β in the oxidative damage class AD rat brain
Compare with normal group and operative control group, oxidative damage AD rat cerebral cortex A β extensively deposits, and cortex A β positive cell number and the painted average optical of SABC significantly increase (P＜0.05).Geniposide changes the effect of having clear improvement (P＜0.05) to These parameters.See Table 3.
Table 3 geniposide is to the oxidative damage class AD rat cerebral cortex sedimentary influence of A β (meansigma methods ± standard deviation)
| Group | n | A β positive cell number | Average optical (A) |
| Normal group operation group model group administration group | 6 6 8 8 | 54.6±9.6 61.6±8.7 # 169.5±42.9 * 85.6±41.8 # | 0.058±0.006 0.089±0.009 # 0.143±0.015 *# 0.093±0.010 # |
Annotate: compare with normal group,
*P＜0.05; Compare #P＜0.05 with model group
Claims (3)
1, a kind of geniposide is as the application of glucagon-like peptide 1 receptor stimulating agent, and the chemical structural formula of described geniposide is:
2, application according to claim 1 is characterized in that: the application of described geniposide in the nervous system degenerative disease treatment that oxidative damage causes.
3, application according to claim 1 is characterized in that: the application of described geniposide in the treatment medicine for senile dementia.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102614514A (en) * | 2011-01-26 | 2012-08-01 | 王永祥 | GLP-1 acceptor agonists used for treating pains |
| CN103860575A (en) * | 2014-04-03 | 2014-06-18 | 重庆理工大学 | Application of geniposide used as acetylcholin esterase inhibitor |
| CN113181202A (en) * | 2021-03-24 | 2021-07-30 | 上海中医药大学附属曙光医院 | Application of iridoid glycoside compound in preparing medicine for treating diseases related to DUSP9 abnormal expression |
| WO2022127868A1 (en) * | 2020-12-16 | 2022-06-23 | The Chinese University Of Hong Kong | A method for reversing aging brain functional decline |
-
2006
- 2006-01-18 CN CN 200610054042 patent/CN1839870A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102614514A (en) * | 2011-01-26 | 2012-08-01 | 王永祥 | GLP-1 acceptor agonists used for treating pains |
| CN102614514B (en) * | 2011-01-26 | 2014-12-10 | 王永祥 | GLP-1 acceptor agonists used for treating pains |
| CN103860575A (en) * | 2014-04-03 | 2014-06-18 | 重庆理工大学 | Application of geniposide used as acetylcholin esterase inhibitor |
| WO2022127868A1 (en) * | 2020-12-16 | 2022-06-23 | The Chinese University Of Hong Kong | A method for reversing aging brain functional decline |
| CN113181202A (en) * | 2021-03-24 | 2021-07-30 | 上海中医药大学附属曙光医院 | Application of iridoid glycoside compound in preparing medicine for treating diseases related to DUSP9 abnormal expression |
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