CN102218055A - Medicament for treating Alzheimer disease(AD) - Google Patents
Medicament for treating Alzheimer disease(AD) Download PDFInfo
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Abstract
The invention relates to a medicament for treating Alzheimer disease (AD). The technical scheme comprises hopeahainol A, of which the molecular weight is 496Da and which is prepared into an oral preparation. The medicament overcomes the defects existing in the AD treating medicaments such as an acetylcholinesterase inhibitor and an NMDA (N-methyl-D-aspartic acid) acceptor antagonist that the further seizure of AD cannot be prevented and the medicaments aiming at the main pathogenesis of AD, namely the mitochondria targeting toxicity of A beta, do not exist currently. The medicament can effectively inhibit the level and the activity of the acetylcholinesterase, avoid apoptosis and death of acetylcholine nerve cells, inhibit the A beta-induced oxidative stress, lower the ROS level caused by the A beta, lessen the potential decrease of the mitochondrial membrane caused by the A beta, directly combine the A beta and inhibit the combination between the A beta and ABAD in the mitochondria so as to protect the mitochondria from damage and inhibit the oxidative stress.
Description
Technical field
The present invention relates to a kind of medicine, particularly a kind of medicine for the treatment of Alzheimer.
Background technology
Alzheimer (AD) is a kind of modal nervous system degenerative disease, and its principal character is the obstacle of memory of carrying out property and cognitive function, prevalence, mortality rate height.
The definite pathogenesis of AD is very unclear at present, and its main possible mechanism is: have neurovirulent amyloid beta (A β) inside and outside deposition of neurocyte in cerebral tissue and cause nerve cell death.A β derives from its precursor protein APP.APP in the AD brain produces sAPP β and C99 through beta-secretase (BACE1) enzyme action, produces A β 40 or A β 42 through the gamma secretase cutting again.Wherein the A β 42 and the thing of living alone as a widow thereof are the main components that causes neurotoxic effect.A β causes that with interior ABAD (amyloid beta protein the combines ethanol dehydrogenase) combination of mitochondrion oxidative stress is one of most important mechanism that causes AD.Be gathered in A β in the mitochondrial matrix with after ABAD combines, the ABAD occurred conformation changes, and suppresses NAD
+Combine with ABAD,, induce oxidative stress to cause apoptosis: 1) suppress enzymatic activity among the krebs cycle pathway, NADH is generated reduce, thereby the cellular energy load is lost by following link.Simultaneously, ABAD needs the assosting effect of NADH to the detoxification of 4-HNE, and NADH generates to reduce and reduced ABAD to the 4-HNE detoxification; 2) ROS produces increases; 3) suppress mitochondrion composite I V activity, cause a large amount of cytochrome C to discharge, activate caspase-9, caspase-3, caspase-7, finally cause Neuron Apoptosis.
Before the present invention, the medicine of Alzheimer is confined to simple cholinesterase inhibitor or EAA antagonists, does not still have the medicine based on the above-mentioned cognition preparation at present.And there are after toxic and side effects big (liver toxicity, the side reaction of periphery cholinergic, gastrointestinal reaction etc.), price high (polyphyly import or joint pharmaceutical factory product), the drug withdrawal shortcomings such as easily recurrence in these several limited chemical synthetic drugs, be difficult to adapt to the needs of AD, even patient is sometimes owing to can't bear to stand toxic and side effects and the Halfway Stopping medication as the long-term medication treatment of chronic disease.
Current main AD medicine is divided into two big classes: one is acetylcholinesteraseinhibitors inhibitors, as medicines such as aricept, tacrine, stone China fir point alkali, has the effect that prolongs acetylcholine in the synaptic space, can alleviate AD patient's dementia symptom to a certain extent, but can not stop pathological changes further to be shown effect.Another kind of is NMDA (N-methyl-D-aspartate) receptor antagonist, and as easy times of Shen (memantine), its mechanism is for suppressing excitatory toxicity.The brain injury that any reason causes all can activate the DNMA path.And in the pathological process of AD, excitatory toxicity is one of link of A β toxic action.Present needleless still is to the medicine of the Mitochondrially targeted toxic action of main pathogenesis-A β of AD.
Summary of the invention
Purpose of the present invention just is to overcome above-mentioned defective, and development is with the application of hopea hainanensis phenol first as preparation treatment Alzheimer medicine.
Technical scheme of the present invention is:
A kind of medicine for the treatment of Alzheimer, its major technique be characterised in that and contain hopea hainanensis phenol first, and molecular weight is 496Da, and molecular structural formula is
Active and the powerful anti-oxidation stress effect of acetylcholinesteraseinhibitors inhibitors that advantage of the present invention and effect are to utilize hopea hainanensis phenol first (being called for short HopA) to have from the pathological process that many target spots are intervened AD, is brought into play important therapeutical effect to AD.
Use the mechanism of HopA:
HopA is the level and the activity of acetylcholine esterase inhibition effectively, reduces acetylcholine apoptosis in neuronal and death, compares no difference of science of statistics with aricept.Aricept has been widely used in clinical, a kind of strong acetylcholinesteraseinhibitors inhibitors.We make positive control with this.
HopA can suppress the beta induced oxidative stress of A, reduces the ROS level that A β causes, alleviates the mitochondrial membrane potential decline that A β causes.Its anti-oxidation stress effect is better than resveratrol.Resveratrol is a kind of sure antioxidant.We also make positive control with this.
A β combines with ABAD (A β's is conjugated protein) in the mitochondrion, causes the ABAD conformational change, causes mitochondrial injury and oxidative stress.HopA can directly combine with A β, suppress A β and combine with ABAD in the mitochondrion, thereby protection mitochondrial injury and inhibited oxidation stress.
Other advantages of the present invention and effect will go on to say below.
Description of drawings
Fig. 1---HopA improves APP/PS1 double transgenic mice behavioristics (cognitive function) and LTP (electric physiological detection) sketch map, and wherein, a is the result of behavioristics, and b is electric physiology result.
Fig. 2---HopA suppresses A β
42Inductive former generation cortical neuron mortality rate and improve its survival rate sketch map, wherein, a is the neuron survival rate, b is the neuronal death rate.
Fig. 3---HopA suppresses mouse brain and periphery acetylcholine esterase active (the positive contrast of aricept) sketch map.
Fig. 4---in body research, HopA suppresses anti-oxidation stress (the positive contrast of resveratrol) sketch map, and wherein, a is the oxidation index of DNA, albumen and three aspects of lipid, and b is a mitochondrial membrane potential.
Fig. 5---in vitro study, HopA suppresses beta induced oxidative stress (ROS and the mitochondrial membrane potential) sketch map of A, and wherein, a is flow cytometer result (ROS), and b is immunofluorescence result (mitochondrial membrane potential).
Fig. 6---HopA and A β have direct combination sketch map, wherein, A is that 10 μ M HopA combine situation with 0.1M A β, B is that 20 μ M HopA combine situation with 0.1MA β, C is that 30 μ M HopA combine situation with 0.1MA β, and D is that 40 μ M HopA combine situation with 0.1M A β, and E is that 50 μ M HopA combine situation with 0.1MA β, F is that 60 μ M HopA combine situation with 0.1MA β, and G is that above-mentioned each concentration HopA combines the general status linear graph with 0.1MA β.
Fig. 7---HopA suppresses the interior A β of mitochondrion and combines sketch map with ABAD.
The specific embodiment
Thinking of the present invention is analyzed as follows:
At existing treatment Alzheimer medicine exist can only symptomatic treatment, can not be at the defective of pathogenesis treatment, utilize the medicinal property of HopA (hopea hainanensis phenol first), make except that having the effect of the acetylcholine esterase of inhibition, have the medicine of the treatment Alzheimer that suppresses the beta induced oxidative stress effect of A simultaneously.
HopA is the chemical compound that separation and purification obtains from the hopea hainanensis of endemic plant Hainan, China torrid zone, and a kind of have a brand-new carbon skeleton natural polyphenol, and molecular weight is 496Da; Its structure is different from any clinically at present AD medicine, its molecular structural formula:
Use the mechanism of HopA:
HopA is the level and the activity of acetylcholine esterase inhibition effectively, reduces acetylcholine apoptosis in neuronal and death, compares no difference of science of statistics with aricept.Aricept has been widely used in clinical, a kind of strong acetylcholinesteraseinhibitors inhibitors.We make positive control with this.
HopA can suppress the beta induced oxidative stress of A, reduces the ROS level that A β causes, alleviates the mitochondrial membrane potential decline that A β causes.Its anti-oxidation stress effect is better than resveratrol.Resveratrol is a kind of sure antioxidant.We also make positive control with this.
A β combines with ABAD (A β's is conjugated protein) in the mitochondrion, causes the ABAD conformational change, causes mitochondrial injury and oxidative stress.HopA can directly combine with A β, suppress A β and combine with ABAD in the mitochondrion, thereby protection mitochondrial injury and inhibited oxidation stress.
Embodiment:
Hopea hainanensis plant crude extract (100g) is gone up silicagel column (5cm*80cm) carry out rough segmentation, carry out drip washing with the chloroform-methanol mixed solvent, and strengthen methanol content gradually, analyze, obtain 8 components altogether by TLC.Second component (2.8g) uses silicagel column (1.5cm*50cm) to separate once more, gets 6 components, and wherein the 3rd component (305mg) shows good active, so then separate with the viscose post, obtains component 3a-3d.At last component 3d purification on the semi-preparative column of high performance liquid chromatogram is obtained HopA 73mg.
HopA is a kind of natural polyphenol chemical compound with brand-new carbon skeleton, is resveratrol oligomer compounds, and molecular weight is 496Da.Red powdery, kept dry is in 0-5 ℃; Face the time spent with a small amount of dehydrated alcohol hydrotropy (volume ratio is less than 5%), ultra-pure water is formulated as 1mg/ml stock solution.Make oral tablet, specification is the 100mg/ sheet.Its oral application dosage is 1-2mg/kg.
Following surface analysis HopA of the present invention is as the mechanism and the effect of Drug therapy Alzheimer.
By Computerized three-dimensional simulation, to its crystal structure and carry out docking with the electric eel crystal structure and analyze, the N atom that its action site is based on its 4b-OH and Trp286 with and the active hydrogen of ester group and Ser293 between the hydrogen bond that forms.Its structure is different from any clinically anti-AD medicine.HopA is the stronger acetylcholinesteraseinhibitors inhibitors of a kind of reversibility and has strong antioxidation.It is approaching in the activity and the huperzine A effect of vitro inhibition electric eel acetylcholinesterase, has kept the monomeric strong anti-oxidation ability of resveratrol simultaneously.We discover that Hopeahainol A can directly combine with A β simultaneously, disturb A β to combine with ABAD, and inhibited oxidation stress.
The interaction of antagonism ABAD and A β can become the active drug target spot of intervening AD.
At first from integral body to the cellular level, checking HopA can improve the ability of learning and memory obstacle of AD and suppress the beta induced neuronal death of A in the present invention, thereby proof HopA has therapeutical effect to AD; Secondly, with the positive contrast of aricept, prove that HopA has the activity of acetylcholine esterase inhibition in vivo.Simultaneously, with the positive contrast of resveratrol, prove that HopA also has strong antioxidant action in vivo.Prompting HopA is the medicine of the AD of target treatment more than; The 3rd, in vitro study proves that also HopA suppresses the beta induced oxidative stress effect of A; The 4th, the mechanism of antioxidation may combine with ABAD in the mitochondrion for HopA suppresses A β, thus the protective wire plastochondria, and inhibited oxidation stress.
Test 1:
Calculate required consumption in body experimental basis mice body weight, extract the injection of stock solution pneumoretroperitoneum; Follow-up isolated experiment is done corresponding dilution with HopA stock solution according to desired concn.
Test 1-1: studies have shown that in the body that HopA has therapeutical effect to AD:
Bull APP/PS1 mice, body weight 20～30 grams, be divided at random: blank group and HopA treatment group, APP/PS1 mice are the AD animal models of generally acknowledging at present, and mice 8-10 month behavioristics is unusual, becomes dementia.By behavioristics and electrophysiology proof HopA AD had therapeutical effect.
1) material and method
(4mg/kg/d), matched group gives the equivalent normal saline to treatment group lumbar injection every day various dose HopA for 1mg/kg/d, 2mg/kg/d, treats 15 days.Selecting medium effective metering 2mg/kg/d is the therapeutic dose of whole research.
Behavioristics is detected: adopt the test of morris water maze: the Morris water maze comprises orientation navigation experiment and space exploration experiment.Orientation navigation experiment is lasted 4 days, regularly trains every day 4 times, detects the time (escape latency) that rat is found safety island, and escape latency is long more, and its ability of learning and memory is poor more, otherwise strong more.Remove safety island on the 5th day and do the space exploration experiment, rat is put into water from same place of entry, the number of times of mice leap safety island reaches the search time at former safety island place quadrant in the record 60s, cross over the safety island number of times in the identical time more less or short more search time at former safety island place quadrant, then its ability of learning and memory is poor more, otherwise strong more.
The electricity physiological detection: each organize mice under etherization fast broken end get brain, the fresh brain sheet of preparation mice, under the anatomic microscope direct-view, to write down glass electrode and insert hippocampal slices CA1 district radiating layer, carry out orthodromic stimulation, record excitatory postsynaptic potential (excitatory postsynaptic potential, EPSP); Use stimulator to stimulate the brain sheet, according to stimulus intensity-reaction efficiency relation, half is the experiment stimulus intensity stimulus intensity of the maximum reaction of selection.Inducing of LTP is to stimulate the brain sheet as condition test with the experiment stimulus intensity earlier, gather 20 minutes as average base value (100%), selecting 80% of the maximum stimulus intensity that reacts then is stimulus intensity, carry out high frequency stimulation (high-frequency stimulation, HFS), behind the HFS, impose the same terms test again, at least stable recording is 1 hour, to be defined as LTP.
2) result
(1) result of behavioristics: the prompting of morris water maze appraisal result, after 15 days, APP/PS1 mice escape latency all shortens (P＜0.05) through each dosage HopA treatment, and distance reduces (P＜0.05) before appearing on the stage, and wearing the platform number of times increases (P＜0.05).HopA obviously improves above situation.(Fig. 1 a).
(2) electric physiology result: compare with the control group, APP/PSI group EPSP slope obviously reduces (P＜0.01); HpoA treatment group is than APP/PSI group EPSP slope significantly raise (P＜0.01).Control group: the LTP that HFS induces stable Hippocampus CA3-CA1 synapse to transmit; Compare with the control group, APP/PSI group LTP induces obstacle (P＜0.01); HopA treatment group LTP induces recovery (comparing P＜0.01 with the APP/PSI group) (Fig. 1 b).
Test 1-2: in vitro study proof HopA has protective effect to the beta induced neuronal damage of A:
1) material and method
Former generation cortical neuron cultivation: conceived 15-17d wild type kunming mice, after disconnected neck is put to death, get its embryo, place the culture dish that fills cold HBSS, separate cerebral cortex, after the 1X trypsinization, put in the culture plate after poly-D-lysine is handled and cultivate 2～3 * 10
6Cell/ml, every 2-3d partly changes liquid, cultivates 10-14d altogether.Cell culture in the culture fluid (Neurobasal adds Hepes, B27 and glutamine) of serum-free, no phenol red and no estrogen, 37 ℃, 5%CO
2Incubator.
A β and Hopeahainol A handle: after 4 μ M A β handle neuron 24h, add various dose HopA, matched group adds the PBS of same concentrations, and HopA is by the dimethyl sulfoxine hydrotropy, and the administration final concentration is respectively 0.1,0.5,1.0,2.0,4.0,8.0,16 and 32 μ M.HopA measures neuron survival rate with the MTT method after handling 24h.
The neuronal cell vigor detects: use tetramethyl azo azoles salt colorimetry (mtt assay) to detect neuronic cell viability.In 100 μ l culture fluid/holes, add MTT, 37 ℃, 5%CO
2Incubator in continue to cultivate 6h, whole culture fluid that incline then add 100 μ l DMSO solution in every hole, shake on the shaking table to hepatic crystallization to dissolve fully, enzyme mark calculating instrument is measured and is respectively organized the OD value.
The Neuron Apoptosis rate detects: the two methods of dying of Annexin-V/PI use flow cytometer to detect the Neuron Apoptosis rate.Collect neuron centrifugal (the centrifugal 5min of 2000rpm); PBS washed cell secondary (the centrifugal 5min of 2000rpm) is collected 1-5 * 10
5Cell; The Binding Buffer suspension cell that adds 500 μ L; After adding 5 μ L Annexin V-FITC mixings, add 5 μ L Propidium Iodide, mixing; Room temperature, lucifuge, reaction 5～15min; Flow cytometer detects.
2) result
Dose curve (0.1,0.5,1.0,2.0,4.0,8.0,16 and 32 μ M) prompting HopA can significantly improve the beta induced neuronic cell viability of A, and it is relevant to be tangible dosage, and (Fig. 2 a) to progress into plateau after concentration reaches 4 μ M.In view of the above, all to choose concentration be that the HopA of 4 μ M is an object of study in follow-up study.
PI dyeing detects the Neuron Apoptosis rate: consistent with preceding result, HopA can significantly reduce apoptosis (Fig. 2 b) due to the A β.
Test 2:
Test 2-1: research in the body, HopA has the effect that suppresses acetylcholine esterase:
1) material and method
8-10 month APP mice, behavioristics uses HopA (2mg/kg), resveratrol (30mg/kg), aricept (0.6mg/kg) 8 weeks of treatment respectively after detecting the proof dementia, extracts mouse cortex and hippocampal tissue then acetylcholine esterase active mensuration (Nanjing is built up bio-engineering research and provided) is provided.
2) result
HopA has the effect of acetylcholine esterase inhibition activity, and its inhibition degree is not than aricept (having obvious significant difference), but strong than resveratrol, sees Fig. 3.
Test 3:
Test 3-1: in the body research HopA inhibited oxidation stress:
1) material and method
The APP/PS1 dementia mice, use HopA (2mg/kg), resveratrol (30mg/kg), aricept (0.6mg/kg) 8 weeks of treatment respectively, extract mouse cortex and Hippocampus then, the fluorescence spectrophotometry agent detects respectively at the oxidative stress index 4-HNE of lipid, DNA and three different aspects of protein (4-hydroxyl nonenyl aldehyde), 8-OHDG (8 hydroxyl deoxyguanosine), 3-NT (3-nitrotyrosine), and mitochondrial membrane potential, concrete operations are carried out (bio-engineering research institute is built up in Nanjing) according to the test kit explanation.
2) result
Discover that APP/PS1 mice Hippocampus 4-HNE, 8-OHDG and 3-NT are apparently higher than normal B6 Mus (p＜0.05), mitochondrial membrane potential decline (p＜0.05), after HopA handles, 4-HNE, 8-OHDG and 3-NT level all reduce (p＜0.05), mitochondrial membrane potential rising (p＜0.05), its effect is better than resveratrol and aricept (p＜0.05), sees Fig. 4.
Test 3-2: in vitro study (former generation cortical neuron), HopA suppresses the beta induced oxidative stress effect of A:
1) material and method
Mitochondrial membrane potential and ROS detect: all use the fluorescent probe detection method to detect.Neuron linear mitochondrial membrane potential level is used the JC-1 fluorescent probe, and ROS detects and uses the DCFH-DA fluorescent probe, detects each fluorescence intensity in conjunction with flow cytometer.
2) result
HopA suppresses decline of neuron linear mitochondrial membrane potential and the ROS rising that A β causes:
Compare with matched group, the neuron linear mitochondrial membrane potential that A β handles descends and the ROS level rises; And HopA obviously improves the influence of A β to neuron linear mitochondrial membrane potential and ROS level.(Fig. 5).
Test 3-3:HopA directly combines with A β:
1) material and method
In 0.01MPBS50ul and 0.1M A β 50 μ l, add 60 μ M HopA, 50 μ L respectively, 37 water-bath 60min behind the mixing, centrifugal 16000rps 15min gets 50 μ l supernatant sample introductions.Adopt high performance liquid chromatography to detect HopA content in two pipes (being responsible for detection) respectively by Southeast China University's Child Development and learning science research center key lab of Ministry of Education physical and chemical inspection Room 3.Add 50 μ M with detecting, 40 μ M, 30 μ M, the content of HopA in A β group and PBS group when 20 μ M and 10 μ M HopA with quadrat method.
2) result
60 μ MHopA50 μ l add among the 0.01M PBS50 μ l, and the measured HopA peak area of high performance liquid chromatogram is 1799130, and adds among the 50 μ l 0.1M A β at the HopA of same concentrations, and measured peak area is 643654, and fall is 643654.Equally, at 50 μ M, behind the adding 0.1M A β 50 μ l, the peak area fall of surveying is respectively 347314,165022 and 123563 among 40 μ M and the 30 μ M HopA50ul.In 20 μ M and 10 μ M HopA50 μ l, add the measured HopA peak area of 0.01M PBS50ul and be respectively 22779 and 11556, but after adding 0.1M A β 50 μ l, HopA peak area disappearance (Fig. 6).
Test 3-4:HopA inhibition A β combines with ABAD's
1) material and method
Adopt co-immunoprecipitation method (IP) to detect the situation that combines of A β and ABAD: former generation cortical neuron cultivation is after 8 days, after handling 24 hours with 2 μ MA β, handle back 3 respectively at adding HopA, collecting cell albumen after 6,12,24 and 48 hours, be divided into the normal neurons group, normal neurons+HopA group, normal neurons+A β group, normal neurons+A β+HopA organizes 4 groups.Adopt the BCA standard measure to detect protein content, get the 1mg cell protein for every group and add 1 μ g A β antibody respectively, vibrated gently 2 hours in 4 ℃ in 4 ℃ of Protein G Beads that add 25 μ l gently after the shaken overnight again; Centrifugal 2 minutes of 4000g collects Protein G Beads, with the PBS washed cell 3 times of pre-cooling and abandon supernatant; Add 5 * sample-loading buffer of respective volume, boiled 5 minutes; Carry out the SDS-PAGE electrophoresis, with the content of ABAD antibody test and the bonded ABAD of A β.Otherwise, carry out pull down with the antibody of ABAD, add the content that A β antibody carries out Western blot detection and the bonded A β of ABAD again.
2) result
A β has raise 2.54 times with the bonded ABAD protein content of A β than matched group after handling, but handles 3 through HopA again, after 6,12,24 and 48 hours, be respectively 52.3%, 46.5%, 23.9%, 25.0% and 23.8% of matched group with the bonded ABAD protein content of A β.And A β has raise 43.7% with the bonded a content of ABAD after handling, and after HopA handled, the bonded a content of ABAD was 83.1% of matched group.See Fig. 7.
Claims (2)
1. a medicine for the treatment of Alzheimer is characterized in that containing hopea hainanensis phenol first, and molecular weight is 496Da, and molecular structural formula is
2. a kind of medicine for the treatment of Alzheimer according to claim 1 is characterized in that oral agents.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103910781A (en) * | 2014-03-18 | 2014-07-09 | 重庆大学 | A beta aggregation inhibitor |
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2010
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Non-Patent Citations (2)
| Title |
|---|
| DA HUA SHI等: "Protective effect of hopeahainol A, a novel acetylcholinesterase inhibitor, on hydrogen peroxide-induced injury in PC12 cells.", 《ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY 》 * |
| HUI MING GE等: "Hopeahainol A: An Acetylcholinesterase Inhibitor from Hopea hainanensis.", 《 CHEM. EUR. J.》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103910781A (en) * | 2014-03-18 | 2014-07-09 | 重庆大学 | A beta aggregation inhibitor |
| CN103910781B (en) * | 2014-03-18 | 2016-02-17 | 重庆大学 | A kind of A beta peptide aggregation inhibitor |
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Application publication date: 20111019 |