CN106667992B - Use of coniferyl aldehyde or coniferyl aldehyde and vanadium compound composition for preventing and treating neurodegenerative diseases - Google Patents
Use of coniferyl aldehyde or coniferyl aldehyde and vanadium compound composition for preventing and treating neurodegenerative diseases Download PDFInfo
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- CN106667992B CN106667992B CN201611231409.XA CN201611231409A CN106667992B CN 106667992 B CN106667992 B CN 106667992B CN 201611231409 A CN201611231409 A CN 201611231409A CN 106667992 B CN106667992 B CN 106667992B
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- vanadyl
- coniferyl aldehyde
- vanadium compound
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- aldehyde
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Abstract
The invention discloses an application of coniferyl aldehyde or a coniferyl aldehyde and vanadium compound composition in preventing and treating neurodegenerative diseases, and the application of the coniferyl aldehyde or a coniferyl aldehyde and vanadium compound combined pharmaceutical composition as a raw material in preparing a medicament for preventing and treating neurodegenerative diseases Alzheimer's disease.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to application of a medicine composition which is prepared by taking coniferyl aldehyde or coniferyl aldehyde and vanadium compound as main raw materials and is used for preparing a medicine for preventing and treating neurodegenerative disease Alzheimer's disease.
Background
Alzheimer's Disease (AD) is one of the major diseases that currently threaten the health of the world population and socioeconomic performance. The reason for this is that the population is getting older, and the number of patients increases year by year. In the population over 65 years old in the United states, one person suffers from the disease every 8 people, and 25 percent of hospitalized elderly patients suffer from AD; domestic conditions are similar to those in the united states. The second is that there is a long time difference between the pathological changes of neural tissue in AD and the visible symptoms of clinical cognitive impairment, resulting in the loss of optimal time for treatment once diagnosed. This dyssynchrony between lesions and symptoms can be explained by the "cognitive reserve" of the brain. Third, there is currently a lack of effective AD treatment regimens and they are expensive. Statistically, the annual cost of treatment for AD in the united states is more than 9 times the cost of treatment for common geriatric conditions. Such huge costs are a serious economic threat to countries and may even lead to the risk of bankruptcy of the medical insurance system. Therefore, the research and the application of the therapeutic drugs for AD have great scientific and application significance.
In the past, the amyloid protein theory (A β hypthesis) has been the focus of the research and development of the acknowledged AD pathological mechanism and the drug AD drug, however, in the past, the drugs based on the strategy of clearing amyloid plaques all failed, which requires researchers to review the mechanism of AD pathological changes, design a treatment scheme and discover the drug with a new action mechanism from a new key pathological link.
A β oligomer has neurotoxicity, causing loss of nerve synapses, reducing neuronal plasticity, altering energy metabolism, causing oxidative stress and mitochondrial dysfunction, therefore the direction of future AD studies should be how to eliminate or inhibit the toxic A β protein before brain nerve damage;
the Tau protein hyperphosphorylation leads to the formation of insoluble double helix filaments (PHF), the loss of microtubule binding capacity makes cytoskeleton unstable, and finally leads to neurodegenerative diseases and neuronal death;
a β appears not only in nerve cells, but also in mitochondria in a corresponding concentration, it inhibits mitochondrial respiratory enzyme complex II and IV, reduces ATP production, increases ROS production, and ultimately leads to mitochondrial dysfunction, and studies have shown that A β accumulation also causes abnormalities in mitochondrial fission (Fis1) and fusion (Mfn1/2 and OPA1) protein expression, disrupts the normal dynamic balance of mitochondria, resulting in impaired mitochondrial clearance, and aggravates neurodegenerative disorders.
In addition, AD and diabetes share many common pathological phenomena and mutually contribute to each other's pathological processes. Over 80% of AD patients have abnormal blood glucose levels or symptoms of insulin resistance, and type II diabetics are more than twice as at risk of AD as healthy people. Antidiabetic vanadium compounds are well known insulin sensitizers and may act to arrest the progression of AD disease by abrogating insulin resistance. A clinical study showed that the cognitive ability of the brain remained better in both diabetic and non-diabetic patients with vanadium-rich drinking water.
Disclosure of Invention
In view of the disadvantages in the above problems, the present invention provides the use of coniferyl aldehyde or a combination of coniferyl aldehyde and vanadium compounds for the prevention and treatment of neurodegenerative diseases.
In order to achieve the purpose, the invention provides application of coniferyl aldehyde or a coniferyl aldehyde and vanadium compound composition in preventing and treating neurodegenerative diseases.
As a further improvement of the present invention, the vanadium compound includes an inorganic vanadium compound including vanadyl complex, hydroxylamine vanadium complex, heteropoly acid complex of vanadium and an organic vanadium compound; the organic vanadium compounds include vanadyl benzoate, vanadyl aspirin, vanadyl acetylacetonate, bis (2-methyl-3-hydroxy-4-pyrone) vanadyl (BMOV), 3-hydroxy-2-ethyl-4-pyrone (BEOV), 3-hydroxy-2-isopropyl-4-pyrone (BIOV), 3-hydroxy-2-n-butyl-4-pyrone (BnBOV), vanadyl bis (pyridine 2-carboxylate) (VO (Pa)2), vanadyl picolinate (VO-DPA), vanadyl picolinate (VO-PAM), vanadyl picolinate (VO-MPA), vanadyl picolinate (VO-PA), vanadyl malonate oxavanadyl oxalate, vanadyl oxyvanadyl valine hydroxylamine, vanadyl oxynitrate, Leucine hydroxylamine vanadyl.
As a further improvement of the invention, the vanadium compound also comprises a BSOV series synthesized by taking pyrone kojic acid as a mother nucleus and introducing an antioxidant group at the 2-position, and a novel vanadyl complex (VOL1-VOL6) prepared by introducing an antioxidant functional ligand with a hydroxyaniline or hydroxyphenylethylamine derivative structure by taking nitrilotriacetic acid as a carbon skeleton.
As a further improvement of the invention, the concentration range of coniferyl aldehyde is between 100 mu M and 0.1 mu M, and the concentration range of coniferyl aldehyde can improve the activity of nerve cells under normal and A β overload conditions to different degrees.
As a further improvement of the present invention, the nerve cells under normal and A β overload conditions are SH-SY5Y human neuroblastoma and cells overexpressing wild-type Amyloid Precursor Protein (APP) and Swiss mutant amyloid precursor protein (APPsw).
As a further improvement of the invention, the action time of the medicament on nerve cells is 12h, 24h, 36h and 48 h.
As a further improvement of the invention, the combined use effect of the coniferyl aldehyde with the concentration of 1 μ M and the vanadium compound with the concentration of 100 μ M-50 μ M is most remarkable.
As a further improvement of the invention, when the concentration of coniferyl aldehyde is 100 mu M, the effect on AD cells and animal models is optimal when the coniferyl aldehyde and vanadium compound are used together at the concentration of 1 mu M.
As a further improvement of the invention, the selected Alzheimer's disease animal model is an APPswe/PS1dE9(APP/PS1) double transgenic mouse.
As a further improvement of the present invention, the neurodegenerative disease is all neurodegenerative diseases including alzheimer's disease.
Compared with the prior art, the invention has the beneficial effects that:
the invention discloses an application of coniferyl aldehyde or coniferyl aldehyde and vanadium compound composition in preventing and treating neurodegenerative diseases, which takes coniferyl aldehyde or coniferyl aldehyde and vanadium compound combined pharmaceutical composition as a raw material to prepare a medicine for preventing and treating neurodegenerative diseases Alzheimer disease, protects nerve cells and maintains nerve cell function by inhibiting A β toxicity, inhibiting Tau protein over-phosphorylation, restoring cell mitochondrial function, stimulating nerve cell regeneration and other mechanisms, and the vanadium compound can protect nerve cell vitality and nerve cognitive function of Alzheimer disease, diabetes and ischemic stroke model animals by regulating brain nerve cell glucose metabolism and stimulating nerve cell regeneration, and the coniferyl aldehyde and vanadium compound combination of food components can be developed into the medicine for preventing Alzheimer disease.
Drawings
FIG. 1 is a MTS assay to examine the effect of coniferyl aldehyde (4H3M), a compound prepared in example 1 of the present invention, on the cell viability of A β -overloaded neural cells APPwt and APPswe;
FIG. 2 is a MitoTracker mitochondrial selection probe method for detecting the effect of coniferyl aldehyde (4H3M), a compound prepared in example 1 of the present invention, on the mitochondrial morphology of SH-SY5Yneo nerve cells;
FIG. 3 is a MitoTracker mitochondrial selection probe method for detecting the effect of coniferyl aldehyde (4H3M), a compound prepared in example 1 of the present invention, on the mitochondrial morphology of A β -overloaded neural cells APPwt;
FIG. 4 is a MitoTracker mitochondrial selection probe method for detecting the effect of coniferyl aldehyde (4H3M), a compound prepared in example 1 of the present invention, on the mitochondrial morphology of A β -overloaded neural cell APPswe;
FIG. 5 is a Western Blot experiment to examine the effects of coniferyl aldehyde (4H3M) and coniferyl aldehyde (4H3M) combined with Vanadyl Acetylacetonate (VAC) prepared in example 1 of the present invention on A β oligomerization and Tau protein phosphorylation in cerebral cortex and hippocampal tissues of an APPswe/PS1dE9(APP/PS1) animal model;
FIG. 6 is an immunohistochemical staining experiment conducted to examine the effect of coniferyl aldehyde (4H3M) and coniferyl aldehyde (4H3M) in combination with Vanadyl Acetylacetonate (VAC) prepared in example 1 of the present invention on A β oligomerization in the cerebral cortex and hippocampus tissues of an APPswe/PS1dE9(APP/PS1) animal model;
FIG. 7 is a Niger's staining experiment examining the effect of coniferyl aldehyde (4H3M) and coniferyl aldehyde (4H3M) in combination with Vanadyl Acetylacetonate (VAC) prepared in example 1 of the present invention on nerve cells in hippocampal tissue of an animal model of APPSwe/PS1dE9(APP/PS 1).
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are some, but not all, embodiments of the present invention. All other embodiments, which can be obtained by a person skilled in the art without any inventive step based on the embodiments of the present invention, are within the scope of the present invention.
The invention provides an application of coniferyl aldehyde or a coniferyl aldehyde and vanadium compound composition in preventing and treating neurodegenerative diseases, and the application of the coniferyl aldehyde or a coniferyl aldehyde and vanadium compound combined pharmaceutical composition as a raw material in preparing a medicine for preventing and treating neurodegenerative diseases Alzheimer's disease.
Wherein the vanadium compound includes all inorganic vanadium compounds and organic vanadium compounds, the inorganic vanadium compounds include vanadyl complex, vanadyl peroxy complex, hydroxylamine vanadium complex, heteropolyacid complex of vanadium, etc., including vanadyl benzoate, vanadyl aspirin, vanadyl acetylacetonate, bis (2-methyl-3-hydroxy-4-pyrone) vanadyl (BMOV), 3-hydroxy-2-ethyl-4-pyrone (BEOV), 3-hydroxy-2-isopropyl-4-pyrone (BIOV), 3-hydroxy-2-n-butyl-4-pyrone (BnBOV), vanadyl bis (pyridine 2-carboxylate) (VO (Pa)2), vanadyl dipicolinate (VO-DPA), vanadyl picolinate (VO-PAM), Vanadyl picolinate (VO-MPA), vanadyl picolinate (VO-PA), vanadyl malonat, vanadyl oxalate, vanadyl hydroxylamine, vanadyl valine hydroxylamine, vanadyl leucine, and the like, and a series of BSOV synthesized by taking pyrone kojic as a mother nucleus and introducing an antioxidant group at the 2-position, and a novel vanadyl complex (VOL1-VOL6) prepared by introducing an antioxidant functional ligand with a hydroxyaniline or hydroxyphenylethylamine derivative structure by taking nitrilotriacetic acid as a carbon skeleton.
Preferably, the concentration ranges of 100 μ M to 0.1 μ M each have different degrees of enhancement of the activity of nerve cells under normal and A β overload conditions, wherein the concentration ranges of 100 μ M to 50 μ M are most significant in the enhancement of the activity of nerve cells under normal and A β overload conditions the nerve cells under normal and A β overload conditions are SH-SY5Y human neuroblastoma and cells overexpressing wild-type Amyloid Precursor Protein (APP) and Swiss mutant amyloid precursor protein (APPsw) (abbreviated as SH-SY5Yneo cell, APPwt cell, APPsw cell, respectively) the action time of the drug on nerve cells is 12h, 24h, 36h, 48h, wherein the 36h effect is most significant.
Preferably, the combined use effect of the coniferyl aldehyde with the concentration ranging from 100 to 50 μ M and the vanadium compound with the concentration of 1 μ M is most remarkable, and the coniferyl aldehyde with the concentration of 100 μ M is optimal.
Preferably, the combination effect of the coniferyl aldehyde with the concentration of 50-100 μ M and the vanadium compound with the concentration of 1 μ M is most remarkable, and the combination effect of the coniferyl aldehyde with the vanadium compound with the concentration of 1 μ M is most effective on AD cells and animal models when the coniferyl aldehyde with the concentration of 100 μ M is used.
Preferably, the selected Alzheimer's disease animal model is an APPswe/PS1dE9(APP/PS1) double transgenic mouse.
Preferably, the neurodegenerative disease is all neurodegenerative diseases including alzheimer's disease.
The invention aims to find the chemical medicine for resisting the Alzheimer disease, which can play a role in the key pathological links by aiming at the disease modification.
Coniferyl aldehyde is a food ingredient that is used mainly as a standard substance for content or potency determination in bioassays, antibiotics or biochemicals. Wherein the content of coniferyl aldehyde in brandy is 1.68-2.8mg/L, and coniferyl aldehyde is also present in various Chinese medicinal materials such as cortex Eucommiae, radix Acanthopanacis Senticosi, caulis Bambusae in Taenia, rhizoma Phragmitis, propolis, etc. However, no clinical medicinal data of coniferyl aldehyde exist at present, and researches on plant-derived bacteriostatic active ingredients in relevant consulted documents show that the coniferyl aldehyde ingredient extracted from juglans regia has bacteriostatic and antibacterial effects; the chemical component coniferyl aldehyde separated from she-medicine herba lobeliae chinensis has certain effect of inhibiting rat neutrophil (PMN) respiratory burst.
Coniferyl aldehyde is known to be a potential product of cinnamoyl-coa reductase (CCR). Cinnamoyl-coa reductase (CCR) is the first rate-limiting enzyme catalyzing lignin-specific pathways and may have potential regulatory effects on lignin biosynthesis pathways. Since coniferyl aldehyde is widely present in a variety of plants, it is considered to be a possible chemical component present in the xylem of plants.
In recent years, researches show that cinnamon and extracts thereof (the main active component is anthocyanin) have certain prevention and treatment effects on AD cells and animal models, and the action and the molecular mechanism of cinnamaldehyde which is the other main component of cinnamon are deeply researched at a cell level, and further, on the basis, SH-SY5Y cells excessively secreted by A β are taken as a research model, an efficient and rapid MTS method is taken as a screening method, an A β and a mitochondrion action target point are taken as a target, and a coniferyl aldehyde (4H3M) which is a compound with good anti-AD activity is screened from a plurality of traditional Chinese medicine active ingredient libraries, so that the research shows that the coniferyl aldehyde (4H 853 aldehyde) can improve the activity of nerve cells under normal and A β overload conditions, has good effects of inhibiting A β oligomerization and the like, the coniferyl aldehyde (4H3M) is one of 4-hydroxy coniferyl aldehyde (4H3M) which is taken as a medicine model, and the research on the preliminary prevention effect and the animal cells (3M) is shown by the animal experiments:
①, inhibiting A β toxicity
②, inhibiting Tau protein hyperphosphorylation
③ restoring mitochondrial function
④ and stimulating nerve cell regeneration
Analysis of the chemical structure of coniferyl aldehyde shows that the activity of coniferyl aldehyde is related to the phenolic hydroxyl group and the α -unsaturated aldehyde ketone structure in the molecular structure, and the chemical environment of the phenolic hydroxyl group and the crowding state of the space environment of the phenolic hydroxyl group affect the activity of the compound.
Based on the molecular mechanism and the preliminary experimental results of the antidiabetic vanadium compound, the antidiabetic metal compound is possible to prevent the pathological process of AD and protect nerve 'cognitive reserve'. the coniferyl aldehyde has obvious synergy in action with the essential biological element vanadium.
The invention is described in further detail below with reference to the attached drawing figures:
example 1
Preparation of coniferyl aldehyde (4H3M) and coniferyl aldehyde (4H3M) in combination with Vanadyl Acetylacetonate (VAC) compound (4H3M + VAC) composition preparation
Weighing 17.18mg (0.1mmol) of coniferyl aldehyde (4H3M), dissolving 10mL of DMSO to obtain a mother solution of coniferyl aldehyde (4H3M) with a concentration of 10 mM; 100 μ L of coniferyl aldehyde (4H3M) stock solution (10mM) was diluted in 9.9mL of DMEM (containing 10% serum) to obtain 200 μ M coniferyl aldehyde (4H3M) solution; then 200. mu.M coniferyl aldehyde (4H3M) solution was diluted to 100. mu.M, 50. mu.M, 10. mu.M, 5. mu.M, 1. mu.M, 0.5. mu.M, 0.1. mu.M, respectively, to prepare coniferyl aldehyde (4H3M) solutions of various concentrations.
26.51mg (0.1mmol) of Vanadyl Acetylacetonate (VAC) is weighed, 10mL of distilled water is taken to dissolve, and the solution is prepared into Vanadyl Acetylacetonate (VAC) mother liquor with the concentration of 10 mM; mu.L of Vanadyl Acetylacetonate (VAC) mother liquor (10mM) was diluted in 9.99mL of DMEM (containing 10% serum) to prepare 10. mu.M of Vanadyl Acetylacetonate (VAC) solution; then 10 μ M Vanadyl Acetylacetonate (VAC) solution was diluted to 2 μ M; coniferyl aldehyde (4H3M) and Vanadyl Acetylacetonate (VAC) at final concentrations of 100. mu.M and 1. mu.M, respectively, coniferyl aldehyde (4H3M) in combination with Vanadyl Acetylacetonate (VAC) compound (4H3M + VAC) composition formulations were prepared by mixing a 200. mu.M solution of coniferyl aldehyde (4H3M) with a 2. mu.M solution of Vanadyl Acetylacetonate (VAC) in a 1:1 ratio.
Example 2
MTS experiment for detecting cell viability
Cell pre-culture and passage: cells were incubated at 37 ℃ with 5% CO2The culture medium was DMEM (containing 10% fetal bovine serum), 100. mu. M G418, 100U/ml penicillin and 100. mu.g/ml streptomycin. (1) Preheating culture medium, pancreatin and PBS in a water bath kettle at 37 ℃; (2) the old medium in the flask was discarded, and 2ml of PBS was added to 25cm3In the cell culture flask of (1), the cell surface was washed 3 times, anddiscarding the PBS; (3) adding 1mL of 0.25% pancreatin to digest cells, observing under a microscope until the cell morphology is slightly changed, pouring out pancreatin in a super clean bench to obtain about 100 mu L, and placing the cells in a cell culture box at 37 ℃ to incubate for 3min until the cells are completely digested; (4) stopping digestion with 2mL of cell culture medium, blowing the wall of a culture flask, transferring the cells into a centrifuge tube, and centrifuging at 1000rpm for 3 min; (5) centrifuging, removing supernatant, adding 1mL of fresh DMEM (containing 10% fetal calf serum) into a culture bottle, blowing and mixing the cells uniformly, carrying out cell passage according to a proper proportion, marking the cell name, the generation number and the passage date on the bottle body, and putting the bottle body into an incubator.
MTS method:
(1) inoculating cells: preparing a cell suspension by using a DMEM (containing 10% fetal bovine serum) culture medium, and then inoculating 3000-4000 cells per well into a 96-well plate, wherein the volume of each well is 100 mu L; (2) after about 60 percent of cells are fused, adding the medicine to act for 36 hours; 3) preparing 10% MTS solution with DMEM (containing 10% fetal calf serum) culture medium, removing the solution in the original culture well after 36h of drug action, adding 100ul of 10% MTS solution into each well, and continuing to incubate for 2 h; (3) after 2h, the light absorption value (excitation wavelength is 490nm) of each hole is measured by an enzyme-labeling instrument, and a drug action curve is drawn by taking the drug concentration as an abscissa and the light absorption value as an ordinate.
As shown in FIG. 1, MTS test detects the effect of coniferyl aldehyde (4H3M) on the cell viability of A β overload nerve cells APPwt and APPswe, and according to FIG. 1, coniferyl aldehyde (4H3M) is present in a concentration range of 100 μ M to 0.1 μ M, which has the most significant effect on enhancing the cell viability under normal and A β overload conditions, wherein the concentration range of 100 μ M to 50 μ M enhances the cell viability under normal and A β overload conditions.
Example 3
MitoTracker mitochondrial selection probe method for detecting cell mitochondrial morphology
As shown in figures 2, 3 and 4, a MitoTracker mitochondrial selection probe method experiment detects the influence of a compound coniferyl aldehyde (4H3M) on the mitochondrial forms of SH-SY5Yneo cells and A β overload nerve cells APPwt and APPswe, and as shown in figures 2, 3 and 4, the coniferyl aldehyde (4H3M) concentration of 100 mu M can reduce the abnormal elliptical mitochondria of three cells, reshape the function of the normal filamentous mitochondrial form, and restore the mitochondrial function by reconstructing the mitochondrial form, thereby resisting A β toxicity.
Example 4
Animal models and drug treatments
Female APPswe/PS1dE9(APP/PS1) animal models of 15 at 8 weeks, randomized into 3 groups: the control group, coniferyl aldehyde (4H3M) group and coniferyl aldehyde (4H3M) combined with Vanadyl Acetylacetonate (VAC) (4H3M + VAC) composition preparation group were fed in 5, 2-3 cages each, 12/12H light and dark cycle, and the ambient temperature was 22-26 ℃. When the age of the mice is about 12 weeks, the mice are fed according to the following method:
control group APP/PS1 mice: feeding with common feed;
coniferyl aldehyde (4H3M) group APP/PS1 mice: feeding with coniferyl aldehyde (4H3M) uniformly mixed into feed at a concentration of 0.2 mmol/kg/day;
coniferyl aldehyde (4H3M) in combination with Vanadyl Acetylacetonate (VAC) (4H3M + VAC) composition preparation group APP/PS1 mice: uniformly mixing coniferyl aldehyde (4H3M) containing 0.2mmol/kg/day and Vanadyl Acetylacetonate (VAC) containing 0.1mmol/kg/day for feeding;
example 5
Diving tower behavioural detection
3 groups of APP/PS1 mice were fed as in example 4 and tested for learning and memory by bench jump behavioural testing after 3 and 4 months, respectively.
A jump bench experiment: the chamber is divided into 8 chambers by opaque black baffles, each chamber is 120mm multiplied by 180mm, and the electric grids at the bottom of the chamber can be electrified. The APP/PS1 mice in each group of experiment are placed in a reaction box for free movement for 5min, the environment is familiar, then a copper grid power supply (0.25mA) is switched on, and the normal reaction of the mice is to find a safe jump table to avoid electric shock after the mice are subjected to electric shock. Each group of mice finds a safe jump platform from the time of receiving an electric shock to the first time, and records the time (latency) of jumping off the platform for the 1 st time and the error times (basic error times) of jumping off the safe jump platform within 5min as the learning test result; after 1 day, the experiment is repeated, and the time (latency) for the 1 st jump of the safety platform and the number of shocks (error number) received within 5min of each group of mice are recorded as the memory test result. In the experiment, if the time for the mouse to stay on the safe platform exceeds 5min, the latency period is calculated by 5 min.
Table 1 shows the effect of coniferyl aldehyde (4H3M) and coniferyl aldehyde (4H3M) in combination with Vanadyl Acetylacetonate (VAC) administered for 3 months in the APPswe/PS1dE9(APP/PS1) animal model tested by Tachtai behavioural experiments.
Table 2 shows the effect of coniferyl aldehyde (4H3M) and coniferyl aldehyde (4H3M) in combination with Vanadyl Acetylacetonate (VAC) administered for 4 months in the APPswe/PS1dE9(APP/PS1) animal model tested by Tachtai behavioural experiments.
TABLE 1
Tablel Learning and memory performance of App/PS1 mice aftertreatmentby 4H3Min absence/presence of VACfor 3 months in a step-down avoidance task.
*P\0.05and**P\0.01 versus the control witheut treatment
TABLE 2
Table 2 Leaming and memory pcrformance of App/PS1 mice aftertreatment by 4H3M in absence/presence of VAC for 4 months in a step-downavoidance task
*P\0.05and**P\0.01versus the control witheut treatment
As can be seen from the results of the jump bench test in tables 1 and 2, the learning and memory abilities of AD rats in the group of coniferyl aldehyde (4H3M) in combination with Vanadyl Acetylacetonate (VAC) (4H3M + VAC) composition preparation were significantly improved compared to the control group three months after administration; four months after administration, the memory capacity of AD rats in both the coniferyl aldehyde (4H3M) group and the coniferyl aldehyde (4H3M) in combination with Vanadyl Acetylacetonate (VAC) (4H3M + VAC) composition preparation group was significantly improved, with a significant difference compared to the control group.
Example 6
Western Blot experimental detection
3 groups of APP/PS1 mice were fed according to example 4, and after 6.5 months, the mice were decapped and sacrificed, brain tissue (with olfactory bulb and cerebellum removed) was divided into left and right hemispheres, one of the hemispheres was frozen in liquid nitrogen, brain cortex and hippocampal tissue were ground, soluble A β protein was extracted with an extract solution containing protease inhibitor and phosphatase inhibitor, protein concentration was measured by BCA method, loading buffer was mixed well with each protein sample, and the samples were boiled in a 100 ℃ water bath for 5-10 min.
A β oligomerization is detected by a Western Blot experiment, (1) gel preparation, namely, 15% of separation gel and 5% of concentrated gel are prepared, (2) electrophoresis is carried out, namely, 15 mu g of protein is loaded in each hole, the low voltage is 50V for 30min, the bromophenol blue is used as an indication, the voltage is adjusted to 120V after the concentrated gel runs on the front edge, the electrophoresis is continued for about 90min, the separation gel runs off the front edge of the bromophenol blue, the electrophoresis is stopped, (3) membrane transfer is carried out for 200V and 100min, the temperature is timely reduced during the membrane transfer, the current cannot exceed 400mA, (4) sealing is carried out, a 5% skimmed milk powder is sealed for 1.5h to 2h, (5) an antibody is incubated, namely, 6E10 primary antibody is diluted to the specification proportion, the membrane is kept overnight by a shaking table at 4 ℃, the membrane is taken out, the membrane is washed by a shaking table for 10min for three times, the corresponding secondary antibody is diluted according to the specification proportion, the membrane is incubated for.
Detection of Tau protein phosphorylation Steps (1) (2) (3) (4) above, (5) incubation of antibodies: diluting the Tau protein primary antibody to the specification ratio, and shaking the table at 4 ℃ overnight; taking out the membrane, washing the membrane with TBST for 10min each time for three times; diluting corresponding secondary antibody according to the proportion of the specification, and incubating for 60min in a shaking table at room temperature; washing the membrane for three times by TBST, and 20min each time; (6) and (6) exposing.
Detection of GAPDH protein: the exposed PVDF membrane is washed by a western blot regeneration solution, then washed by TBST for 10min, and then incubated with a primary antibody and a secondary antibody according to the same method as above, and exposed.
As shown in FIG. 5, the Western Blot experiment examined the content of soluble A β protein and the phosphorylation of Tau protein in brain tissues of three groups of AD mice, namely a control group, a coniferyl aldehyde (4H3M) group and a coniferyl aldehyde (4H3M) combined Vanadyl Acetylacetonate (VAC) (4H3M + VAC) composition preparation group, and it was confirmed from FIG. 5 that the content of soluble A β protein was significantly reduced and the content of phosphorylated Tau protein was significantly reduced in the brains of AD mice of the coniferyl aldehyde (4H3M) group and the coniferyl aldehyde (4H3M) combined Vanadyl Acetylacetonate (VAC) (4H3M + VAC) composition preparation group, compared with the control group, demonstrating that the coniferyl aldehyde (4H3M) and 4H3M + VAC compositions could significantly inhibit the oligomerization of A β protein and reduce the phosphorylation of Tau protein.
Example 7
Immunohistochemical assay for detection of A β plaque deposition in APP/PS1 murine brain tissue
3 groups of APP/PS1 mice were fed as in example 4, sacrificed by cervical dislocation after 6.5 months, and brain tissue (olfactory bulb and cerebellum removed) was harvested and divided into left and right hemispheres. One of the hemispheres was fixed in 4% formalin for 48 hours to prepare paraffin sections having a thickness of about 5 μm. (1) Paraffin section is dewaxed to water; (2) 3% H2O2Incubating at room temperature for 5-10min to eliminate the activity of endogenous peroxidase; (3) washing with distilled water, and soaking in PBS for 5min twice; (4) blocking with 5-10% normal goat serum (PBS dilution), incubating at room temperature for 10min, discarding the serum, diluting 6E10 primary antibody to the specification ratio, adding dropwise primary antibody working solution, 37Incubating at the temperature of 1-2 h; (5) washing with PBS for 5min for 3 times; (6) dropwise adding a proper amount of biotinylated secondary antibody working solution, and incubating for 30min at 37 ℃; (7) washing with PBS for 5min for 3 times; (8) dripping a proper amount of horseradish peroxidase-labeled streptavidin working solution, and incubating for 10-30min at 37 ℃; (9) washing with PBS for 5min for 3 times; (10) DAB color development for 5 min; (11) fully washing with tap water, re-dyeing, dewatering, transparentizing and sealing. (11) The film was photographed by observation under a microscope.
The immunohistochemical experiment shown in FIG. 6 examined the deposition of A β protein in brain tissue of three AD rats in the control group, coniferyl aldehyde (4H3M) group and coniferyl aldehyde (4H3M) in combination with Vanadyl Acetylacetonate (VAC) (4H3M + VAC) composition preparation group, and it was found from FIG. 6 that the deposition of A β protein was reduced in the brains of AD rats in the coniferyl aldehyde (4H3M) group and coniferyl aldehyde (4H3M) in combination with Vanadyl Acetylacetonate (VAC) (4H3M + VAC) composition preparation group, and the volume size and number of protein deposition plaques were reduced under high power microscope observation, as compared with the control group.
Example 8
Method for detecting hippocampal nerve cells in APP/PS1 mouse brain tissue by Nissen staining method
3 groups of APP/PS1 mice were fed as in example 4, sacrificed by cervical dislocation after 6.5 months, and brain tissue (olfactory bulb and cerebellum removed) was harvested and divided into left and right hemispheres. One of the hemispheres was fixed in 4% formalin for 48 hours to prepare paraffin sections having a thickness of about 5 μm. Firstly, placing slices in a dye vat containing tar violet dye, incubating for 1h at 56 ℃, heating on an alcohol lamp for about 10min, washing with distilled water, differentiating for 1-3min, and observing under a microscope until the background is colorless; the absolute ethyl alcohol is dehydrated rapidly, the dimethylbenzene is transparent, and the neutral gum is sealed; the film was photographed by observation under a microscope.
The hippocampal region of brain tissue of three groups of AD rats was experimentally examined by nissl staining as shown in fig. 7 for the control group, coniferyl aldehyde (4H3M) group, and coniferyl aldehyde (4H3M) in combination with Vanadyl Acetylacetonate (VAC) (4H3M + VAC) composition preparation group; as can be seen from fig. 7, significant differences from the control group were observed in the presence of a large number of nissl bodies in the hippocampal region of the brains of AD mice in the coniferyl aldehyde (4H3M) group and coniferyl aldehyde (4H3M) in combination with Vanadyl Acetylacetonate (VAC) (4H3M + VAC) composition preparation group. Since nissl is an important part for synthesizing protein in the neuron, and the nissl in a cell body is obviously reduced after the neuron is stimulated, the two groups of drugs 4H3M and 4H3M + VAC are proved to be capable of protecting the neuron or have the function of stimulating the regeneration of the neuron.
Example 9
Brain weight detection of APP/PS1 mice
3 groups of APP/PS1 mice were fed as in example 4, sacrificed by cervical dislocation after 6.5 months, and heart, liver, kidney and brain tissues (with olfactory bulb and cerebellum removed) were weighed separately to compare the difference in weight of the organs in three groups of APP/PS1 mice.
Viscera weighing experiments shown in table 3 examine the weight of heart, liver, kidney and brain tissues after 6.5 months of administration in three animal models of APPswe/PS1dE9(APP/PS1) of a control group, a coniferyl aldehyde (4H3M) group and a coniferyl aldehyde (4H3M) combined with Vanadyl Acetylacetonate (VAC) (4H3M + VAC) composition preparation group.
TABLE 3
Table3 The organcoefficients(Organweight(g)/Bodyyweight(100g))ofbrain，heart，live，and kidney were analyzed
According to the weight of heart, liver, kidney and brain tissues of three groups of AD mice after 6.5 months of administration, namely, the control group, the coniferyl aldehyde (4H3M) group and the coniferyl aldehyde (4H3M) combined Vanadyl Acetylacetonate (VAC) (4H3M + VAC) composition preparation group shown in Table 3, the AD mice brains of the coniferyl aldehyde (4H3M) group and the coniferyl aldehyde (4H3M) combined Vanadyl Acetylacetonate (VAC) (4H3M + VAC) composition preparation group are found to be heavier than the control group, and the results show that the two groups of drugs may have the effects of protecting neurons and stimulating the regeneration of neurons.
The detailed experimental process of the present invention and three cell models such as SH-SY5Y and APP/PS1 double transgenic AD animal models are illustrated by the above examples, but the present invention is not limited to the above detailed experimental process and AD cell and animal models, i.e., the present invention is not limited to the above detailed experimental process and AD cell and animal models. It will be apparent to those skilled in the art that any modification of the invention, any structural change to the product of the invention, and equivalent replacement of the vanadium compound, etc., are within the scope and disclosure of the invention.
Claims (8)
1. The application of the coniferyl aldehyde or the coniferyl aldehyde and vanadium compound composition in preparing the medicine for preventing and treating neurodegenerative Alzheimer disease is characterized in that the coniferyl aldehyde or the coniferyl aldehyde and vanadium compound combined medicine composition is used as a raw material for preparing the medicine for preventing and treating neurodegenerative Alzheimer disease.
2. The use according to claim 1, wherein the vanadium compound comprises an inorganic vanadium compound comprising a vanadyl complex, a peroxovanadium complex, a hydroxylamine vanadium complex, a heteropolyacid complex of vanadium and an organic vanadium compound; the organic vanadium compounds include vanadyl benzoate, vanadyl aspirin, vanadyl acetylacetonate, bis (2-methyl-3-hydroxy-4-pyrone) vanadyl (BMOV), 3-hydroxy-2-ethyl-4-pyrone (BEOV), 3-hydroxy-2-isopropyl-4-pyrone (BIOV), 3-hydroxy-2-n-butyl-4-pyrone (BnBOV), vanadyl bis (pyridine 2-carboxylate) (VO (Pa)2), vanadyl picolinate (VO-DPA), vanadyl picolinate (VO-PAM), vanadyl picolinate (VO-MPA), vanadyl picolinate (VO-PA), vanadyl malonate oxavanadyl oxalate, vanadyl oxyvanadyl valine hydroxylamine, vanadyl oxynitrate, Leucine hydroxylamine vanadyl.
3. The use of claim 1, wherein said coniferyl aldehyde is present in a concentration range of 100 μ Μ to 0.1 μ Μ to enhance the viability of neural cells under normal and a β overload conditions to varying degrees.
4. The use of claim 3, wherein the neural cells under normal and A β overload conditions are SH-SY5Y human neuroblastoma and cells overexpressing wild-type Amyloid Precursor Protein (APP) and Swiss mutant amyloid precursor protein (APPsw).
5. The use of claim 3, wherein the duration of action of the medicament on the nerve cells is 12h, 24h, 36h, 48 h.
6. Use according to claim 1, wherein the coniferyl aldehyde is used in a concentration range of 100 μ Μ to 50 μ Μ in combination with a vanadium compound concentration of 1 μ Μ with the most pronounced effect.
7. The use according to claim 1, wherein the combination of coniferyl aldehyde at a concentration of 100 μ M and vanadium compounds at a concentration of 1 μ M is most effective in AD cells and animal models.
8. The use of claim 1, wherein the animal model of Alzheimer's disease selected is an APPswe/PS1dE9(APP/PS1) double transgenic mouse.
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