CN113069454A - Application of donepezil in preparation of medicine for inhibiting tau protein aggregation and pharmaceutical composition - Google Patents

Application of donepezil in preparation of medicine for inhibiting tau protein aggregation and pharmaceutical composition Download PDF

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CN113069454A
CN113069454A CN202110341203.7A CN202110341203A CN113069454A CN 113069454 A CN113069454 A CN 113069454A CN 202110341203 A CN202110341203 A CN 202110341203A CN 113069454 A CN113069454 A CN 113069454A
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donepezil
tau protein
pharmaceutical composition
mouse
protein aggregation
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王建枝
杨莹
吴冬琴
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Huazhong University of Science and Technology
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

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Abstract

The invention relates to the field of pharmaceutical chemistry, in particular to application of donepezil in preparation of a drug for inhibiting tau protein aggregation and a pharmaceutical composition. The pharmaceutical composition contains donepezil and a pharmaceutically acceptable carrier or excipient. According to the invention, donepezil can specifically degrade human tau protein, reduce abnormal aggregation of tau protein, and improve cognitive function.

Description

Application of donepezil in preparation of medicine for inhibiting tau protein aggregation and pharmaceutical composition
Technical Field
The invention relates to the field of pharmaceutical chemistry, in particular to application of donepezil in preparation of a drug for inhibiting tau protein aggregation and a pharmaceutical composition.
Background
Donepezil (DZ), belonging to the piperidine oxide, is a second-generation specific reversible central acetylcholinesterase (AChE) inhibitor with little effect on peripheral AChE. By inhibiting AChE activity, the decomposition of synaptic cleft acetylcholine (ACh) is slowed down, thereby increasing the content of ACh and improving the cognitive function of Alzheimer Disease (AD) patients.
The Tau protein aggregation to form neurofibrillary tangles is one of two pathological features of AD patients and is the gold standard for pathological grading diagnosis of AD. The major component of neurofibrillary tangles is abnormally hyperphosphorylated tau protein, the content of which is positively correlated with dementia symptoms in AD patients. Another pathological feature of AD is senile plaques, the main component of which is beta-amyloid peptide; numerous studies have demonstrated that beta-amyloid peptide exerts toxic effects in the presence of tau protein. It can be seen that abnormal aggregation of tau protein plays a key role in degenerative degeneration and memory impairment of AD neurons. Tau protein abnormalities play an important role in the pathogenesis of AD, and are also involved in the occurrence and development of more than 20 other neurodegenerative diseases, such as Progressive Supranuclear Palsy (PSP), Cortical Basal Degeneration (CBD), Pick disease (PiD), chromosome 17-linked frontotemporal dementia (FTDP-17) and the like; tau protein abnormalities are also involved in Traumatic Brain Injury (TBI), Stroke (Stroke), cerebral ischemia, epilepsy, autism and the like; such diseases caused by structural abnormality or gene mutation of tau protein are collectively called "tauopathies". In the above tauopathies, except FTDP-17 is caused by mutations in the tau gene, the remaining tauopathies are caused by abnormal post-translational modifications and aggregation. In FTDP-17, abnormal aggregation of tau protein, simply due to mutation in the tau gene, can lead to dementia and paralysis agitans. Therefore, the elimination of tau protein aggregation can be used for preventing and treating more than 20 kinds of tau diseases which currently lack effective intervention means, besides the treatment (disease modification) aiming at etiology and pathology rather than simple symptomatic treatment effect on AD.
According to the relevant data, although donepezil can treat alzheimer disease by inhibiting AChE activity, no report on the treatment of tau protein aggregation by donepezil is found at present, and no donepezil is used for treating other tau diseases. Thus, the use of donepezil in the treatment of tau protein aggregation is of great interest in the treatment of AD and other more than 20 tau diseases that have been discovered.
Disclosure of Invention
The following describes in detail specific embodiments of the present invention. It should be understood that the detailed description and specific examples, while indicating the present invention, are given by way of illustration and explanation only, not limitation.
The invention aims to provide a novel medical application of donepezil, in particular to an application and a pharmaceutical composition of donepezil in preparing a medicament for inhibiting tau protein aggregation.
In order to achieve the above object, one aspect of the present invention provides the use of donepezil in the preparation of a medicament for inhibiting tau protein aggregation.
In a second aspect, the present invention provides a pharmaceutical composition for inhibiting tau protein aggregation, comprising donepezil and a pharmaceutically acceptable carrier or excipient.
Preferably, the excipient is selected from at least one of a binder, a filler, a tableting agent, a lubricant, a colorant, a flavoring agent, and a wetting agent.
Preferably, the pharmaceutical composition is in the form of tablets, pills, granules, powders, capsules, syrups, emulsions, injections or suspensions. Various dosage forms of the pharmaceutical composition may be prepared by methods known in the art.
The inventor of the invention discovers that donepezil can effectively reduce over-expressed human tau protein in mouse brain and improve the nerve cell function and learning and memory ability of mouse through animal experiments in the research process. Also, low doses of donepezil are more able to degrade tau protein than high doses of donepezil. Therefore, donepezil can specifically degrade human tau protein, reduce abnormal tau protein aggregation, and improve cognitive function.
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FIG. 1 shows the results of detection of exogenous human tau and total tau protein in mice of example 1;
FIG. 2 shows the results of examination of learning and memory behavior of mice in example 2;
FIG. 3 shows the electrophysiological measurement results of the mouse brain slice in example 3;
FIG. 4 shows the results of measuring the density of mouse dendritic spines in example 4.
Detailed Description
Example 1
This example demonstrates that Donepezil (DZ) can effectively degrade exogenously over-expressed human tau protein in the medial brain septal nucleus of mice.
Selecting 2-month-old male C57 mice, injecting AAV-tau at the position of a medial nucleus septa (MS), and injecting AAV-vec into control mice; after 5 months, donepezil or solvent (saline) was intraperitoneally injected at 1.0mg/kg/day [ low dose group, hTau: DZ (L) ] or 2.0mg/kg/day [ high dose group, hTau: DZ (H) ] once a day for one month. After anesthesia, the mouse is subjected to acute decapitation and brain harvesting, the medial septal nucleus tissue is separated on ice, tissue protein is extracted to carry out an immunoblotting (WB) experiment, and the levels of human Tau protein (HT7) and total Tau protein (Tau5) are detected.
The western blot pretreatment process comprises the following steps:
1. anesthetizing a mouse by using 1% sodium pentobarbital, then taking a brain by acute decapitation, carrying out oscillation slicing (the thickness is 300um) in precooled oxygen-saturated artificial cerebrospinal fluid by using a freezing microtome, and then separating a tissue in an inner nucleus septate region on ice according to a brain map;
2. adding RIPA lysis solution (containing protease inhibitors such as PMSF) into the inner nuclear septal tissue, homogenizing thoroughly, centrifuging at 4 deg.C for 5min at 12000rpm, and collecting the supernatant as sample protein;
3. taking 1-3 mu L of supernatant solution, diluting by 10 times, determining the concentration of sample protein by using a BCA method, adding one third volume of 4xBuffer (containing 2 weight percent of SDS, 100mM dithiothreitol, 10 weight percent of glycerol and 0.25 weight percent of bromophenol blue) into the sample protein, uniformly mixing, carrying out boiling water bath for 10min, adding 1/10 volumes of uniformly mixed beta-mercaptoethanol and bromophenol blue solution (bromophenol blue: beta-mercaptoethanol is 1: 3, and the bromophenol blue and the beta-mercaptoethanol are toxic substances and have volatility, and need to be operated in a fume hood), uniformly mixing, and freezing at-20 ℃ for later use.
The western blotting process comprises the following steps:
1. preparing 10% SDS-PAGE electrophoresis gel;
2. unfreezing the protein sample, carrying out boiling water bath for 5min, and then centrifuging;
3. loading and separating protein samples by SDS-PAGE electrophoresis;
4. transferring the electrophoretically separated protein by using a nitrocellulose membrane (NC membrane);
5. the NC membrane was blocked with TBS blocking solution containing 5 wt% skimmed milk powder, followed by primary antibody incubation, secondary antibody incubation and color development in this order.
FIG. 1 shows the results of detection of human Tau (HT7) and total Tau (Tau5) overexpressed in mouse brain, wherein FIG. 1A shows the results of Western blot experiment and FIG. 1B shows the quantitative results of 1A. 3 mice per group, one-way anova, HT7, P <0.0001(110 kDa); tau-5, P <0.0001(110kDa) # P <0.05, # P <0.01vs hTAUMS: veh, $ P <0.05, data are shown in mean + -SEM.
As can be seen from fig. 1, Donepezil (DZ) treatment significantly reduced tau protein levels in mice compared to vehicle control, with low doses of DZ (l) acting more significantly than high doses of DZ (h). Thus, donepezil was effective in reducing exogenous overexpressed hTau (HT7) and total Tau (Tau5) levels in the MS region, with the effect being more pronounced in the low dose group than in the high dose group.
Example 2
This example illustrates that donepezil can effectively improve spatial memory impairment in mice caused by tau protein aggregation without affecting the motor ability of normal mice.
Behavioral testing of the Morris water maze was performed 4 weeks after intraperitoneal administration of donepezil to mice overexpressing hTau by MS for 5 months, with 11-18 mice per group, and the data are presented as mean ± SEM.
The mouse water maze experiment mainly comprises training at 1-5 days and detection at 7 days. The operation steps are as follows:
1. mice were stroked by the experimental operator continuously to become familiar with each other 3 days prior to the experiment. The mice are brought into a behavior detection room from a feeding room 1 hour before the beginning of the experiment to know the environment, and clue markers with different shapes are arranged around a maze scene;
2. in the training stage of 1-5 days, an experimenter A sequentially puts a mouse to be trained into water from the fixed positions of four quadrants of a water maze, wherein the mouse faces the side wall of a water tank, and an experimenter B quickly presses a video recording key to start an experiment when observing the moment when an animal enters the water through a monitoring system;
3. the mouse needs to be trained 1 time in each of 4 quadrants every day, each time interval is 30min, and a hidden platform with a fixed position needs to be freely found underwater in each training. If the platform can not be found within 60s, the experimenter B stops recording the video, immediately informs the experimenter A to guide the mouse to stand on the hidden platform by using a tuck net, and allows the mouse to stay on the platform for 30 seconds and be familiar with the surrounding environment and then taken away;
4. if the experimenter B observes that the mouse hides the platform at the upstream within 60 through the monitoring system, stopping video recording, and informing the experimenter A to take the mouse away after the mouse stays on the platform for 30 seconds;
5. after each training, the experimenter A takes the mouse out of the water maze, dries the mouse by a towel and then puts the mouse back into the cage;
6. the training is repeated for 5 days, and the average time (escape latency) required by the mouse to find the platform every day is recorded and used for evaluating the space learning capacity of the mouse;
7. in the detection stage of day 7, the hidden safety platform is removed, the mouse is allowed to freely search for 60s in the maze, the time (latency) required for the mouse to go to the original safety platform area for the first time is detected, the crossing times of the mouse in the original safety platform area are detected, and the staying time of the mouse in the quadrant where the original safety platform is located is detected.
FIG. 2 shows the water maze test result of mouse spatial learning memory, wherein FIG. 2A shows the spatial learning result; FIGS. 2B-E show spatial memory capabilities. As can be seen from fig. 2A, the water maze learning phase detection found that there was no significant difference in latency to reach the hidden platform between the groups, indicating that there was no effect on learning ability (two-factor analysis of variance, P ═ 0.8766). As can be seen from fig. 2B-E, the water maze examination phase found that administering donepezil could effectively reverse spatial memory impairment caused by hTau, as shown by the effective reduction of latency for the mouse to reach the region of the target platform after administering donepezil, compared to the hTau: veh group (fig. 2B, one-way anova, P0.0037, post-hoc analysis, P0.0110, P <0.05vs Vec: veh, P0.0104, # P <0.05vs hTauMS: veh), could increase the number of times of crossing the region of the target platform (fig. 2C, one-way anova, P0.0138, post-hoc analysis, P0.0173, P <0.05vs Vec: veh, P0.0340, # P <0.05 vs. htausms: veh), and could increase the residence time for the mouse in the target platform (P0.0016, P0.0026, # P <0.01vs hTauMS: veh). Wherein the low dose of donepezil has a better effect of reversing spatial memory impairment compared to the high dose group. There was no significant difference in the distance of movement between groups of mice during the water maze test phase (E, one-way anova, P-0.6759), suggesting that there was no difference in the ability of the mice to move.
Donepezil treatment significantly improved spatial memory impairment due to tau aggregation compared to vehicle control, with low doses of dz (l) being more pronounced than higher doses of dz (h). Thus, donepezil can reverse spatial memory impairment caused by overexpression of hTau by the MS domain.
Example 3
This example illustrates that donepezil is effective in ameliorating synaptic transmission impairment in mice caused by tau protein aggregation.
Ex vivo electrophysiological signal recording was performed 4 weeks after intraperitoneal injection of donepezil into mice overexpressing hTau for 5 months in MS.
The steps for preparing the electrophysiological in vitro recorded hippocampal brain slice are as follows:
1. mice were anesthetized and brains were harvested by acute decapitation under mild conditions.
2. Opening skull, rapidly separating brain tissue in ice-cold environment, introducing 95% O2And 5% CO2 gas mixture in ice-water mixed oxygen saturated artificial cerebrospinal fluid (ACSF).
4. Rapidly trimming brain tissue shape on a pre-cooling operation table, adhering the trimmed tissue to a section base with the aid of agar block, and transferring into a section groove (containing continuous introduction of 95% O2And 5% CO2 blend).
5. The brain tissue was coronal sectioned with a shaker microtome (300 μm, completed in 10 minutes).
6. The brain pieces were recovered by incubation in artificial cerebrospinal fluid (25 ℃) with continuous aeration for 30 minutes to 1 hour.
7. The signals of LTPs were induced and recorded using the MED64 electrophysiological recording system and a circulating perfusion apparatus.
FIG. 3 shows the results of testing the synaptic transmission function of mice, 5 mice in each group, 9-12 brain slices, P<0.05,**P<0.01vs.Vec:veh,#P<0.05,##P<0.001vs hTauMSVeh, data are shown as mean + -SEM.
In which, FIG. 3A shows the amplitude of the field excitatory post-synaptic potential (fEPSP), i.e., synaptic transmission I-O response curve (two-way ANOVA, P < 0.0001). As can be seen in FIG. 3A, donepezil reversibly overexpresses hTau, causing a decrease in synaptic transmission I-O response. Figure 3B shows the fEPSP slope (two-way analysis of variance, P < 0.0001). As can be seen in FIG. 3B, donepezil increased the decrease in fEPSP slope caused by overexpression of hTau. Figure 3C shows fpsps slope quantification, i.e., Long Term Potentiation (LTP) (one-way analysis of variance, P < 0.0001). As can be seen in FIG. 3C, donepezil reversibly overexpresses the attenuation of LTP caused by hTau.
Donepezil treatment significantly improved synaptic transmission in mice compared to vehicle illumination, and the low dose of dz (l) was more pronounced than the higher dose of dz (h). Therefore, donepezil can effectively reverse impairment of synaptic transmission caused by MS overexpression, and the low dose effect is more significant.
Example 4
This example illustrates that donepezil is effective in ameliorating dendritic damage in mice caused by tau protein aggregation.
Golgi staining analysis was performed 4 weeks after donepezil administration by intraperitoneal injection in mice overexpressing hTau for 5 months in MS.
The preparation method of the Golgi dyeing brain slice comprises the following steps:
1. solution preparation:
preparing a Golgi-Cox staining solution: 200ml of 5% potassium dichromate solution, 200ml of 5% mercuric chloride solution and 160ml of 5% potassium chromate solution are prepared before the experiment is started, the solutions are uniformly mixed according to a certain proportion and sequence, and the mixture is sealed and kept in a dark place for later use.
Preparing a tissue protection solution: adding 300g of sucrose, 10g of pvp40 and 300ml of ethylene glycol into 500ml of PBS solution, fully mixing uniformly, adding ddH2O to a constant volume of 1000ml, and storing at 4 ℃ in a dark place
2. Tissue soaking: directly cutting off the head of an anesthetized mouse to take out the brain, separating the brain tissue, soaking the anesthetized mouse by using a prepared Golgi-Cox staining solution, soaking the anesthetized mouse at room temperature in the dark for 24 hours, replacing the anesthetized mouse by using a new Golgi-Cox staining solution, and continuously soaking and fixing the anesthetized mouse at room temperature for 3-4 weeks;
3. preparing a slice: dehydrating with a pre-prepared tissue protective solution (30 wt% sucrose solution, 0.1M PBS solution as solvent), storing at 4 deg.C in dark place, replacing with new tissue protective solution after 24 hr, and soaking for one week; then, slicing in a vibration slicer containing tissue protection solution to obtain coronal section with the thickness of 100 μm, sequentially pasting on a gelatin slide according to the slicing sequence, drying in the dark, and dyeing after 48 hours;
4. and (3) dyeing analysis: and sequentially immersing the gelatin slide pasted with the brain slices into a staining jar containing the following solutions for staining: distilled water 2 times (5 min each), 5% sodium thiosulfate (light-shielding staining for 10min), distilled water 2 times (1 min each), 70%, 95%, 100% alcohol (6min each), xylene (6 min). After the dyeing is finished, the piece is sealed by neutral gum diluted by dimethylbenzene. Slides were then read using Olympus SV120(Tokyo) and Nikon ni.e (Tokyo) and counted statistically.
Fig. 4 is a graph showing the results of the measurement of the number of mouse dendritic spines, one-way anova, MS: p < 0.0001; CA1: P <0.0001. P <0.01vs Vec: veh, # # P <0.01vs hTauMS: veh, $ P <0.01vs hTauMS: DZ (L), data are shown as mean + -SEM.
FIG. 4A is a diagram showing the shape of dendritic spines in the MS region and dCA1 region. FIG. 4B is a statistical plot of the density of dendritic spines in the MS region and the dCA1 region. Injection of donepezil increased the density of dendritic spines compared to vehicle control mice. The fact that the donepezil can effectively reverse the reduction of dendritic spine density caused by the overexpression of hTau, and the effect of the low-dose donepezil is more obvious.
The experimental results show that donepezil can effectively reduce over-expressed human tau protein in mouse brain, and improve mouse nerve cell function and learning and memory ability.
The preferred embodiments of the present invention have been described above in detail, but the present invention is not limited thereto. Within the scope of the technical idea of the invention, many simple modifications can be made to the technical solution of the invention, including combinations of various technical features in any other suitable way, and these simple modifications and combinations should also be regarded as the disclosure of the invention, and all fall within the scope of the invention.

Claims (4)

1. Use of donepezil in the preparation of a medicament for inhibiting tau protein aggregation.
2. A pharmaceutical composition for inhibiting tau protein aggregation, comprising donepezil and a pharmaceutically acceptable carrier or excipient.
3. The pharmaceutical composition of claim 2, wherein the excipient is selected from at least one of a binder, a filler, a tableting agent, a lubricant, a colorant, a flavoring agent, and a wetting agent.
4. The pharmaceutical composition of claim 2, wherein the pharmaceutical composition is in the form of a tablet, a pill, a granule, a powder, a capsule, a syrup, an emulsion, an injection or a suspension.
CN202110341203.7A 2021-03-30 2021-03-30 Application of donepezil in preparation of medicine for inhibiting tau protein aggregation and pharmaceutical composition Pending CN113069454A (en)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018226674A1 (en) * 2017-06-05 2018-12-13 The Methodist Hospital System Tau phosphorylation inhibitors and methods for treating or preventing alzheimer's disease

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018226674A1 (en) * 2017-06-05 2018-12-13 The Methodist Hospital System Tau phosphorylation inhibitors and methods for treating or preventing alzheimer's disease

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
YASUMASA YOSHIYAMA ET AL.: "AntiInflammatory Action of Donepezil Ameliorates Tau Pathology, Synaptic Loss, and Neurodegeneration in a Tauopathy Mouse Model", 《 JOURNAL OF ALZHEIMER’S DISEASE.》 *
姚海涛等: "山茱萸多糖对阿尔茨海默病模型大鼠tau 蛋白的影响", 《中国老年学杂志.》 *

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Application publication date: 20210706