CN117064894A - Application of STM2457 in preparation of medicine for preventing and treating Alzheimer disease - Google Patents
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Classifications
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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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
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- 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
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- 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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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
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Abstract
The invention discloses application of STM2457 in preparation of a medicament for preventing and treating Alzheimer's disease, and belongs to the technical field of biological medicines. In order to solve the problem that the prior Alzheimer disease lacks effective therapeutic drugs, the invention discovers that STM2457 inhibits Mettl3 mediated N6-adenylate methylation (m 6 A) The modified level can reduce the deposition level of amyloid protein, inhibit neuroinflammatory reaction and improve cognitive function, and can be used for preparing medicines or health-care foods for preventing and treating Alzheimer's disease or other neuroinflammatory related diseases. The invention verifies the treatment effect of STM2457 in the Alzheimer's disease model mice, and the STM2457 is used for amyloid deposition and neuritis of the Alzheimer's disease model miceThe STM2457 has an inhibiting effect, has an improving effect on learning and memory disorders of mice with Alzheimer's disease models, can obviously inhibit the generation of amyloid deposition of the mice with Alzheimer's disease models, reduce the neuroinflammation level and obviously improve the learning and memory disorders of the mice with Alzheimer's disease models.
Description
Technical Field
The invention relates to the technical field of biological medicines, in particular to application of STM2457 in preparation of medicines for preventing and treating Alzheimer's disease.
Background
Alzheimer's disease is an senile neurodegenerative disease characterized clinically by loss of memory and decline of cognitive function in the brain. A significant pathological feature of alzheimer's disease patients is the massive aggregation of amyloid aβ in the brain and the presence of neuroinflammation, leading to massive neuronal death. Thus, understanding how aβ deposition and neuroinflammation are controlled is critical for the prevention and delay of onset of neurodegenerative diseases. Previous studies have shown that m in the brain of Alzheimer's disease patients and mouse models 6 A modification level and Mettl3 protein expression level are abnormal, but for Mettl3 mediated m 6 The specific role of modification a in alzheimer's disease is currently unknown.
m 6 The A modification is one of the most abundant and widely studied types of modification present on messenger ribonucleic acid (mRNA). In mammalian cells, m is present in about 20% to 40% of transcripts 6 And A modification. Mettl3 belongs to the Mettl methyltransferase family, which catalyzes m by providing methyl with S-adenosylmethionine 6 The methylation reaction of a occurs. Studies have shown that the deletion of Mettl3 results in m in mRNA 6 The a level almost completely disappeared. There are studies on transcriptome sequencing and m of human brain and brain-like samples 6 A methylation sequencing, through disease-related enrichment analysis of differential genes, found that a large number of genes related to Alzheimer's disease exist m in both brain-like organs and human brain 6 A modified, suggesting that m 6 A may play a considerable role in the development of AD disease. There is study on m in the Alzheimer's disease model mouse APP/PS1 mouse 6 A methylation sequencing revealed that APP/PS1 transgenic mice were m in cortical and hippocampal regions 6 Elevated A methylation level and increased expression level of Mettl3Adding.
STM2457 of formula C 25 H 28 N 6 O 2 (FIG. 1) the activity of MetTL3 methyltransferase is inhibited by binding to the METTL3 binding site of S-adenosylmethionine, and thus STM2457 is a specific inhibitor of METTL3 and has been used in acute myelogenous leukemia studies. Studies show that STM2457 inhibits proliferation and expansion of cancer cells, reduces the number of leukemia cells in bone marrow and spleen of mice, and remarkably prolongs the life of mice after treatment of mice with STM2457, and the drug has no toxic side effects. Several studies have found that STM2457 liver cancer and non-small cell lung cancer have good effects. STM2457 has high safety in the aspect of intraperitoneal injection and oral administration in animal models at present, and the effect of STM2457 in the aspect of treating neurodegenerative diseases is not reported at present, and clinical trials are not searched.
Disclosure of Invention
The invention aims to overcome the defect that the existing Alzheimer disease lacks effective therapeutic drugs, and on the one hand, the invention provides application of STM2457 in preparing drugs for treating Alzheimer disease.
The invention also provides application of STM2457 in preparing a medicament for inhibiting neurodegenerative diseases related to amyloid deposition.
The invention also provides application of STM2457 in preparing medicines for treating neuroinflammation caused by amyloid.
The invention also provides application of STM2457 in preparing medicines and/or health care products for improving memory or cognitive functions.
Preferably, STM2457 is used to reduce m in the brain of mice in the Alzheimer's disease model 6 A modification level, inhibiting the production of amyloid deposition and thereby inhibiting and improving cognitive function.
The invention passes m in Alzheimer's disease model mice 6 A methylation sequencing, western Blot, immunofluorescent staining, qPCR, behavioural, and the like detect the presence of amyloid deposition, elevated Mettl3 expression level, m in Alzheimer's disease model mice 6 Increased A modification level and cognitive function in miceA handicapped phenotype.
STM2457 is administered daily by intraperitoneal injection to mice with Alzheimer's disease model, and STM2457 is detected by Western Blot, immunofluorescence staining and Dot Blot for two months after continuous administration, so that amyloid generation and neuroinflammation can be inhibited. The results indicate that STM2457, as an inhibitor of Mettl3, can be used to reduce m in the brain 6 The modification level of A can obviously inhibit the generation of amyloid protein, obviously improve neuroinflammation and obviously improve the cognitive memory function of mice with Alzheimer's disease.
STM2457 thus reduces m in the brain 6 The A modifies the level, thereby inhibiting the level of amyloid and improving the cognitive function, and can be used for preparing medicines or health-care foods for preventing and treating Alzheimer's disease or other neurodegenerative diseases. Accordingly, the application of STM2457 described below is within the scope of the present invention.
Application of STM2457 in preparation of medicines and/or health products for preventing and treating Alzheimer's disease or other neurodegenerative diseases and/or improving memory, and STM2457 inhibits m in brain 6 A modifies the level, thereby inhibiting the level of amyloid and improving cognitive function.
In theory, all drugs containing STM2457 are within the scope of the present invention; the STM2457 can be extracted by extraction means conventional in the art.
The invention provides a medicine for preventing and treating Alzheimer's disease, which comprises STM2457. Further, the medicament further comprises a pharmaceutically acceptable excipient or carrier.
Specifically, the pharmaceutical preparation is a tablet, a hard capsule, a soft capsule, powder, tincture, oral liquid, dripping pill or injection.
Compared with the prior art, the invention has the following beneficial effects:
the invention discloses application of STM2457 (Mettl 3 inhibitor) in preparation of Alzheimer's disease drugs, and in particular discloses application of STM2457 in inhibiting Mettl 3-mediated N6-adenylate methylation (m) 6 A) Modification levels, thereby reducing amyloid deposition levels and inhibiting neuroinflammationThe composition responds and improves cognitive function, and can be used for preparing medicines or health-care foods for preventing and treating Alzheimer's disease or other related neuroinflammation diseases. According to the invention, the treatment effect of STM2457 is verified in the Alzheimer's disease model mice, the STM2457 has an inhibiting effect on the amyloid level in the Alzheimer's disease model mice and an improving effect on the learning and memory disorder of the Alzheimer's disease model mice, and the STM2457 can obviously reduce the amyloid level and the neuroinflammation level in the Alzheimer's disease model mice and obviously improve the cognitive memory disorder of the Alzheimer's disease model mice.
Drawings
FIG. 1 shows the chemical formula of STM2457.
Fig. 2 is an evaluation of amyloid (aβ) and cognitive memory impairment in mice model for alzheimer's disease.
FIG. 3 shows changes in the expression level of Mettl3 and m in the brain of mice model of Alzheimer's disease 6 Changes in A-related enzymes.
FIG. 4 shows the m in the brain of mice with Alzheimer's disease model 6 A modification sequencing analysis.
FIG. 5 shows STM2457 inhibiting m in brain of Alzheimer's disease mice 6 Level of A modification.
Fig. 6 is a graph showing that STM2457 reduces amyloid levels and neuroinflammation levels in mice with alzheimer's disease.
Fig. 7 is a graph showing that STM2457 can improve cognitive memory dysfunction in mice with alzheimer's disease.
Detailed Description
The invention is further illustrated in the following drawings and specific examples, which are not intended to limit the invention in any way. Unless specifically stated otherwise, the reagents, methods and apparatus employed in the present invention are those conventional in the art.
Example 15 xfad model mice mimic the pathological features of alzheimer's disease and cognitive memory disorders.
1. Method of
The Alzheimer's disease model mice used in this study were 5xFAD model mice purchased from Jax Lab, and the mouse strain number was: jax #034848.
Immunofluorescent staining: mice were anesthetized with isoflurane, perfused systemically with 1xPBS, then further perfused with 4% Paraformaldehyde (PFA), and fixed with 4% PFA for 2 days after brain dissection. After 3 days of complete dehydration of 30% sucrose at 4℃a 30 μm sagittal section was taken with a frozen microtome. The slices were stored in a preservation solution at-20 ℃. Brain sections containing hippocampal areas were taken and stained by washing 3 times with PBS. The primary antibody was incubated overnight at 4℃with blocking solution (containing 3% goat serum in PBS and 0.1% Triton x-100) for 1 hour at room temperature. The next day, samples were washed with PBS, then incubated with DAPI for 1 hour at room temperature, and slides were prepared by adding a capper after further washing. Images were taken using an Olympus confocal microscope, all taken under the same conditions and settings.
Morris Water Maze (MWM): the MWM was performed in a circular, water filled bathtub (120 cm diameter) with visual cues outside the maze, the water becoming opaque by the titanium dioxide covering its surface, the bathtub being divided into 4 virtual quadrants. MWM is divided into two phases, training and testing. In the training phase, a blind escape platform (diameter 11 cm) is located 1 cm below the water surface. Mice entered the water maze from 4 different starting positions of the pool, respectively. The time of arrival of each animal at the escape platform was recorded, and each animal was trained 4 times per day for 4 days. The testing phase was performed 24 hours after the end of the last training, during which the platform was removed, the ratio of the time the mice were swim in 4 virtual quadrants within 120 seconds was measured, and the first time to reach the position where the escape platform was previously placed and the total number of passes through the platform position were recorded. The experiments were video recorded and analyzed using mazerscan software.
New thing recognition: the test is based on the mouse's preference to contact a novel object. The mice in the experiment were placed in an illuminated white plastic box (60 cmx60cmx30 cm), monitored by overhead cameras, and analyzed by an automated tracking system (San Diego Instruments, CA). On the first day, two identically shaped objects were placed in a test box and mice were placed in the box for free exploration for 10 minutes. After 24 hours, one of the objects was replaced with another object of a different shape. The mice were again placed in the box for 10 minutes to explore the objects, and the time taken to explore both objects was assessed and the ratio calculated.
Y maze spontaneously alternates: three identical opaque arms (35 cm long, 8 cm wide, 8 cm high) at 120 degrees to each other were used, with spatial cues at the distal end. The continuous spontaneous alternation test is based on the natural tendency of mice to explore new environments. The mice were placed in the Y maze facing the wall of one arm at random, and three arms in the Y maze were freely explored for 8 minutes. In general, mice tend to explore the nearest and non-visited arms, forming alternates between the three arms, depending on their spatial working memory. Taking the percent spontaneous alternation as an indicator of the measurement, all alternations (i.e. each time the mouse explores three arms in succession) were divided by all possible alternations (i.e. the total number of entering arms minus 2), and multiplied by 100.
Statistical analysis: data are expressed as mean ± SEM and analyzed using GraphPad Prism software. Determining the difference between the two groups using unpaired t-test; two-way anova and Bonferroni multiple comparison test were used to determine differences between the groups. P <0.05 is statistically significant for the differences.
2. Results
Aβ immunofluorescent staining of 5xFAD mice aged 2 months, 3 months, 4 months, 5 months was used to detect the level of Aβ amyloid deposition, and the results indicated that 5xFAD mice aged 5 months had more amyloid deposition (FIG. 2 a). Behavioral tests were performed on 5xFAD mice (AD) and wild-type mice (WT) at 5 months of age. The water maze test results showed that the 5xFAD mice took longer to reach the platform, had less residence time in the quadrant where the platform was located, had fewer passes through the platform, and had unchanged total movement distance and speed (FIGS. 2b-1 h). The spontaneous alternation test of the Y maze found that the spontaneous alternation rate of the 5xFAD mice was lower, suggesting the presence of working memory impairment (FIGS. 2i-2 j). The new thing recognition experiments showed that 5xFAD mice explored less time for new objects than wild-type mice (fig. 2k-2 m). Overall, the results indicate that 5xFAD mice mimic the typical pathological features of alzheimer's disease, namely amyloid deposition and cognitive memory impairment.
Example 2 Mettl3 expression levels were increased in 5xFAD mice.
1. Method of
Western Blot: the dissected brain hippocampus tissue was rapidly frozen in liquid nitrogen and total protein was extracted. Tissues were ground on ice with RIPA Lysis buffer, then transferred to a centrifuge tube, centrifuged at 12000rpm for 30 minutes at 4 ℃, and the supernatant was collected and quantified by BCA protein assay. Proteins were subjected to sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) at various concentrations of separation gel according to the molecular weight of the target protein, and then transferred to nitrocellulose membrane. Membranes were blocked with 5% skim milk in TBST for 1 hour at room temperature and incubated with primary antibodies overnight at 4 ℃. After 3 washes of TBST, incubation with the enzyme-labeled secondary antibody was performed for 1 hour at room temperature. Membranes were rinsed 3 times with TBST and incubated with ultrasensitive ECL. Protein bands were displayed with a molecular imager imaging system and band intensities were measured with ImageJ software.
2. Results
To determine the change in expression levels of Mettl3 in 5xFAD mice, western Blot detection was performed by extracting proteins from brain Cortex (CTX), olfactory Bulb (OB), hippocampal (HIPPO) tissues of wild-type mice 2 months old (2M), 3 months old (3M), 5 months old (5M) and 5xFAD mice, and as a result, it was found that the levels of Mettl3 were increased in 5 month old hippocampal tissues (fig. 3a-3 d). In the experiment, the m of the hippocampal tissue with the age of 2 months, 3 months and 5 months was also detected 6 A the expression of the other related enzymes Mettl14 and Fto, resulted in no change in protein levels of Mettl14 and Fto (FIGS. 3e-3 g).
Taken together, these results indicate that there is an increased level of expression of Mettl3 in the hippocampal tissue of mice model for alzheimer's disease, and that there is no change in Mettl14 and Fto, suggesting that Mettl3 may be involved in the amyloid deposition process and cognitive memory impairment in mice model for alzheimer's disease.
EXAMPLE 3 Alzheimer's disease model mice are m in the brain 6 Increased A modification level
1. Method of
m 6 A-IP-Seq：
After extracting total RNA from the sample with Trizol, usemRNA purification kit (Ambion, 61006) separates mRNA and removes DNA using DNaseI. mRNA was incubated with RNA fragmentation reagent (Ambion, AM 8740) at 94℃for 1min, broken into 100nt fragments, and purified by ethanol precipitation for m 6 A-MeRIP。10μg m 6 A polyclonal antibody (synthetic Systems, 202003) and 40. Mu.l Dynabeads TM Protein A (Invitrogen, 10001D) was incubated in 500. Mu.l IPP buffer (150 mM NaCl,0.1% NP-40,10mM Tris-HCl, pH 7.4) for 1 hour at room temperature. RNA was heated at 75℃for 5min and then immediately placed on ice, after cooling, 5. Mu.g of RNA was mixed with antibody-magnetic beads and incubated at 4℃for 4 hours. The beads were retained and the supernatant discarded and the beads were washed 5 times with IPP buffer. RNA was eluted from the beads with 300. Mu.l of 0.5mg/ml N6-methylidenosine at room temperature for 1 hour. The eluted supernatant was extracted with chloroform, precipitated with ethanol, and dissolved in RNase Free Water for subsequent experiments. m is m 6 Analysis of A sequencing data is described in published literature Donimissini et al, geula et al (2015) and Lence et al (2016). Analysis of m by data 6 Total peak number and distribution characteristics, m 6 A modified gene name and enrichment signal pathway, m 6 Amotif. And (3) performing cross analysis on the RNA sequencing analysis result to obtain the relation with gene expression (up-regulation and down-regulation), and screening the specific target genes.
2. Results
To determine whether m is present in 5xFAD mice 6 Abnormality of A modification m was performed on 5xFAD mice of 5 months of age 6 A sequencing analysis. As a result, it was found that m was present in the CDS partial region and 3' UTR region of mRNA of 5xFAD mice 6 An increase in the level of modification A (FIGS. 4a-4 c). For m 6 Kegg analysis of the increased A level gene found that m 6 The A-modified up-regulated gene was closely related to neurodegenerative disease Alzheimer's disease (FIGS. 4d-4 e). GO enrichment analysis finds m 6 A modification up-regulated genes were associated with synaptic assembly of neurons, axon production (fig. 4 f). Transcriptome sequencing analysis revealed 769 out of 5xFAD mice compared to WT miceThe expression level of the gene increased and the expression level of 360 genes decreased (FIG. 4 g). GO enrichment analysis found that up-regulated genes were functionally related to inflammatory response, etc., down-regulated genes were functionally related to neuronal synaptic assembly, etc. (FIGS. 4h-4 i). And to m 6 Deep analysis of A up-regulated genes shows that m 6 A affects the functionally related gene expression levels of synaptic assembly, senescence, microglial activation, neuronal apoptosis, etc. (fig. 4 j).
Taken together, m on mRNA of 5xFAD mice 6 The A modification is changed, and the gene m related to Alzheimer's disease 6 Increased levels of A modification, suggesting that it may be m 6 An increase in the level of modification a affects the pathological course of alzheimer's disease.
Example 4STM2457 significantly reduces m in mice with Alzheimer's disease 6 Level of A modification
1. Method of
Formulation and use of STM 2457: STM2457 was purchased from MCE company under the catalog number: HY-134836. STM2457 was dissolved in physiological saline. 5xFAD mice were divided into two groups and injected with physiological saline and STM2457 solution, respectively. The two groups of mice were sacrificed for 60 days (50 mg/kg, i.p. injection, 1 time/day) and 4 mice per group were tested.
m 6 A dot blot：
Total RNA extraction and qRT-PCR: total RNA of cells and tissues was extracted by TRIzol reagent according to the manufacturer's protocol and the concentration was determined by Nanodrop spectrophotometer 2000 (Thermo Fisher Scientific). The RNA was denatured by formaldehyde, formamide treatment and high temperature, and then placed on ice for cooling. The Hybond N+ membrane of the appropriate size was prepared and placed on a 96-well dot blotting apparatus and the instrument assembled as required. After DEPC water washing instrument was added to the well, RNA sample was added to the well in sequence, and the liquid in the well was sucked off by vacuum. The Hybond N+ film was removed and crosslinked at 80℃or UV-crosslinked at 254 nm. Taking out the cross-linked Hybond N+ membrane, sealing, adding corresponding primary antibody and secondary antibody for incubation, washing, and exposing with ECL color developing solution. Methylene blue staining can be used as a control for RNA equivalent loading.
2. Results
Alzheimer's disease mice begin to inject STM2457 at 3 months of age, two months of continuous dosing, after mice are sacrificed at 5 months of age, total RNA is extracted and then m is detected using Dot Blot 6 Changes in A modification, results show that after SRTM2457 treatment, m is in brain compared to control group 6 The level of a modification was significantly reduced (fig. 5a-5 b). Western Blot was performed after extraction of proteins from the mouse brain and examined for Mettl3 levels, and STM2457 was found not to affect protein level expression of Mettl3, consistent with previous studies reports (FIGS. 5c-5 d). Taken together, STM2457 can significantly inhibit m in brain of mice with Alzheimer's disease 6 Level of A modification.
Example 5STM2457 significantly improves the pathological features of mice with alzheimer's disease
1. Method of
Immunofluorescent staining: mice were anesthetized with isoflurane, perfused systemically with 1xPBS, then further perfused with 4% Paraformaldehyde (PFA), and fixed with 4% PFA for 2 days after brain dissection. After 3 days of complete dehydration of 30% sucrose at 4℃a 30 μm sagittal section was taken with a frozen microtome. The slices were stored in a preservation solution at-20 ℃. Brain sections containing hippocampal areas were taken and stained by washing 3 times with PBS. The primary antibody was incubated overnight at 4℃with blocking solution (containing 3% goat serum in PBS and 0.1% Triton x-100) for 1 hour at room temperature. The next day, samples were washed with PBS, then incubated with DAPI for 1 hour at room temperature, and slides were prepared by adding a capper after further washing. Images were taken using an Olympus confocal microscope, all taken under the same conditions and settings, and fluorescent areas were counted using ImageJ, with 4 to 6 brain slices per mouse.
2. Results
To determine whether STM2457 can affect amyloid deposition levels and neuroinflammation levels in brains of alzheimer's disease mice, two groups of mice were perfused, frozen sections were performed, and immunofluorescent staining was performed. The aβ staining area was reduced in mice in the cortical and hippocampal areas of the brains of mice compared to control (ad+vehicle) and we detected the intermediates sappβ and ctfβ in the amyloid production pathway using Western Blot, which showed a significant reduction in sappβ and ctfβ protein levels in STM2457 treated (ad+stm2457) groups (fig. 6d-6 f). To detect the effect of STM2457 on neuroinflammatory levels in alzheimer's disease, immunofluorescent staining was performed using the astrocyte marker GFAP and the microglial marker Iba 1. The results showed a decrease in the areas of GFAP and small Iba1 signal, markers of neuroinflammation (fig. 6g-6 i).
These results indicate that STM2457 treated mice with alzheimer's disease were able to reduce the levels of amyloid and neuroinflammation in the brain.
Example 6STM2457 significantly improves cognitive dysfunction in mice with alzheimer's disease
1. Method of
Morris Water Maze (MWM): the MWM was performed in a circular, water filled bathtub (120 cm diameter) with visual cues outside the maze, the water becoming opaque by the titanium dioxide covering its surface, the bathtub being divided into 4 virtual quadrants. MWM is divided into two phases, training and testing. In the training phase, a blind escape platform (diameter 11 cm) is located 1 cm below the water surface. Mice entered the water maze from 4 different starting positions of the pool, respectively. The time of arrival of each animal at the escape platform was recorded, and each animal was trained 4 times per day for 4 days. The testing phase was performed 24 hours after the end of the last training, during which the platform was removed, the ratio of the time the mice were swim in 4 virtual quadrants within 120 seconds was measured, and the first time to reach the position where the escape platform was previously placed and the total number of passes through the platform position were recorded. The experiments were video recorded and analyzed using mazerscan software.
New thing recognition: the test is based on the mouse's preference to contact a novel object. The mice in the experiment were placed in an illuminated white plastic box (60 cmx60cmx30 cm), monitored by overhead cameras, and analyzed by an automated tracking system (San Diego Instruments, CA). On the first day, two identically shaped objects were placed in a test box and mice were placed in the box for free exploration for 10 minutes. After 24 hours, one of the objects was replaced with another object of a different shape. The mice were again placed in the box for 10 minutes to explore the objects, and the time taken to explore both objects was assessed and the ratio calculated.
Y maze spontaneously alternates: three identical opaque arms (35 cm long, 8 cm wide, 8 cm high) at 120 degrees to each other were used, with spatial cues at the distal end. The continuous spontaneous alternation test is based on the natural tendency of mice to explore new environments. The mice were placed in the Y maze facing the wall of one arm at random, and three arms in the Y maze were freely explored for 8 minutes. In general, mice tend to explore the nearest and non-visited arms, forming alternates between the three arms, depending on their spatial working memory. Taking the percent spontaneous alternation as an indicator of the measurement, all alternations (i.e. each time the mouse explores three arms in succession) were divided by all possible alternations (i.e. the total number of entering arms minus 2), and multiplied by 100.
Statistical analysis: data are expressed as mean ± SEM and analyzed using GraphPad Prism software. Determining the difference between the two groups using unpaired t-test; two-way anova and Bonferroni multiple comparison test were used to determine differences between the groups. P <0.05 is statistically significant for the differences.
2. Results
The Y maze test results showed that STM2457 treated AD mice had significantly increased spontaneous alternation rate compared to normal saline treated AD mice, while the total number of times into the exploratory arm was unchanged (fig. 7a-7 b). The novelty recognition task test shows that the STM2457 processes the time of the group to explore the novelty increases (fig. 7c-7 d). In the training phase of the Morris water maze test, the STM2457 treatment group took shorter time to reach the platform than the saline treatment group (FIG. 7 e). During the test phase, the time required for the STM2457 treatment group to reach the platform for the first time was reduced, the dwell time in the target quadrant was increased, the number of passes through the platform was increased, and the total swim distance and swim time remained unchanged (FIGS. 7f-7 k).
Taken together, these results indicate that STM2457 can improve cognitive dysmnesia in mice with alzheimer's disease.
The foregoing examples illustrate only a few embodiments of the invention and are described in detail herein without thereby limiting the scope of the invention. It should be noted that it will be apparent to those skilled in the art that several variations and modifications can be made without departing from the spirit of the invention, which are all within the scope of the invention. Accordingly, the scope of protection of the present invention is to be determined by the appended claims.
Claims (8)
- Application of STM2457 in preparing medicament for preventing and treating Alzheimer's disease.
- Use of stm2457 in the manufacture of a medicament for treating a neurodegenerative disease.
- Use of stm2457 in the manufacture of a medicament for ameliorating/treating an amyloid-related neurodegenerative disease.
- Use of stm2457 in the manufacture of a medicament and/or a health care product for improving/treating memory or cognitive impairment.
- 5. The use of any one of claims 1 to 4 wherein STM2457 inhibits brain m 6 A modifies the level, thereby reducing the level of amyloid deposition and inhibiting neuroinflammatory reactions and improving cognitive function.
- 6. A medicine for preventing and treating Alzheimer's disease, which is characterized by comprising STM2457.
- 7. The medicament of claim 6, further comprising a pharmaceutically acceptable excipient or carrier.
- 8. The medicament according to claim 6, wherein the pharmaceutical preparation is a tablet, a hard capsule, a soft capsule, a powder, a tincture, an oral liquid, a dripping pill or an injection.
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| CN113244248A (en) * | 2021-05-21 | 2021-08-13 | 浙江大学 | Application of N-acetyl-D-glucosamine in preparation of medicine for preventing and treating Alzheimer's disease |
| CN114042072A (en) * | 2021-12-16 | 2022-02-15 | 华中科技大学同济医学院附属协和医院 | New application of STM2457 |
| CN116251105A (en) * | 2023-02-14 | 2023-06-13 | 华中科技大学同济医学院附属同济医院 | Application of STM2457 in preparation of medicines for treating allergic rhinitis |
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| CN113244248A (en) * | 2021-05-21 | 2021-08-13 | 浙江大学 | Application of N-acetyl-D-glucosamine in preparation of medicine for preventing and treating Alzheimer's disease |
| CN114042072A (en) * | 2021-12-16 | 2022-02-15 | 华中科技大学同济医学院附属协和医院 | New application of STM2457 |
| CN116251105A (en) * | 2023-02-14 | 2023-06-13 | 华中科技大学同济医学院附属同济医院 | Application of STM2457 in preparation of medicines for treating allergic rhinitis |
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