Application of CGS21680 in preparation of intervention medicine for preventing / treating autism

Abstract

The invention relates to an application of CGS21680 in preparation of an intervention drug for preventing / treating autism, the CGS21680 can activate A2AR, down-regulate the levels of TNF-alpha, IL-6 and MCP-1 in cerebral cortex tissues and reduce the inflammation of a central nervous system in the early stage after growth so as to intervene in autism spectrum disorder engraving behaviors, and the drug effect of the early intervention after growth can last to the adult stage. The autism related behaviors after the adult are improved. An animal level experiment result shows that A2AR is activated in the early stage of the mouse after birth, so that the activation degree of microglial cells of the cortex of the BTBR mouse can be remarkably reduced, the neural immune microenvironment of the cortex of the mouse is improved, the defects of a three-box social experiment of the adult BTBR mouse are improved, the engraving behavior, the spontaneous activity capability and the anxiety behavior of the adult BTBR mouse are reduced, and the survival rate of the adult BTBR mouse is increased. And the adult BTBR mouse is protected from being influenced by autism-related behaviors.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of biomedical technology, and particularly relates to application of CGS21680 in preparation of intervention drugs for preventing / treating autism. BACKGROUND

[0002] Autism spectrum disorder (ASD, simply autism) is a neurodevelopmental disorder characterized by stereotyped repetitive behavior, impaired social interaction and communication deficits. The cause of autism is not clear, and is related to many possible causes including genetic factors and environmental factors; among them, excessive immune inflammation of the central nervous system also plays an important role. Autism patients often have an onset in early childhood, and the course progresses with age. Due to the characteristics of human neural development, the treatment time window of autism patients is before the age of 6. However, there is no specific drug for autism at present, and the purpose of drug treatment in clinic is mainly to reduce complications such as seizures, hyperactivity and sleep problems, in order to try to reduce the overall severity of autism symptoms. Therefore, how to effectively treat or intervene autism is a problem to be solved.

[0003] BTBRT+Itpr3tf / J (BTBR) mice have been widely used as an animal model of autism-like phenotypes. Because BTBR mice exhibit attention and learning impairments, lower social skills, high levels of self-grooming behavior, and abnormal patterns such as repetitive behavior and communication deficits similar to those of autism patients. BTBR mice exhibit abnormal immune responses associated with behavioral disorders, showing signs of increased microglial activation, and significantly increased expression of pro-inflammatory factors in the central nervous system. This is consistent with the finding that autism patients show increased activation of microglia and increased secretion of pro-inflammatory factors in the central nervous system.

[0004] At present, existing researches cannot meet the needs of early intervention and long-term treatment of autism. Adenosine A2A receptor (A2AR) is considered an important potential target for therapeutic intervention in neurodegenerative diseases, and is highly expressed in microglia and macrophages in central nervous system lesions and inhibits their function. However, the existing researches are all focused on the immediate effect of drugs on adult BTBR mice, and the behavior changes of the animals are detected after the drugs are administered to the adult animals, and there is no research report on the long-term sustained effect of the drugs on the behavior improvement of adult animals. In addition, the brain development of BTBR mice is relatively fixed after adulthood, and it is difficult to fundamentally and continuously improve autism-related symptoms by changing the brain structure, and the research on early intervention effect and the exploration of the sustained effect of early treatment on behavior improvement of adult BTBR mice are still a technical gap. SUMMARY

[0005] In view of the deficiencies of the prior art, the application provides application of CGS21680 in preparation of an intervention drug for preventing and treating autism.

[0006] The technical scheme of the application is as follows: Application of CGS21680 in preparation of an intervention drug for preventing and treating autism.

[0007] Further, the CGS21680 can activate A2AR.

[0008] Further, the CGS21680 can reduce inflammation of the central nervous system.

[0009] Further, the CGS21680 can improve the abnormal activation state of cortical microglia.

[0010] Further, the drug acts on an autism patient in the early postnatal period.

[0011] Further, the drug is administered intracranially.

[0012] Further, the effective dose of the drug is 0.006 mg / kg.

[0013] Further, the drug contains a pharmaceutically acceptable excipient.

[0014] Further, the drug contains a pharmaceutically acceptable excipient. The excipient includes but is not limited to a diluent, a buffer, a suspending agent, an emulsion, a granule, a capsule, an excipient, a filler, a binder, a spray, a transdermal absorption agent, a wetting agent, a disintegrating agent, an absorption promoter, a surfactant, a coloring agent, a flavoring agent or an adsorption carrier.

[0015] Compared with the prior art, the application has at least the following advantages: the application relates to application of CGS21680 in preparation of an intervention drug for preventing and treating autism, the CGS21680 can activate A2AR in the early postnatal period, down-regulate the levels of TNF-alpha, IL-6 and MCP-1 in cerebral cortex tissue, reduce inflammation of the central nervous system, thereby intervene in the stereotyped behavior of autism spectrum disorder, and the effect of the drug for early postnatal intervention can be sustained to adulthood, thereby improving autism-related behaviors in adulthood. The experimental results at the animal level show that activation of A2AR in the early postnatal period of mice can significantly reduce the activation degree of cortical microglia cells of BTBR mice, improve the neural immune microenvironment of the cortex of the mice, and improve the defects of the three-box social experiment of BTBR mice in adulthood, reduce the stereotyped behavior, spontaneous activity ability and anxiety behavior of BTBR mice in adulthood, and protect BTBR mice in adulthood from autism-related behaviors. BRIEF DESCRIPTION OF DRAWINGS

[0016] In order to more clearly illustrate the specific embodiments of the present application, the following will briefly introduce the drawings required to be used in the specific embodiments or prior art description.

[0017] Figure 1 The RNA-seq data analysis, enrichment analysis of immune cell type markers, Western blotting and real-time RT-PCR results of P7-BTBR mice and P7-C57BL / 6 mice in Test Example One of the present application; Figure 2 The homology analysis, functional similarity comparative analysis results of human and mouse A2AR proteins in Test Example Two of the present application; Figure 3 The homology and protein structure prediction analysis of human and mouse A2AR proteins in Test Example Two of the present application; Figure 4 The mutual interaction molecule prediction analysis of human and mouse A2AR proteins in Test Example Two of the present application; Figure 5 The core function enrichment of human and mouse A2AR proteins by bioinformatics analysis in Test Example Two of the present application; Figure 6 The significant reduction of cortical neuroimmunity reaction of BTBR mice after activating A2AR at early postnatal stage in Test Example Three of the present application; Figure 7 The activation degree of cortical microglia cells before and after activating A2AR at early postnatal stage in Test Example Four of the present application; Figure 8 The expression degree of CXCR2 of cortical microglia cells before and after activating A2AR at early postnatal stage in Test Example Four of the present application; Figure 9 The real-time PCR evaluation results of mRNA levels of TNF-α, IL-6 and MCP-1 before and after activating A2AR at early postnatal stage in Test Example Four of the present application; Figure 10 The three-chamber social test results of four groups of mice at adult stage in Test Example Five of the present application; Figure 11 The stereotypy and open field test results of four groups of mice at adult stage in Test Example Six of the present application. DETAILED DESCRIPTION

[0018] It is necessary to point out that the following specific embodiments are only used to further illustrate the present application, and cannot be understood as limiting the protection scope of the present application, and the skilled in the art can make some non-essential improvements and adjustments to the present application according to the above application content.

[0019] The materials used in the experiment and the test method are generally and / or specifically described. The test method or test method involved, if not specially stated, is a conventional method; the reagent or instrument used, if not specified by the manufacturer, is a conventional product on the market, prepared or used by a conventional method.

[0020] Material source: BTBR mice (autism model mice), male and female BTBR T+Itpr3tf / J (BTBR) breeding population was purchased from Jackson Laboratory (Bar Harbor, ME, USA), and the offspring was used for the experiment of the patent; C57BL / 6 mice (wild type mice), purchased from the laboratory of the Army Medical University; The above mice were raised in an environment of 5-6 mice per cage, grouped according to a 12-hour light-dark cycle, and placed in a standard animal facility with free access to water and food.

[0021] CGS21680 (CGS, A2AR agonist), purchased from Sigma-Aldrich Company.

[0022] Example one, BTBR mice, C57BL / 6 mice pretreatment The BTBR pups were randomly divided into two groups, 10 in each group, and the birth day was set as postnatal day 0 (P0). In order to avoid the litter effect, the animals in each treatment group were randomly selected from multiple litters, and one pup was selected from each litter. As a control group, C57BL / 6 mice were treated the same.

[0023] Group ①: BTBR-Vehicle group mice (solvent control), intracerebroventricular injection of 0.9% NaCl:DMSO=2:3 at P5 (5 days after birth) and P6 (6 days after birth).

[0024] Group ②: BTBR-CGS group mice (autism mice affected by CGS), intracranial injection of CGS21680 with a concentration of 0.006 mg / kg at P5 and P6 to activate A2AR in the central nervous system of BTBR mice.

[0025] Group ③: C57BL / 6-Vehicle group mice (solvent control), intracranial injection of 0.9% NaCl:DMSO=2:3 at P5 and P6.

[0026] Group ④: C57BL / 6-CGS group mice (wild type mice affected by CGS), intracranial injection of CGS21680 with a concentration of 0.006 mg / kg at P5 and P6.

[0027] The mice in the above group were detected, and the detection results were as follows.

[0028] Test Example One P7-BTBR (BTBR mice at 7 days after birth) mouse cortex inflammation aggravation, A2AR expression increased The transcriptome of the cortex of P7-BTBR mice and P0-C57BL / 6 mice was analyzed, and after sequencing on an illumine NovaSeq 6000 sequencer, paired-end reads were harvested and quality controlled by Q30. Clean data was obtained by 3' adapter-trimming and removing low-quality reads fastp software, and then the clean data was aligned to the reference genome GRCm38.91 by software Hisat2 (v2.0.4). Read counts were standardized by fragments per kilobase million (FPKM). Differential expression analysis of each gene was performed by the edgeR (v3.28.1) package of R (v3.6.0) software. Genes with p-value <0.05 and absolute fold change ≥1.5 were considered to be differentially expressed.

[0029] The RNA-seq data showed that there were a large number of differentially expressed genes (DEGs) between the two groups, and the significantly enriched Kyoto Gene and Genome Encyclopedia (KEGG) pathways and their distribution in the five categories were as follows Figure 1 As shown in A, compared with C57BL / 6 mice, the immune system processes and inflammatory responses of BTBR mice were significantly enriched; the KEGG annotated pathway classification pie chart is as shown in Figure 1 B, as can be seen from the figure, nearly 50% of the enriched pathways are related to the immune system, such as complement and coagulation cascades, IL-17 signaling pathway, etc., in addition, some other pathways such as TNF signaling pathway and cytokine-cytokine receptor interaction are annotated as related to environmental information processing, and may also contribute to immune or inflammatory processes; therefore, from the above analysis, it can be seen that compared with P0-C57BL / 6-Vehicle mice, the immune system related biological processes of the cortex of P0-BTBR-Vehicle mice have changed significantly, and tend to be up-regulated.

[0030] The enrichment analysis of immune cell type markers is as shown in Figure 1C. As seen from the figure, microglia and neutrophil-related markers were enriched with differentially expressed markers, while in BTBR-Vehicle mice, a high percentage of upregulated markers were enhanced. As mentioned before, A2AR expression would be elevated during inflammation. Likewise, the present test case found that mRNA and protein expression levels of A2AR in the cortex of BTBR-Vehicle mice were significantly higher than those of C57BL / 6-Vehicle mice (n=6 vs n=7, p<0.05) in the early postnatal period, which might be a response to excessive inflammation in BTBR-Vehicle mice (Fig. 1A and Fig. 1B). Figure 1 D and E, p<0.05 in Fig. E.

[0031] Test Case Two: Comparative Analysis of Human and Murine A2AR Gene and Protein Homology and Functional Similarity ① Obtain human and murine A2AR gene and protein sequences from NCBI and Uniprot databases.

[0032] Human A2AR protein sequence: MPIMGSSVYITVELAIAVLAILGNVLVCWAVWLNSNLQNVTNYFVVSLAAADIAVGVLAIPFAITISTGFCAACHGCLFIACFVLVLTQSSIFSLLAIAIDRYIAIRIPLRYNGLVTGTRAKGIIAICWVLSFAIGLTPMLGWNNCGQPKEGKNHSQGCGEGQVACLFEDVVPMNYMVYFNFFACVLVPLLLMLGVYLRIFLAARRQLKQMESQPLPGERARSTLQKEVHAAKSLAIIVGLFALCWLPLHIINCFTFFCPDCSHAPLWLMYLAIVLSHTNSVVNPFIYAYRIREFRQTFRKIIRSHVLRQQEPFKAAGTSARVLAAHGSDGEQVSLRLNGHPPGVWANGSAPHPERRPNGYALGLVSGGSAQESQGNTGLPDVELLSHELKGVCPEPPGLDDPLAQDGAGVS (SEQ ID NO. 1) Mouse A2AR protein sequence: MGSSVYIMVELAIAVLAILGNVLVCWAVWINSNLQNVTNFFVVSLAAADIAVGVLAIPFAITISTGFCAACHGCLFFACFVLVLTQSSIFSLLAIAIDRYIAIRIPLRYNGLVTGMRAKGIIAICWVLSFAIGLTPMLGWNNCSQKDENSTKTCGEGRVTCLFEDVVPMNYMVYYNFFAFVLLPLLLMLAIYLRIFLAARR QLKQMESQPLPGERTRSTLQKEVHAAKSLAIIVGLFALCWLPLHIINCFTFFCSTCQHAPPWLMYLAIILSHSNSVVNPFIYAYRIREFRQTFRKIIRTHVLRRQE PFRAGGSSAWALAAHSTEGEQVSLRLNGHPLGVWANGSAPHSGRRPNGYTLGPGGGGSTQGSPGDVELLTQEHQEGQEHPGLGDHLAQGRVGTASWSSEFAPS (SEQ ID NO.2) ② By predicting and comparing with BLAST sequences (using the Basic Local Alignment Search Tool), the human A2AR gene is located on chromosome 22q11.23, with a gene structure containing two exons and one intron, encoding a G protein-coupled receptor (GPCR) family protein. The mouse A2AR gene is located on chromosome 10 (corresponding to the homologous region of human chromosome 22q11.23), also consisting of two exons and one intron. Both genes exhibit highly conserved gene structures, with identical exon numbers and transmembrane protein topologies. From... Figure 2 As shown in A and 2B, BLAST comparison reveals that the amino acid sequence homology between human and mouse A2AR is approximately 83%. Figure 2 As shown in C, in terms of key regions, the human and mouse A2AR proteins are highly conserved in key ligand binding sites, such as the 6th transmembrane helix (TM6) and the extracellular second loop (ECL2), which are core functional regions (Uniprot: mouse A2AR: Q60613, human A2AR: P29274). A search of the Uniport database for similar proteins to the human A2AR protein, which includes the mouse A2AR protein, showed 100% similarity. Figure 3 A); and predicted the structures of human and mouse proteins using SWISS-MODEL. Figure 3 B represents the predicted structure of the murine A2AR protein. Figure 3 C represents the predicted structure of the human A2AR protein.

[0033] ③ Bioinformatics comparative analysis of the functions and interacting proteins of human and mouse A2AR proteins was performed using STRING. The results are as follows: Figure 4 As shown, Figure 4 A represents the predicted murine A2AR interacting protein. Figure 4 B is a prediction of human A2AR interacting proteins. As shown in the figure, both human and mouse A2AR interaction networks contain DRD2, POMC, GNAS, GNAQ, GNAL, and ADORA2B, indicating that the core interacting molecules of human and mouse A2AR are highly similar.

[0034] ④ Protein functional enrichment was performed using Uniprot bioinformatics analysis. Figure 5 A represents the core function of the murine A2AR protein. Figure 5 B represents the core function of the human A2AR protein. The figure shows that the human and mouse A2AR proteins exhibit high conservation in their core functions. Both are significantly enriched in the adenylate cyclase-activated G protein-coupled receptor signaling pathway and the dopamine receptor signaling pathway. Highly correlated pathways include the adenylate cyclase-regulated G protein-coupled receptor signaling pathway and cAMP-mediated positive regulation of signal transduction (both involving cyclase regulation), positive regulation of neurotransmitter transport and amine transport (both involving neurotransmitter regulation), and regulation of glutamatergic synaptic transmission and potassium / metal ion transport (both involving ion channel regulation). The highest functional significance of the mouse A2AR reaches FDR 1.0e-14, while that of the human is FDR 1.0e-12. The number of genes involved in the functional modules is comparable (4-9 in the mouse and 3-10 in the human), suggesting a high degree of conservation of the core functions of human and mouse A2AR.

[0035] Test Case 3: Early activation of A2AR after birth significantly reduced the cortical neuroimmune response in BTBR mice. Following intraventricular injection of CGS21560 into the brain of BTBR mice in early postnatal period to specifically activate A2AR, transcriptome sequencing and bioinformatics analysis of the cortical tissue of BTBR mice were performed. Figure 6As shown in A, after early postnatal activation of A2AR, the functional enrichment of DEGs in P7-BTBR-CGS mice (P7-day BTBR-CGS mice) also showed a significant improvement in immune system-related pathways, with 400 up-regulated genes and 322 down-regulated genes detected in P7-BTBR-CGS mice, which was much less than the DEGs between P7-BTBR-Vehicle mice and P7-C57BL / 6-Vehicle mice (1629 up-regulated genes and 921 down-regulated genes). And from Figure 6 As shown in B, early postnatal activation of A2AR changed the basic differences between BTBR-CGS mice and C57BL / 6-Vehicle mice, such as IL-17 signaling pathway, Th17 cell differentiation, Th1 and Th2 cell differentiation, TNF signaling pathway, and Toll-like receptor signaling pathway, which have been focused on in current autism research.

[0036] Example Four: Early postnatal activation of A2AR can significantly reduce the activation degree of cortical microglia cells in BTBR mice ① The activation of cortical microglia cells in P7-BTBR-Vehicle (P7-day BTBR-Vehicle mice) mice was detected by immunofluorescence experiment, and the results confirmed that the number and activation degree of cortical microglia cells in P7-BTBR-Vehicle mice, i.e. the microglia cell body became larger and the branches decreased, were significantly higher than those in P7-C57BL / 6-Vehicle mice, and the results are shown in Figure 7 A.

[0037] ② After intracerebroventricular injection of CGS21680 to activate A2AR in the cortex of BTBR mice in early postnatal period, the immunofluorescence experiment confirmed that compared with P7-BTBR-Vehicle mice, the number of cortical microglia cells (Iba1 + TotalCells) in P7-BTBR-CGS mice decreased significantly ( Figure 7 B); at the same time, the degree of activated microglia cells also decreased significantly (Iba1 + Positived Cellspercentage) ( Figure 7 C); from Figure 7 A, it can be seen that the volume of activated microglia cells decreases, and the branches increase and grow.

[0038] ③ Immunofluorescence was used to detect the expression of the proinflammatory factor CXCR2 (CXC chemokine receptor 2) in the cortex of mice in each group, and the results are shown in Figure 8 Figure 8 As shown in A and 8B, the expression of proinflammatory factor CXCR2 in the cortex of P7-BTBR-Vehicle mice was significantly increased compared with P7-C57BL / 6-Vehicle mice; after activating A2AR in the cortex of P7-BTBR mice using CGS21680, immunofluorescence found that the expression of proinflammatory factor CXCR2 in the cortex of P7-BTBR-CGS mice was significantly reduced, as shown in C, the average fluorescence intensity in the cortex of P7-BTBR-CGS mice was significantly reduced. Figure 8

[0039] ④ Figure 9 To detect the mRNA levels of proinflammatory factors TNF-α (tumor necrosis factor-α), IL-6 (interleukin-6) and MCP-1 (monocyte chemotactic protein 1) in the cortex of P7-BTBR mice using real-time quantitative PCR, compared with the control group P7-C57BL / 6-Vehicle mice, P7-BTBR-Vehicle mice had significantly more severe inflammation, and the mRNA levels of TNF-α, IL-6 and chemokine MCP-1 in the cortex of P7-BTBR-Vehicle mice were significantly increased (p<0.05); after activating A2AR in the cortex of BTBR mice using CGS21580, the mRNA levels of proinflammatory factors TNF-α, IL-6 and MCP-1 were significantly reduced.

[0040] The above results confirm that the level of immune inflammation in the cortex of P7-BTBR-Vehicle mice is significantly increased compared with wild-type P7-C57BL / 6-Vehicle mice, and the level of immune inflammation is significantly reduced after activating A2AR by CGS21680, which confirms that activating A2AR in the early postnatal period can reduce the excessive immune inflammation in the central nervous system of BTBR mice (p<0.05).

[0041] Test Example Five: Activation of A2AR in the early postnatal period improves the defects of adult BTBR mice in the three-chamber social experiment In the three-chamber social experiment, the sociality of mice was determined by testing the time spent in the mouse chamber or the object chamber, and spending more time in the unfamiliar mouse chamber was defined as better sociality. The mice used in this test example were 8-week-old adult mice given A2AR activation in the early postnatal period.

[0042] The results of the three-chamber social experiment are shown in Figure 10 ​​As shown, BTBR-CGS mice showed better sociability compared to BTBR-Vehicle mice; repeated measures ANOVA (paired t-test) analysis showed that BTBR-CGS mice spent more time in the chamber with a stranger mouse compared to BTBR-Vehicle mice from Figure 10 As shown in A, both C57BL / 6-Vehicle and C57BL / 6-CGS mice showed normal sociability in terms of chamber time, and spent more time in the chamber with a stranger mouse than in the chamber with a stranger object; BTBR-Vehicle mice showed typical sociability deficits in terms of chamber time, but the sociability deficits of adult BTBR mice were improved after early postnatal injection of CGS21680. “S” and “O” represent mouse and object, respectively, and warmer colors (red) indicate longer time spent. Figure 10 B shows the results of sociability chamber time, from Figure 10 As shown in B, BTBR-Vehicle mice spent similar time in the chamber with a stranger mouse and in the chamber with a stranger object, while BTBR-CGS mice spent significantly more time in the chamber with a stranger mouse after P5 and P6 injection of CGS21680.

[0043] In addition, social sniffing is a more sensitive and direct measure of sociability than chamber time. From Figure 10 As shown in C, C57BL / 6 mice spent more time sniffing a stranger mouse, while BTBR-Vehicle mice spent similar time sniffing a stranger mouse and a stranger object; similarly, BTBR-CGS mice increased the time spent sniffing a stranger mouse in adult BTBR mice after P5 and P6 injection of CGS21680.

[0044] Statistical analysis of exploratory movement time in the three-chamber sociability test is shown in Figure 10 D-F, activation of A2AR in early postnatal life did not significantly affect exploratory movement in the three-chamber sociability test in BTBR mice and C57BL / 6 mice. Figure 10 D shows the performance index from chamber time, from which it can be seen that BTBR-Vehicle mice showed significantly lower preference index (time spent in the chamber with a stranger mouse - time spent in the chamber with a stranger object / total time) than C57BL / 6-Vehicle mice in terms of chamber time, and that BTBR-CGS mice, which were injected with CGS21680 in early postnatal life, reversed this deficiency and improved the preference index of BTBR mice. Figure 10E is the number of times that the mice entered the sociability chamber in this example. As can be seen from the figure, there was no significant difference in the number of times that the mice entered the sociability chamber among the four groups. From Figure 10 F, it can be seen that no congenital chamber side preference was found among the four groups of mice.

[0045] Test Example Six: Early postnatal activation of A2AR reduces stereotypy, locomotor activity and anxiety behavior in adult BTBR mice In this test example, the number of marbles buried and the time spent on self-grooming were measured as stereotypy, and the open field test was used to measure locomotor activity and anxiety behavior. The mice used in this test example were postnatal 8-week-old adult mice that were given A2AR activation in the early postnatal period.

[0046] The results of stereotypy and open field test of adult mice are shown in Figure 11 Figure 11 A-B show that early postnatal activation of A2AR reduces stereotypy in adult BTBR mice, Figure 11 As can be seen in A, the number of marbles buried by C57BL / 6-Vehicle, C57BL / 6-CGS group mice within 30 minutes after treatment at P5 and P6 stages was close to the level, and was significantly lower than that of BTBR-Vehicle group mice, and the number of marbles buried by BTBR-CGS group mice treated with CGS21680 was significantly reduced (p = 0.01, p = 0.001); Figure 11 As can be seen in B, the time spent on self-grooming by C57BL / 6-Vehicle, C57BL / 6-CGS group mice was almost the same, and the time spent on self-grooming by BTBR-Vehicle group mice was significantly longer, but this situation was significantly improved in BTBR-CGS group mice treated with CGS21680.

[0047] In this test example, in order to determine whether early postnatal activation of A2AR will affect the overall locomotor activity and exploratory behavior of adult BTBR mice (as it may interfere with the results obtained in the social ability task (number of compartments and interactions) and self-grooming behavior detection), the open field test was performed on BTBR and C57BL / 6 mice, and the results of the open field test are shown in Figure 11 C-E, Figure 11 C is the representative motion trajectory of the four groups of mice, which is the moving distance test for 30 minutes; Figure 11 ​D is the distance of the four groups of mice in the open field experiment, compared with C57BL / 6-Vehicle and C57BL / 6-CGS groups of mice, the spontaneous activity of BTBR-Vehicle group of mice is significantly enhanced, and the total distance of BTBR-CGS group of mice in the open field experiment after CGS21680 treatment is similar to that of C57BL / 6 group of mice; Figure 11 E represents the representative movement trajectory of the four groups of mice is divided into six time periods, each time period is 5 minutes, compared with BTBR-CGS group of mice, BTBR-Vehicle group of mice only in the first 5 minutes (the first time period) presents a significantly higher level, there is obvious difference.

[0048] The above examples are only used to illustrate the technical solutions of the present application, but not to limit it; although the present application has been described in detail with reference to the foregoing examples, those skilled in the art should understand that the technical solutions recorded in the foregoing examples can still be modified, or some or all of the technical features can be replaced by equivalents; and these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the scope of the technical solutions of the embodiments of the present application, and they should be covered in the scope of the claims and the specification of the present application.

Claims

1. Use of CGS21680 in the preparation of an intervention drug for preventing / treating autism.

2. Use according to claim 1, characterized in that, The CGS21680 can activate A2AR.

3. Use according to claim 2, characterized in that, The CGS21680 can reduce central nervous system inflammation.

4. Use according to claim 3, characterized in that, The CGS21680 can improve the abnormal activation state of cortical microglia.

5. Use according to any one of claims 1 to 4, characterized in that, The drug acts on patients with autism in the early postnatal period.

6. Use according to claim 5, characterized in that, The drug is administered intracranially.

7. Use according to claim 6, characterized in that, The effective dose of the drug is 0.006 mg / kg.

8. Use according to claim 7, characterized in that, The drug contains pharmaceutically acceptable excipients.

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