CN111514149B

CN111514149B - Application of XAV939 in preparing medicine for treating autism spectrum disorder

Info

Publication number: CN111514149B
Application number: CN202010550702.2A
Authority: CN
Inventors: 武胜昔; 王梦梦; 王亚周
Original assignee: Air Force Medical University of PLA
Current assignee: Air Force Medical University of PLA
Priority date: 2020-06-16
Filing date: 2020-06-16
Publication date: 2021-02-23
Anticipated expiration: 2040-06-16
Also published as: CN111514149A

Abstract

The invention discloses application of a compound XAV939 in preparing a medicament for treating autism spectrum disorder. In a mouse autism model of single gene knockout of Shank3b, the three-box behavior experiment results show that the time for the treatment group to contact with the social mouse and the corresponding preference coefficient (preference score) are increased at the third day after the continuous injection of XAV 939; the results of the residence-invasion behavior experiments showed that the treatment groups had increased time and frequency of exposure to the pups. Therefore, the animal experiment result disclosed by the invention shows that XAV939 can effectively improve the social ability of autism mice, and supports the application of XAV939 in the preparation of the medicine for resisting autism social disorder.

Description

Application of XAV939 in preparing medicine for treating autism spectrum disorder

Technical Field

The invention belongs to the field of autism drug therapy, and relates to application of XAV939 in preparation of a drug for treating autism spectrum disorder.

Background

Autism Spectrum Disorder (ASD) is a group of neurodevelopmental mental disorders that arise in infancy. Social disorder, one of the core symptoms of ASD, is usually manifested in the infant stage of a patient, often accompanied by life-long, even the patient loses self-care ability of life, causing enormous economic burden and mental stress to families and society. According to the results of global disease burden research, 5200 ten thousand of ASD patients exist in the world by 2010, and the ratio of children to children is 1:88, so that the disease becomes a non-negligible mental disease of children.

To date, the pathogenesis of ASD is not fully understood, and specific early diagnosis and effective intervention of ASD is still lacking. The current treatment aims to mainly relieve relevant symptoms, improve the independent life self-care ability of patients and improve the life quality, such as psychosocial intervention, application of behavioral analysis therapy and the like. But has no breakthrough progress in the research and development of the medicine for improving the social disorder of the ASD.

Beta-catenin is reported to be a risk gene of autism in relevant literatures. Clinical screening studies have shown that approximately 39% of exon-severe mutations occur in β -catenin in patients with sporadic ASD. The molecular mechanism of epigenetic aberration is closely related to the classical beta-catenin pathway observed in other animal models of autism.

XAV939, formula C₁₄H₁₁F₃N₂OS, a white or off-white powder-like reagent with a molecular weight of 312.31, readily soluble in DMSO. The mechanism of action is to target the tankyrase1/2Inhibit the beta-catenin signal. XAV939 belongs to small molecular beta-catenin inhibitors, and has been used for treating cancers such as colon cancer, breast cancer, hepatocellular carcinoma, etc. However, there is currently no report of any relevant application of XAV939 in alleviating social disorders of autism.

Disclosure of Invention

In order to overcome the above-mentioned drawbacks of the prior art, the object of the present invention is to provide the use of the compound XAV939 for the preparation of a medicament for the treatment of autism spectrum disorders.

In order to achieve the purpose, the invention adopts the following technical scheme to realize the purpose:

the invention discloses application of a compound XAV939 in preparing a medicament for treating autism spectrum disorder.

Preferably, animals of XAV939 are dosed daily at a concentration of 20 μ M, at a dose of 600nl, for three consecutive days.

Preferably, the drug is a drug that improves social ability.

Preferably, the drug is a drug that increases social contact time and frequency.

Compared with the prior art, the invention has the following beneficial effects:

the invention discloses application of a compound XAV939 in treating autism. In a mouse autism model of single gene knockout of Shank3b, the three-box behavior experiment results show that the time for the treatment group to contact with the social mouse and the corresponding preference coefficient (preference score) are increased at the third day after the continuous injection of XAV 939; the results of the residence-invasion behavior experiments showed that the treatment groups had increased time and frequency of exposure to the pups. Therefore, the animal experiment result disclosed by the invention shows that XAV939 can effectively improve the social ability of the autism mouse, and fully supports the application of XAV939 in preparing the medicine for resisting the autism social disorder.

Drawings

FIG. 1 is a heat map of behavior traces of three experimental control groups, 24h, 3d and 7d groups after administration;

FIG. 2 shows the contact time of the three experimental control groups and the

social mouse groups

24h, 3d and 7d after administration;

FIG. 3 shows the preference factors of the three

experimental control groups

24h, 3d and 7d after administration;

FIG. 4 shows the frequency of exposure of the control group of residence-invasion test to the young mouse at 24h, 3d and 7d after the administration.

Detailed Description

In order to make the technical solutions of the present invention better understood by those skilled in the art, the technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to specific embodiments and the accompanying drawings, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

The compound XAV939 used in the invention has the molecular formula C₁₄H₁₁F₃N₂OS, molecular weight 312.31, white or off-white powder-like reagent, structural formula:

the invention is described in further detail below with reference to specific experiments and associated results figures, which are intended to be illustrative, but not limiting, of the invention.

1.1 for the animal model of autism, a commonly used Shank3b monogene knock-out mouse was selected.

1.2 formulation of XAV 939: in order to ensure the accuracy of in vivo experimental results, the working solution of xav939 is recommended to be prepared and used on the same day. Weighing a certain mass of xav939, dissolving in 10% Dimethyl sulfoxide (DMSO), dissolving in 40% polyethylene glycol (300 peg), dissolving in 5% sorbitan monooleate polyoxyethylene ether (tween-80), and diluting with 45% physiological saline (the above percentages refer to the volume ratio of the solution in the prepared final solution, and dissolving can be promoted by ultrasonic or heating if precipitation or precipitation occurs during the preparation process.

1.3 methods of administering XAV 939: wherein the Anterior Cingulate Cortex (ACC) is considered a key brain region for integrating social information and regulating social behavior. Thus, XAV939 is injected into the brain area during administration, and the specific steps are as follows:

1) after the animal is anesthetized, the head of the animal is fixed on a brain stereotaxic instrument, the coordinates of a target brain area are positioned, a cranial drill or a dental drill is used for drilling holes, 2-3 small holes are drilled near the hole positions for fixing screws, and then a needle is used for slightly puncturing the dura mater.

2) The screw is fixed in the hole, and then the prepared catheter is slowly implanted into the cranium

3) After the animals recover for 2-3 days, the animals are anesthetized and then injected intracerebrally with the drug through a catheter.

4) After setting the injection amount (300 muL on one side) and the injection speed (30 muL/min) of the micro-injection pump, the micro-injection pump starts to inject the medicine into the brain of the mouse, and the needle is left for 10min after the injection is finished. After the medicine is fully absorbed, the injection in the brain area on the other side is continued, the injection inner tube is slowly pulled out after the completion, and the catheter cap is continuously inserted and locked. The mice are placed on a heating pad and placed back into the cage for feeding after waking up.

5) The preparation is administered continuously for 3 days according to the above procedures, with a daily dose of 600nl and a molar concentration of 20 μ M.

1.4 behavioral experiments

1) Three-box experiment: the autistic mice were first placed in the middle chamber for 10min, then the duration (time) and distance to move (duration) of the subsequent 10min autistic mice into the Social mouse-equipped chamber ("Social" chamber) or empty chamber ("Non-Social" chamber) were recorded and analyzed using SMART3.0 software (Panlab Harvard Apparatus, Spain), using the above parameters

As a measure of the preference score for sociability, a higher preference score indicates better sociability of the mouse.

2) Residence-invasion experiments: the autistic mouse is freely explored for 1min in the cage until adaptation, another young mouse which is obviously smaller than the autistic mouse is taken and introduced into the cage, and the contact time and frequency of each social behavior among the mice are recorded. The longer the contact time and the more frequent the contact time between the experimental mouse and the young mouse are, the better the social ability is shown.

1.5 specific Experimental procedures

1) The mice with autism knockout from Shank3b were treated with XAV939 reagent by continuous injection for 3 days.

2) Taking an autism mouse without medication as a control mouse, taking

experimental mice

24h, 3d and 7d after medication as 24h groups, 3d groups and 7d groups, wherein the number of the experimental mice in each group is 10, and carrying out three-box and residence-invasion behaviourology experiments.

3) And (4) counting the results of the behavioral experiments, and analyzing the change of social ability of the autism mouse over time after the drug is taken.

1.6 analysis of results

Referring to fig. 1, which is a heat map of behavior traces of mice in control, drug-treated 24h, 3d, and 7d groups in a three-box experiment, the more red color indicates more frequent activity at this location. From the results, it was found that the mice with autism treated with XAV939, Shank3 b-/-mice, started a great deal of research on social mice at the time of 3d administration and were able to remain until 7d after administration.

FIG. 2 shows the contact time of the control group and the

groups

24h, 3d and 7d after drug administration with the social mouse in three cases of experiments. From the results, it is clear that the xanv 939-treated Shank3 b-/-mice showed a significant increase in contact time with social mice after 3d, indicating a rapid improvement in the social potency of the autistic mice after administration of XAV 939.

FIG. 3 is a graph showing the preference factors of the control group and the

groups

24h, 3d and 7d after administration in three cases. The results show that the preference coefficient of the mice with autism treated by XAV939 is obviously improved after 3d, and the effectiveness of the medicament is also proved.

Fig. 4 shows the frequency of contact between the control group of residence-invasion experiment and the young mouse at 24h, 3d and 7d after administration, and the results show that the frequency of contact between the mice with autism treated with XAV939 and the young mouse is obviously increased after 3d, which indicates that the social ability of the mice with autism is improved.

The above-mentioned contents are only for illustrating the technical idea of the present invention, and the protection scope of the present invention is not limited thereby, and any modification made on the basis of the technical idea of the present invention falls within the protection scope of the claims of the present invention.

Claims

1. The application of a compound XAV939 in preparing a medicine for treating autism spectrum disorder is characterized in that the medicine is a medicine for improving social ability;

wherein the compound XAV939 has the molecular formula C₁₄H₁₁F₃N₂OS, structural formula as follows:

2. the use according to claim 1, wherein the animals of XAV939 are administered daily at a concentration of 20 μ M, at an amount of 600nl, for three consecutive days.

3. The use of claim 1, wherein the medicament is a medicament that increases social contact time and frequency.