Application of azelaic acid in preparation of product for treating autism spectrum disorder

Abstract

The invention belongs to the technical field of medicines, and particularly provides novel application of azelaic acid in preparation of a product for treating autism spectrum disorder (ASD). Experimental evaluation of an ASD mouse induced by valproic acid (VPA) proves that the total movement distance and the movement distance in a central area in an open field experiment can be remarkably increased, the time difference of interaction with a strange mouse and an empty cage or a new strange mouse is remarkably increased, and the number of embedded beads is reduced. Therefore, the azelaic acid provided by the invention can be applied to preparation of the product for treating ASD.

Description

Technical Field

[0001] The invention belongs to the field of medical technology and specifically discloses a use of azelaic acid in preparing a product for treating autism spectrum disorders. Background Art

[0002] Autism spectrum disorder (ASD) is a group of genetically heterogeneous neurobehavioral disorders characterized by impairments in three behavioral areas: communication, social interaction, and stereotyped repetitive behaviors. In addition, other comorbidities may occur, including: epilepsy; attention, mood, and language disorders; sleep disorders; gastrointestinal problems; intellectual disability. It is reported that the estimated prevalence of ASD in the United States has been increasing, from 1.1% in 2008 to 2.3% in 2018. In the United States, ASD affects about 2.3% of 8-year-old children and about 2.2% of adults. Compared with normal people, ASD patients have higher rates of depression (20% vs 7%), anxiety (11% vs 5%), sleep difficulties (13% vs 5%), and epilepsy (21% vs 0.8%). According to the "China ASD Education and Rehabilitation Industry Development Status Report", the current prevalence of ASD in my country is conservatively estimated to be 1%, and the number of ASD patients has exceeded 10 million. ASD seriously affects the normal life of patients and their families, and brings a huge burden to society. The cause of ASD is still unclear, and it may be related to factors such as genetics, early developmental environment, and abnormal brain structure development. Due to the limitations of current treatment methods, dietary intervention for ASD has received increasing attention. Finding safe and effective substances from natural products such as food to improve autism spectrum disorders has important clinical application value.

[0003] Azelaic acid, also known as azelaic acid, is a nine-carbon dicarboxylic acid that is widely found in cereals such as wheat, rye, and sorghum. In recent years, research on the biological activity of azelaic acid has mainly focused on its anti-inflammatory and antibacterial capabilities, and it has been approved by the U.S. Food and Drug Administration for the treatment of skin diseases with good safety and effectiveness. Existing studies have shown that azelaic acid can inhibit the mRNA expression and protein secretion of proinflammatory cytokines induced by ultraviolet rays, thereby exerting an anti-inflammatory effect. In addition, studies have shown that the antibacterial activity of azelaic acid is related to changes in the intracellular pH of bacterial cells. However, there are currently no reports on the preventive and therapeutic effects of azelaic acid on neurodevelopmental disorders such as ASD. Summary of the invention

[0004] The purpose of the present invention is to provide a new use of azelaic acid, specifically, to provide a new use of azelaic acid in preparing a product for treating autism spectrum disorder (ASD).

[0005] In order to achieve the above object, the technical solution adopted by the present invention is:

[0006] Use of azelaic acid in preparing a product for treating ASD.

[0007] Preferably, the azelaic acid can increase the total movement distance and the movement distance in the central area in the open field test, and improve the exploratory behavior.

[0008] Preferably, the azelaic acid can increase the time difference between interacting with a strange mouse and an empty cage or a new strange mouse in the three-box test, and improve social preference and social novelty preference.

[0009] Preferably, the azelaic acid can reduce the number of bead burying and improve repetitive stereotyped behaviors in ASD mice induced by valproic acid (VPA).

[0010] The present invention also provides a health food composition for improving ASD, comprising the azelaic acid described in any one of the above items, and an auxiliary material acceptable to food.

[0011] Preferably, the health food composition can increase the total movement distance and the movement distance in the central area in the open field test, increase the time difference of interaction with strange mice and empty cages or new strange mice, and reduce the number of buried beads.

[0012] The present invention also provides a pharmaceutical composition for treating ASD, comprising the azelaic acid described in any one of the above items, and a pharmaceutically acceptable excipient or carrier.

[0013] Preferably, the medicine can be an oral solution, powder, tablet, capsule or injection.

[0014] Compared with the prior art, the present invention has the following beneficial effects:

[0015] The present invention has discovered a new use of azelaic acid. Animal experimental results show that supplementing azelaic acid at an addition amount of 0.2% (w / w) for 17 weeks can significantly increase the total movement distance and the movement distance in the central area in the open field test, significantly increase the time difference in interaction with unfamiliar mice and empty cages or new unfamiliar mice, and reduce the number of buried beads, indicating that azelaic acid can treat VPA-induced ASD. The present invention provides a new use of azelaic acid in the preparation of related health foods and medicines that have the effect of treating VPA-induced ASD. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] Figure 1 Effect of azelaic acid on body weight of ASD mice.

[0017] Figure 2 The figure shows the effect of azelaic acid on body weight gain in ASD mice.

[0018] Figure 3These are the results of the open field experiment for three groups of mice; A is the trajectory diagram of the open field experiment, from left to right they are the SAL group, VPA group and AA group, B is the total movement distance, and C is the movement distance of the mice in the central area. * p<0.05, ** p<0.01.

[0019] Figure 4 These are the results of the three-box experiment with three groups of mice; A is the trajectory diagram of the social preference experiment in the three-box experiment, which includes the SAL group, VPA group and AA group from left to right; B is the interaction time of mice with stranger mouse No. 1 and the empty cage; C is the trajectory diagram of the social novelty preference experiment in the three-box experiment, which includes the SAL group, VPA group and AA group from left to right; D is the interaction time of mice with stranger mouse No. 1 and stranger mouse No. 2. * p<0.05, ** p<0.01.

[0020] Figure 5 These are the results of the bead-burying experiment on three groups of mice; A is a representative picture of the bead-burying experiment, from left to right they are the SAL group, VPA group and AA group, and B is the number of buried beads. * p<0.05.

[0021] Note: The present invention Figures 1 to 5 middle:

[0022] SAL represents the control group, which was fed AIN-93G growth diet;

[0023] VPA represents the model group, which was fed with AIN-93G growth feed;

[0024] AA represents the azelaic acid intervention group, which was fed with AIN-93G growth feed containing 0.2% (w / w) azelaic acid. DETAILED DESCRIPTION

[0025] The present invention is further described below in conjunction with the embodiments of the present invention and the accompanying drawings, but the protection scope of the present invention is not limited thereto.

[0026] Example 1

[0027] Effects of azelaic acid on body weight and weight gain in mice fed a high-fat diet

[0028] C57BL / 6J mice were housed under specific pathogen-free (SPF) conditions (ambient temperature 22±2°C, relative humidity 40-70%, 12h-12h light-dark cycle). At the beginning of the experiment, female C57BL / 6J mice aged 8-12 weeks were selected for mating with male mice of the same age. The next day, if vaginal plugs were found, mating was considered successful, and the gestational period of the female mice was recorded as 0.5 days. The pregnant female mice were housed separately. On the 12.5th day of pregnancy, some pregnant female mice were randomly selected to receive a single intraperitoneal injection of VPA solution (600 mg / kg), and the remaining pregnant female mice were given a single intraperitoneal injection of an equal volume of 0.9% sodium chloride solution. The offspring female mice were intervened at 7 weeks of age and were divided into a control group, a model group and azelaic acid intervention group. The offspring female mice born by female mice injected with sodium chloride solution were included in the control group, and the offspring female mice born by female mice injected with VPA solution were randomly included in the model group and the azelaic acid intervention group, with 8 mice in each group. The control group and the model group were fed with AIN-93G growth feed; the azelaic acid intervention group was fed with AIN-93G growth feed containing 0.2% (w / w) azelaic acid. The experimental period was 17 weeks, during which all mice had free access to food and water, and the weight of the mice was recorded weekly.

[0029] according to Figure 1 , 2 As shown, compared with the model group, azelaic acid supplementation had no significant effect on the body weight and weight gain of ASD mice.

[0030] Example 2

[0031] Effects of azelaic acid on the exploratory behavior of VPA-induced ASD mice

[0032] The mice fed for 7 weeks in Example 1 were subjected to an open field experiment. The specific steps of the open field experiment are as follows: the mice were placed in an open field of 40×40 cm, with the middle 20×20 cm area as the central area and the rest as the surrounding area. Each mouse was allowed to adapt to the environment for 5 minutes before the experiment. After the adaptation, the camera system was used to monitor and record the activities of the mice in the open field for 10 minutes, and trajectory tracking and data collection were performed to analyze the total movement distance, total activity time, and movement distance and time in the central area of ​​the mice. After the end, the mice were taken out, and before the next experiment, the mine area was wiped with 75% ethanol solution and dried. After all the data were measured, statistical analysis was performed.

[0033] according to Figure 3 As shown, compared with the control group, the total movement distance and movement distance in the central area of ​​the model group mice in the open field were significantly reduced, indicating that the exploratory behavior of ASD mice was reduced; azelaic acid supplementation can significantly increase the total movement distance and movement distance in the central area of ​​the mice in the open field, indicating that azelaic acid has the effect of improving the exploratory behavior of mice.

[0034] Example 3

[0035] Effects of azelaic acid on social preference and social novelty preference induced by VPA in ASD mice

[0036] The mice fed for 8 weeks in Example 1 were subjected to a three-box experiment. The experimental device consists of a 60×40 cm rectangular box, which is evenly divided into three spaces of 20×40 cm by a partition. There is a passage in the middle to connect the three boxes. A mouse cage is placed in the center of the left and right boxes, and the size should be large enough to accommodate a mouse. The specific steps of the three-box experiment are as follows: before the experiment begins, the test mouse is placed in the central area, the partition is opened to allow it to move freely, and the test mouse is taken out and put back into the original mouse cage after 10 minutes of adaptation, and the device is wiped clean with 75% alcohol. In the first stage of the experiment, in order to evaluate the social preference of mice, the No. 1 strange mouse (S1) is placed in the mouse cage on the left side of the three boxes, and the mouse is not placed on the right side, and the empty cage state (E) is maintained. The test mouse is placed in the central area, and the partition is opened to allow it to freely explore in the device for 10 minutes. The social time of the mouse with S1 and E and its behavioral trajectory in the three-box device are recorded respectively. After the first stage of the experiment, the test mouse is taken out and put back into the original mouse cage, and the device is wiped clean with 75% alcohol. In the second stage of the experiment, in order to evaluate the social novelty preference of mice, the No. 2 stranger mouse (S2) was placed in the mouse cage on the right side of the three boxes, and the test mice were placed in the central area. The partition was opened to allow them to freely explore the device for 10 minutes. The social time of the mice with S1 and S2 and their behavioral trajectories in the three-box device were recorded respectively. After the second stage of the experiment, the test mice were taken out and put back into the original mouse cage, and the device was wiped clean with 75% alcohol.

[0037] according to Figure 4 As shown, in the first stage of the three-box experiment, the social time of the control group mice with the strange mice was significantly increased compared with the social time with the empty cage, showing a strong social preference for the strange mice, while the social time of the model group mice with the empty cage and the strange mice was similar, and there was no preference; after azelaic acid supplementation, the mice showed a longer exploration and communication with the strange mice, indicating that azelaic acid improved the social preference of mice. In the second stage of the three-box experiment, the control group mice showed a greater preference for the new strange mice, and a lower preference for the strange mice after the first stage of contact. There was no significant difference in the social time of the model group mice with the new strange mice and the strange mice after the first stage of contact; after azelaic acid supplementation, the mice showed a higher preference for the new strange mice than the strange mice after the first stage of contact, indicating that azelaic acid improved the social novelty preference of mice. The above results show that azelaic acid has the effect of improving the social preference and social novelty preference of mice.

[0038] Example 4

[0039] Effects of azelaic acid on repetitive stereotypic behaviors in ASD mice induced by valproic acid (VPA)

[0040] The mice fed for 9 weeks in Example 1 were subjected to a bead-burying experiment. The specific steps of the bead-burying experiment are as follows: a cage of 42.5 cm × 26.5 cm × 19 cm is placed in the test room, in which a 5 cm thick wood shavings bedding (about 150 g) is laid and flattened. The mouse to be tested is gently placed in the cage to adapt for 10 minutes (without marbles), and then the mouse is placed back in the original mouse cage. 20 black glass marbles with a diameter of 14 mm are evenly placed in the test cage in a 4×5 manner, and then the mouse is put back in. After the mouse is allowed to move freely in the test cage for 30 minutes, the mouse is taken out and placed in the original mouse cage. Take pictures to record the experimental results, and find three experimenters to calculate the number of buried beads of the mouse (judgment criteria: the bedding covers 1 / 2 of the area of ​​the marbles). In order to eliminate the potential bias caused by the odor clues left by the previous experimental mice, the marbles and rat cages are cleaned with 75% ethanol solution before each test, wiped clean and set aside. The more buried beads, the more severe the repetitive stereotyped behavior of the mouse.

[0041] according to Figure 1 As shown, compared with the control group, the mice in the model group showed more bead-burying behavior, indicating that the repetitive stereotyped behavior of ASD mice is serious; azelaic acid supplementation can reduce the number of bead-burying mice, indicating that azelaic acid has the effect of improving the repetitive stereotyped behavior of mice.

[0042] Example 2

[0043] The present invention is not limited to the above-mentioned embodiments. Without departing from the essential content of the present invention, any deformation, improvement and substitution that can be conceived by those skilled in the art shall fall within the scope of the present invention.

Claims

1. Use of azelaic acid in the preparation of products for treating autism spectrum disorder (ASD).

2. The use according to claim 1, characterized in that The azelaic acid can treat autism spectrum disorder (ASD) induced by valproic acid (VPA), and 3,3-dimethylglutaric acid can improve the behavioral characteristics of the treated subjects.

3. The use according to claim 2, characterized in that: The azelaic acid can improve the exploratory behavior of ASD mice.

4. The use according to claim 2, characterized in that: The azelaic acid can improve the social preference and social novelty preference of ASD mice.

5. The use according to claim 2, characterized in that: The azelaic acid can improve the repetitive stereotyped behaviors of ASD mice.

6. The use according to claim 1, characterized in that: The product is a health food composition or a pharmaceutical composition.

7. A health food composition for preventing ASD, characterized in that: The invention comprises the azelaic acid according to any one of claims 1 to 5, and an auxiliary material acceptable to food.

8. The health food composition according to claim 7, characterized in that The health food composition can increase the total movement distance and the movement distance in the central area of ​​mice in an open field test, increase the time difference of interaction with strange mice and empty cages or new strange mice, and reduce the number of buried beads.

9. A pharmaceutical composition for preventing ASD, characterized in that: It comprises the azelaic acid according to any one of claims 1 to 5, and a pharmaceutically acceptable auxiliary material or carrier.

10. The drug for preventing ASD according to claim 9, characterized in that The medicine can be oral solution, powder, tablet, capsule or injection.

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