Use of 3,3-dimethylglutaric acid in the manufacture of a product for the treatment of autism spectrum disorders

Abstract

The application belongs to the technical field of medicine, and specifically provides a new use of 3,3-dimethyl pentandioic acid in preparation of a product for treating autism spectrum disorder (ASD). The ASD mouse experiment induced by valproic acid (VPA) proves that the 3,3-dimethyl pentandioic acid can significantly increase the total movement distance and total activity time in an open field experiment, the movement distance and time in a central area, the time difference of interaction with a strange mouse and an empty cage or a new strange mouse, and the number of buried beads. Therefore, the 3,3-dimethyl pentandioic acid can be applied to preparation of a product for treating ASD.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of medicine, and specifically discloses a use of 3,3-dimethylglutaric acid in preparation of a product for treating autism spectrum disorder. BACKGROUND

[0002] Autism spectrum disorder (ASD) is a group of heterogeneous genetic neurobehavioral disorders, which is characterized by disorders in three behavior domains of communication, social interaction and stereotyped repetitive behavior. In addition, other comorbidities may also occur, including: epilepsy; attention, emotional 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, and ASD patients have a higher incidence of depression (20% vs 7%), anxiety (11% vs 5%), sleep difficulties (13% vs 5%) and epilepsy (21% vs 0.8%) compared with normal people. According to the China ASD Education and Rehabilitation Industry Development Report, the current ASD prevalence rate in China 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 the society. The cause of ASD is not clear, which may be related to genetic, early environmental and abnormal brain structure development factors. Due to the limitations of current treatment methods, dietary intervention for ASD is attracting more and more attention, and it is of important clinical application value to find safe and effective substances for improving autism spectrum disorder from natural products such as food.

[0003] 3,3-dimethylglutaric acid belongs to a kind of methyl branched fatty acid. Methyl branched fatty acids are widely present in animal fat and milk. When studying the influence of the structure of silver-containing polymer on antibacterial activity, the silver-containing polymer designed from 3,3-dimethylglutaric acid has antibacterial activity against Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa and Candida albicans. At present, there is no report on the prevention and treatment effect of 3,3-dimethylglutaric acid on ASD and other neurodevelopmental disorders. SUMMARY

[0004] The purpose of the present application is to provide a new use of 3,3-dimethylglutaric acid, and specifically to provide a use of 3,3-dimethylglutaric acid in preparation of a product for treating autism spectrum disorder (ASD).

[0005] In order to achieve the above purpose, the technical scheme adopted by the present application is as follows:

[0006] 3,3-dimethylglutaric acid for use in the preparation of a product for treating ASD.

[0007] Preferably, the 3,3-dimethylglutaric acid can increase the total distance of movement, the total time of activity, the distance of movement and the time of activity in the central area in the open field test, and improve the exploratory behavior.

[0008] Preferably, the 3,3-dimethylglutaric acid can increase the difference in the time of interaction with a strange mouse and an empty cage or a new strange mouse in the three-box test, improve the social preference and the social novelty preference.

[0009] Preferably, the 3,3-dimethylglutaric acid can reduce the number of beads buried by the VPA-induced ASD mice, and improve the repetitive stereotyped behavior.

[0010] The present application also provides a pharmaceutical composition for treating ASD, which comprises the 3,3-dimethylglutaric acid according to any one of the above, and a pharmaceutically acceptable adjuvant or carrier.

[0011] Preferably, the medicine can be an oral liquid, a powder, a tablet, a capsule or an injection.

[0012] Compared with the prior art, the present application has the following beneficial effects:

[0013] The present application finds a new use of 3,3-dimethylglutaric acid. The animal experiment results show that: supplementing 3,3-dimethylglutaric acid at an addition amount of 0.2% (w / w) for 17 weeks can significantly increase the total distance of movement and the total time of activity in the open field test, and the distance of movement and the time in the central area, increase the difference in the time of interaction with a strange mouse and an empty cage or a new strange mouse, and reduce the number of beads buried, indicating that 3,3-dimethylglutaric acid can treat VPA-induced ASD. The present application provides a new use of 3,3-dimethylglutaric acid in the preparation of related medicines with the effect of treating VPA-induced ASD. BRIEF DESCRIPTION OF DRAWINGS

[0014]

[0015] Figure 1 The effect of 3,3-dimethylglutaric acid on the body weight of ASD mice.

[0016] Figure 2 The effect of 3,3-dimethylglutaric acid on the increase in the body weight of ASD mice.

[0017] Figure 3 The open field test results of the three groups of mice; wherein A is the open field test trajectory diagram, from left to right, the SAL group, the VPA group and the DA group, B is the total distance of movement, C is the total time of activity, D is the distance of movement of the mice in the central area, and E is the time of movement of the mice in the central area.​* p<0.05, ** p<0.01, *** p<0.001.

[0018] Figure 4 The results of the three-box experiment for three groups of mice; among them, A is the trajectory graph of the social preference experiment in the three-box experiment, from left to right, SAL group, VPA group and DA group, B is the interaction time of the mouse with No. 1 strange mouse and empty cage, C is the trajectory graph of the social novelty preference experiment in the three-box experiment, from left to right, SAL group, VPA group and DA group, D is the interaction time of the mouse with No. 1 strange mouse and No. 2 strange mouse. * p<0.05, ** p<0.01.

[0019] Figure 5 The results of the three groups of mice burying beads experiment; among them, A is a representative picture of the burying beads experiment, from left to right, SAL group, VPA group and DA group, B is the number of burying beads. * p<0.05.

[0020] Note: in the present application Figures 1-5

[0021] SAL represents the control group, fed with AIN-93G growth feed;

[0022] VPA represents the model group, fed with AIN-93G growth feed;

[0023] DA represents the 3,3-dimethyl glutaric acid intervention group, fed with AIN-93G growth feed containing 0.2% (w / w) 3,3-dimethyl glutaric acid. DETAILED DESCRIPTION

[0024] The present application will be further described below in conjunction with the embodiments of the present application and the drawings. However, the protection scope of the present application is not limited to this.

[0025] Example 1

[0026] Effect of 3,3-dimethyl glutaric acid on body weight and body weight gain of ASD mice

[0027] ​C57BL / 6J mice were raised under specific pathogen-free (SPF) conditions (ambient temperature 22±2℃, relative humidity 40-70%, 12h-12h light-dark cycle). At the beginning of the experiment, 8-12-week-old female C57BL / 6J mice were selected and caged with male mice of the same age for mating. The next day, if a vaginal plug was found, it was considered successful mating, and the female mice were recorded as 0.5 days of gestation, and the pregnant female mice were raised separately. On the 12.5th day of gestation, a portion of the pregnant female mice were randomly selected and given a single intraperitoneal injection of VPA solution (600mg / kg), and the rest of the pregnant female mice were given a single intraperitoneal injection of the same volume of 0.9% sodium chloride solution. The female offspring of the mice were intervened at 7 weeks of age, divided into control group, model group and 3,3-dimethylglutaric acid intervention group, and the female offspring of the mice injected with sodium chloride solution were included in the control group, and the female offspring of the mice injected with VPA solution were randomly included in the model group and the 3,3-dimethylglutaric acid intervention group, 8 in each group. The control group and the model group were fed with AIN-93G growth feed; the 3,3-dimethylglutaric acid intervention group was fed with AIN-93G growth feed containing 0.2% (w / w) 3,3-dimethylglutaric acid. The experimental period was 17 weeks, during which all mice had free access to food and water, and the body weight of the mice was recorded every week.

[0028] According to Figure 1 , 2 Compared with the model group, 3,3-dimethylglutaric acid supplementation had no significant effect on the body weight and body weight gain of ASD mice.

[0029] Example 2

[0030] Effect of 3,3-dimethylglutaric acid on exploration behavior of VPA-induced ASD mice

[0031] The mice fed for 7 weeks in Example 1 were subjected to the open field test. The specific steps of the open field test were as follows: the mice were placed in a 40×40cm open field, and the middle 20×20cm area was divided into a central area, and the rest was a peripheral area. Each mouse was adapted to the environment for 5min before the experiment. After the adaptation, the activity of the mice in the open field was recorded for 10min using a camera system for tracking and data collection, and the total movement distance, total activity time, and movement distance and time in the central area of the mice were analyzed. After the experiment, the mice were taken out, the open field area was wiped with 75% ethanol solution and dried before the next experiment, and all data were measured for statistical analysis.

[0032] According to Figure 3As shown, compared with the control group, the total movement distance in the open field, the movement distance and time in the central area of the model group mice were significantly reduced, and the total activity time was reduced but not significantly different, indicating that the exploration behavior of ASD mice was reduced; 3,3-dimethylglutaric acid supplementation can significantly increase the total movement distance of mice in the open field, the total activity time, and the movement distance and time in the central area, indicating that 3,3-dimethylglutaric acid has the effect of improving the exploration behavior of mice.

[0033] Example 3

[0034] Effect of 3,3-dimethylglutaric acid on social preference and social novelty preference of VPA-induced ASD mice

[0035] The mice fed for 8 weeks in Example 1 were subjected to a three-chamber experiment. The experimental device consisted of a 60x40cm rectangular box, which was equally divided into three spaces of 20x40cm in size by a partition, with a passage connecting the three chambers, and a mouse cage was placed in the center of the left and right chambers, large enough to accommodate one mouse. The specific steps of the three-chamber experiment: before the experiment, the test mouse was placed in the central area, the partition was opened to allow it to freely explore, and after 10 minutes, the test mouse was taken out and placed back in the original mouse cage, and the device was cleaned with 75% alcohol. In the first stage of the experiment, to evaluate the social preference of the mice, a No. 1 stranger mouse (S1) was placed in the mouse cage on the left side of the three-chamber, and the right side was left empty (E), the test mouse was placed in the central area, and the partition was opened to allow it to freely explore the device for 10 minutes, and the social time of the mouse with S1 and E and its behavior trajectory in the three-chamber device were recorded. After the first stage of the experiment, the test mouse was taken out and placed back in the original mouse cage, and the device was cleaned with 75% alcohol. In the second stage of the experiment, to evaluate the social novelty preference of the mice, No. 2 stranger mouse (S2) was placed in the mouse cage on the right side of the three-chamber, and the test mouse was placed in the central area, and the partition was opened to allow it to freely explore the device for 10 minutes, and the social time of the mouse with S1 and S2 and its behavior trajectory in the three-chamber device were recorded. After the second stage of the experiment, the test mouse was taken out and placed back in the original mouse cage, and the device was cleaned with 75% alcohol.

[0036] According to Figure 4As shown, in the first phase of the three-chamber experiment, the control group mice showed a significant increase in social time with the empty cage compared with the strange mice, showing a strong social preference for the strange mice, while the model group mice showed similar social time with the empty cage and the strange mice, and there was no preference; After 3,3-dimethylglutaric acid supplementation, the mice showed longer exploration and communication with the strange mice, indicating that 3,3-dimethylglutaric acid improved the social preference of mice. In the second phase of the three-chamber experiment, the control group mice showed a greater preference for new strange mice, while the preference for the strange mice after the first phase of contact was lower, and the model group mice showed no significant difference in social time with new strange mice and strange mice after the first phase of contact; After 3,3-dimethylglutaric acid supplementation, the mice showed a higher preference for new strange mice than the strange mice after the first phase of contact, indicating that 3,3-dimethylglutaric acid improved the social novelty preference of mice. The above results show that 3,3-dimethylglutaric acid has the effect of improving the social preference and social novelty preference of mice.

[0037] Example 4

[0038] Effect of 3,3-dimethylglutaric acid on repetitive stereotypy of valproic acid (VPA)-induced ASD mice

[0039] The mice fed for 9 weeks in Example 1 were subjected to the marble burying experiment. The specific steps of the marble burying experiment are as follows: a cage box of 42.5 cm x 26.5 cm x 19 cm is placed in the test room, and a thickness of 5 cm of shaving wood bedding (about 150 g) is laid flat. Gently place the test mouse into the cage box for 10 minutes (without marbles), then put the mouse back into the original mouse cage. Place 20 black glass marbles, each with a diameter of 14 mm, in the test cage in a 4 x 5 pattern, then reinsert the mouse into the test cage and allow the mouse to freely move in the test cage for 30 minutes, then remove the mouse and place it into the original mouse cage. Take a photo to record the experimental results, and find three experimenters to count the number of marbles buried by the mouse (judgment standard: 1 / 2 of the area of the marbles covered by the bedding). In order to eliminate the potential bias caused by the odor clues left by the previous experimental mice, clean the marbles and rat cage with 75% ethanol solution before each test, and then wipe them clean for use. The more marbles buried, the more severe the repetitive stereotypy of the mouse.

[0040] According to Figure 5 As shown, compared with the control group, the model group mice showed more marble burying behavior, indicating that the repetitive stereotypy of ASD mice was severe; 3,3-dimethylglutaric acid supplementation can significantly reduce the number of marbles buried by mice, indicating that 3,3-dimethylglutaric acid has the effect of improving the repetitive stereotypy of mice.

[0041] The present application is not limited to the above-described embodiments, and any modification, improvement, replacement that can be conceived by those skilled in the art without departing from the essential content of the present application falls within the scope of the present application.

Claims

1,3,3-Dimethylglutaric acid in the preparation of drugs for the treatment of autism spectrum disorder.

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

3. The use according to claim 1, characterized in that, The drug is an oral liquid, powder, tablet, capsule, or injection.

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