Application of neomangiferin in preparation of anti-depression drugs

Abstract

The invention belongs to the technical field of medical application, and particularly relates to application of neomangiferin in preparation of an anti-depression drug, experiments find that the effect of neomangiferin is obviously better than that of mangiferin, although the neomangiferin and the mangiferin have the same main structure, the inventor finds that the effects of the neomangiferin and the mangiferin have obvious difference, and the effect of the neomangiferin and the mangiferin is obviously different. The compound is unexpected by the inventor before experiments, a new optional medicine is provided for research and development of anti-depression, and the effect of the anti-depression medicine is effectively improved.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of medical purposes, and particularly relates to a use of neomangiferin in preparation of an antidepressant. BACKGROUND

[0002] Neomangiferin is a natural flavonoid compound with a molecular formula of C 25 H 28 O 16 , a 7-O-glucoside derivative of mangiferin, and belongs to the double glucosyl xanthene ketone compound. It mainly exists in the rhizome of Anemarrhena asphodeloides. It can reduce the level of cellular reactive oxygen species (ROS), improve the activity of superoxide dismutase (SOD), and reduce oxidative damage. It can improve non-alcoholic fatty liver disease (NAFLD) induced by high-fat diet, inhibit the activity of osteoclasts, prevent and treat osteolysis diseases (such as osteoporosis), reduce sorbitol accumulation and urinary protein excretion in diabetic animal models, and delay kidney lesions.

[0003] There is no literature to prove that neomangiferin has an antidepressant effect. Mangiferin exerts antidepressant and neuroprotective effects by acting on NLRP3 inflammasome. Zhang Lei et al. (Journal of Hebei University (Natural Science Edition), 2021, Vol. 41, No. 3) disclosed the treatment effect and mechanism of mangiferin on chronic unpredictable mild stress depression rats. However, neomangiferin is a 7-O-glucoside derivative of mangiferin, and there is no evidence to show that neomangiferin also has the above-mentioned depression inhibiting effect. SUMMARY

[0004] The technical problem to be solved by the present application is to provide a use of neomangiferin in preparation of an antidepressant, and to provide a drug with better antidepressant effect.

[0005] The embodiment of the present application provides a use of neomangiferin in preparation of an antidepressant.

[0006] Preferably, the dosage form of the antidepressant is a tablet, an injection, a capsule, a solution or a granule.

[0007] Preferably, the antidepressant contains a pharmaceutically acceptable excipient.

[0008] Preferably, the excipient includes a filler, a binder, a disintegrant, a lubricant, a preservative, a colorant, a sustained-release agent, a stabilizer, an emulsifier, an osmotic pressure regulator, a wetting agent, a glidant or a coating material.

[0009] The beneficial effects of the present application are that the present application finds that the effect of new mangiferin is obviously better than that of mangiferin through experiments, although both have the same main structure, but the inventors find that the effects of the two are obviously different, which is unexpected before the experiments, and it brings new optional drugs for the research and development of anti-depression, and effectively improves the effect of anti-depression drugs. DETAILED DESCRIPTION

[0010] Embodiment 1 1.1 Experimental materials 1.1.1 Main reagents The main reagents include new mangiferin, fluoxetine hydrochloride capsules, methanol, ammonium formate, acetonitrile, Nissl staining solution, hematoxylin-eosin staining solution, IL-6 kit, TNF-α kit, IL-1β kit, apoptosis kit, BCA kit, CCK-8 kit, 4% paraformaldehyde general tissue fixing solution, anhydrous ethanol 1.1.2 Main solutions and buffers Preparation of new mangiferin solution: 9 mg of new mangiferin powder was dissolved in 90 μL of DMSO, and 9 mL of normal saline (NS) was added for dissolution to prepare a new mangiferin solution with a concentration of 1 mg / mL.

[0011] Preparation of fluoxetine hydrochloride solution: 10 mg of drug powder was added to 10 mL of pure water for dissolution to prepare a fluoxetine hydrochloride solution with a concentration of 1 mg / mL.

[0012] Preparation of mangiferin solution: 9 mg of mangiferin powder was dissolved in 90 μL of DMSO, and normal saline was added for dissolution to prepare a solution with a concentration of 1 mg / mL.

[0013] 1.2 Experimental methods 1.2.1 Experimental animals SPF level male C57BL / 6 mice aged 8-10 weeks were purchased from Hunan Slike Jingda Experimental Animal Co., Ltd. and were raised in the Experimental Animal Center of Hunan University of Chinese Medicine under the conditions of room temperature (22±2) ℃, free access to feed and water, and adaptive feeding in a 12 h / 12 h light-dark cycle environment for 7 days. The animal experiments were approved by the Experimental Animal Ethics Committee of Hunan University of Chinese Medicine (No. SLBH-202307110001).

[0014] 1.2.2 Animal grouping and model establishment 70 C57BL / 6J mice were randomly divided into 7 groups (10 mice / group) according to body weight: blank control group, model group (CUMS), fluoxetine group (10 mg / kg), mangiferin group (5.0 mg / kg), new mangiferin high-dose group (NG-H, 10 mg / kg), new mangiferin medium-dose group (NG-M, 5.0 mg / kg), and new mangiferin low-dose group (NG-L, 2.5 mg / kg).

[0015] After one week of adaptive feeding, all mice except those in the blank control group were subjected to chronic unpredictable stress (CUMS) modeling. A total of 9 stress stimuli were used, including: (1) water deprivation for 24 h, (2) restraint for 6 h, (3) horizontal shaking for 20 min, (4) wet bedding for 24 h, (5) 4°C ice water swimming for 2 min, (6) noise for 1 h, (7) food deprivation for 24 h, (8) tail clamping for 2 min, and (9) no bedding for 24 h. The modeling time was 35 days, with one stimulus per day and no repetition within 3 days.

[0016] Drug administration began on the first day of modeling, and the dosages were as follows: (1) Fluoxetine group mice were given intragastrically 10 mg / kg of fluoxetine hydrochloride solution once a day. (2) The mangiferin group was given intragastrically at a dose of 5 mg / kg, with intraperitoneal injection once every 2 days. (3) The new mangiferin low, medium, and high-dose groups were given intraperitoneal injections at doses of 2.5 mg / kg, 5 mg / kg, and 10 mg / kg, respectively, once every 2 days. The control and model groups were given pure water daily, with intraperitoneal injection of normal saline once every 2 days.

[0017] 1.2.3 Tail suspension test The animals were gently removed from the cage, and medical tape was wrapped around the tip of the mouse tail 1 cm from the end. The mouse was then hung from the hook of the tail suspension box. No additional stress should be caused to the mouse during the operation. After hanging, the mouse was placed in a head-down position, and the test lasted for 6 min (2 min of adaptation and 4 min of testing). The immobility time of the mouse was recorded.

[0018] 1.2.4 Open field test The open field test is mainly used to evaluate the anxiety behavior, exploration behavior, and motor activity of experimental animals (such as rats or mice). The mouse open field test device specifications are: 50 cm*50 cm*40 cm. Before the experiment, the mice were placed in the detection laboratory for 1-2 h to adapt and check whether the experimental box was clean and odorless. During the experiment, the mice were gently taken out of the feeding cage, placed in the center with their backs to the box wall, and then immediately recorded the activity of the mice in the box within 5 min. After each mouse completed the experiment, the experimental box was sprayed with 75% alcohol to remove the odor and wiped clean with a paper towel to avoid the influence of animal odor on the experiment.

[0019] 1.2.5 Morris water maze experiment The mouse Morris water maze device consists of a circular pool with a diameter of 120 cm and a platform with adjustable height. The water maze area is divided into four quadrants, and the second quadrant is set as the target quadrant and the fourth quadrant as the initial quadrant. After modeling, each group of mice first undergoes 3 days of continuous water maze learning and training, with a fixed time of 8:00 to 12:00. A suitable amount of edible alum is sprinkled in the pool to make the pool background white, which facilitates the recording of the mouse's whereabouts. During the training period, a circular platform with a diameter of 6 cm is placed in the second quadrant, 1-2 cm above the water surface. The mice are placed in the water from different quadrants facing the pool wall, and allowed to explore freely for 1 min. If the mouse successfully finds and climbs onto the platform within 1 min, it is allowed to stay for 5 s. If the mouse fails to find the platform within 1 min, it is guided to the platform and stays for 30 s. On the fourth day, the positioning navigation experiment is conducted, and the mouse is placed in the water from the fourth quadrant facing the pool wall, and its whereabouts are recorded for 1 min. The time when the mouse successfully reaches the platform is defined as the escape latency. On the fifth day, the platform is removed, and the spatial exploration experiment is conducted. The mouse is placed in the water from the fourth quadrant facing the pool wall, and the mouse's swimming trajectory, target quadrant latency, target quadrant swimming time, and platform crossing times are recorded within 1 min.

[0020] 1.2.6 Forced swimming test The cylindrical water tank (30 cm high, 20 cm in diameter) required for the mouse forced swimming test is made of transparent organic glass, and the water level is 15 cm from the bottom to ensure consistent water volume for all mice during the experiment. The mouse is placed alone in the water tank, ensuring that the mouse's nose is above the water level. First, the mouse is allowed to swim adaptively for 2 min, and then the mouse's immobile time (hunched and upright, passive floating, nose above the horizontal plane) is observed and recorded for the next 4 min. During the experiment, ensure that mice in the same period cannot see each other to reduce interference. After the experiment, the mouse is taken out of the water tank, dried with a towel, and placed back in the cage.

[0021] 1.2.7 Hematology test After the behavioral experiment, the mouse is anesthetized, and the orbital blood is collected. The serum and plasma are separated by centrifugation, and the hippocampal tissue is taken out on ice. According to the instructions in the 5-HT kit, the absorbance value (OD value) of each well at 450 nm wavelength is measured using a microplate reader.

[0022] 1.2.8 Statistical analysis Statistical analysis was performed using SPSS 25.0 software, and (x ± S) was used for representation. Single factor analysis of variance was used for comparison between groups, and LSD and Dunett methods were used for multiple comparisons between groups. P<0.05 was considered statistically significant. Column charts were completed using Graph Pad Prism 9.4.0.

[0023] 1.3 Experimental results 1.3.1 Effect of new mangiferin on forced swimming test in CUMS mice Compared with the blank group, the swimming immobility time of the model group mice was significantly increased (P<0.01); compared with the model group, the swimming immobility time of the positive drug group and the new mangiferin high, medium and low dose groups was significantly reduced (P<0.01 or P<0.01). Compared with the mangiferin group, the swimming immobility time of the new mangiferin high dose group was significantly reduced (P<0.05). This indicates that new mangiferin helps to improve the despair mood of depressed model mice. See Table 1.

[0024] Table 1 Changes in swimming immobility time of mice in each group (n=10)

[0025] Note: compared with the control group, P P<0.05, P P<0.01; compared with the model group, △ P P<0.05; △△ P P<0.01; compared with the mangiferin group, # P P<0.05; ## P P<0.01.

[0026] 1.3.2 Effect of new mangiferin on tail suspension test in CUMS mice Compared with the blank group, the tail suspension immobility time of the model group mice was significantly reduced (P<0.01); compared with the model group, the immobility time of the fluoxetine group and the new mangiferin high and medium dose groups was significantly reduced (P<0.01 or P<0.05), and the immobility time of the mangiferin group was significantly reduced (P<0.05); compared with the mangiferin group, the immobility time of the new mangiferin high dose group was reduced, but the difference was not statistically significant. See Table 2.

[0027] Table 2 Changes in tail suspension immobility time of mice in each group (n=10)

[0028] Note: compared with the control group, P<0.05, P <0.01; compared with the model group, △ P <0.05; △△ P <0.01; compared with the mangiferin group, # P <0.05; ## P <0.01.

[0029] 1.3.3 Effect of new mangiferin on the open field test of CUMS mice Compared with the blank group, the total distance in the central area and the number of times crossing the central area of the model group mice were significantly reduced (P <0.01); compared with the model group, the total distance in the central area of the positive drug group and the high and medium dose groups of new mangiferin mice was significantly increased (P <0.01 or P <0.05), and the number of times crossing the central area was significantly increased (P <0.01 or P <0.05); compared with the mangiferin group, the number of times crossing the central area of the high dose group of new mangiferin mice was significantly increased, and the difference was not statistically significant.

[0030] Table 3 Behavioral changes of mice in the open field test in each group (n=10)

[0031] Note: compared with the control group, P <0.05, P <0.01; compared with the model group, △ P <0.05; △△ P <0.01; compared with the mangiferin group, # P <0.05; ## P <0.01.

[0032] 1.3.4 Effect of new mangiferin on the water maze test of CUMS mice The positioning navigation stage display, compared with the blank group, the model group of mice escape latency significantly increased (P<0.01); compared with the model group, fluoxetine group and new mango glycoside high, medium dose group of mice escape latency decreased (P<0.05), target quadrant swimming distance increased (P<0.01). The results of space exploration stage show that, compared with the blank group, the model group of mice target quadrant swimming distance significantly reduced (P<0.01 or P<0.01), while the target quadrant latency increased (P<0.01); compared with the model group, fluoxetine group and new mango glycoside high, medium dose group of mice target quadrant swimming distance significantly increased (P<0.01), target quadrant latency significantly reduced (P<0.01). In addition, compared with mango glycoside group, new mango glycoside can significantly reduce the escape latency of model mice (P<0.05), while also can increase the target quadrant swimming distance of model mice (P<0.01), reduce the target quadrant latency (P<0.01).

[0033] Table 4 Changes of cognitive function of mice in each group , n=10)

[0034] Note: compared with the control group, P P<0.05,** P P<0.01; compared with the model group, △ P P<0.05; △△ P P<0.01; compared with the mango glycoside group, # P P<0.05; ## P P<0.01.

[0035] 1.3.5 Effect of new mango glycoside on blood 5-hydroxytryptamine of CUMS mice Compared with the blank group, the content of 5-hydroxytryptamine of model group of mice was significantly reduced (P<0.01); compared with the model group, the content of 5-hydroxytryptamine of positive drug group and new mango glycoside high, medium dose group of mice was significantly increased (P<0.01 or P<0.05); compared with the mango glycoside group, the content of 5-hydroxytryptamine of new mango glycoside high dose group of mice was significantly increased (P<0.05).

[0036] Table 5 Changes of serum 5-HT of mice in each group , n=10)

[0037] Note: compared with the control group, P P<0.05,** P P<0.01; compared with the model group, △P <0.05; △△ P <0.01; compared with mangiferin, # P <0.05; ## P <0.01.

[0038] From Tables 1-5, it can be seen that the effect of the new mangiferin is obviously better than that of mangiferin, although they have the same main structure, but the inventors found that the effects of the two are obviously different, which is unexpected before the experiment, and it brings new optional drugs for the research and development of anti-depression, and effectively improves the effect of anti-depression drugs.

[0039] Those skilled in the art will understand that the above discussion of any embodiment is merely exemplary in nature and is not intended to suggest that the scope of the application, as claimed, is limited to these examples, determinations, or embodiments. Under the teachings of the application, any of the examples or technical features of the embodiments may be combined, and steps may be implemented in any order, and there are many other variations of the different aspects of the application as described above, which are not listed in detail. In order to be brief, they are not provided in detail.

[0040] One or more embodiments of the present application are intended to cover all such alternatives, modifications, and variations as fall within the broad scope of the application. Therefore, any omission, modification, equivalent replacement, improvement, etc. made within the spirit and principles of one or more embodiments of the present application should be included in the scope of the present application.

Claims

1. Use of a new mangiferin in the preparation of an antidepressant drug.

2. The use according to claim 1, characterized in that, The dosage form of the antidepressant drug is a tablet, an injection, a capsule, a solution or a granule.

3. The use according to claim 1, characterized in that, The antidepressant drug contains a pharmaceutically acceptable excipient.

4. Use according to claim 3, characterized in that, The excipient includes a filler, a binder, a disintegrant, a lubricant, a preservative, a colorant, a sustained-release agent, a stabilizer, an emulsifier, an osmotic pressure adjusting agent, a wetting agent, a glidant or a coating material.

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