WO2020168760A1 - Use of albiflorin in preparation of drugs for rapidly treating depression - Google Patents

Abstract

Provided is use of albiflorin or pharmaceutically acceptable salts thereof, or extracts containing albiflorin or pharmaceutically acceptable salts thereof in preparation of drugs, foods, healthcare products, food additives or nutritional supplements for rapidly treating depression by inhibiting an NMDA receptor. Also provided is use of albiflorin or pharmaceutically acceptable salts thereof, or extracts containing albiflorin or pharmaceutically acceptable salts thereof in preparation of NMDA receptor inhibitors. In addition, also provided is a method for rapidly treating depression by inhibiting an NMDA receptor. Compared with various rapid-acting anti-depression drugs under development such as ketamine, NMDA receptor inhibitors, albiflorin and pharmaceutically acceptable salts thereof are safer, do not yield any mental side effect such as dissociation and hallucination, and likewise do not have the hidden trouble of addiction.

Description

Application of paeoniflorin in preparing medicine for rapid treatment of depression Technical field

The invention belongs to the field of medicine, and relates to the use of Albiflorin to rapidly treat depression, and more specifically to the use of Albiflorin as an N-methyl-D-aspartate receptor (NMDAR) inhibitor. And its use as an N-methyl-D-aspartate receptor (NMDAR) inhibitor for rapid treatment of depression.

Background technique

Depression is a common neurodegenerative disease, which is easily disabled and may lead to suicide. Although conventional antidepressants have a certain effect, they have a slow onset of action, and usually take 2 to 4 weeks to improve symptoms. Simon et al. found that due to the slow onset of antidepressant drugs, the risk of suicide in patients was significantly increased. This phenomenon has been confirmed by other studies. Biological studies on suicide in depression have found that the level of 5-HT and its metabolite 5-hydroxyindole acetic acid in the brainstem of suicides is low, which quickly resists depression and effectively regulates 5-HT and its metabolite 5-hydroxyl The level of indole acetic acid can reduce the chance of suicide ("Suicide: An Unnecessary Death" P63). In addition, at the initial stage of treatment, if the antidepressant has a slow onset of action, the patient will not be able to clearly feel the effect after taking the drug, and compliance with the drug will be significantly reduced. Stopping the drug in the middle of the treatment will not only seriously affect the efficacy, but may even cause the patient to give up completely treatment. Therefore, in the early stage of antidepressant treatment, the rapid production of curative effects and the improvement of patients' obvious sensory symptoms are the key factors for the effectiveness, stability and reliability of clinical treatment. Rapid antidepressant drugs will bring many benefits to treatment, such as reducing the risk of suicide, recovering patients' emotional and functional health faster, and improving the cost-effectiveness of treatment. In view of the shortcomings of conventional antidepressant drugs, the successful development of a new generation of rapid antidepressant drugs has always been a long-awaited goal for doctors and patients, and it is also a major issue that needs to be solved urgently by the international neuropsychiatric community. Tamas Bartfai, the author of the book "The Future of Drug Discovery", wrote in the book specifically on the need to develop rapid antidepressant drugs: "(Existing antidepressants) none of them has a 7 to 21 An antidepressant that can effectively prevent suicide within a day, and an antidepressant that has a rapid effect and thus reduces the risk of suicide must be the first-line drug, and if such drugs exist, it is unethical to start treatment with other drugs." "The Future of Drug Discovery" P117)

In the past ten years, researchers have increasingly believed that glutamate disorders play a very important role in the onset of depression. Glutamate is a neurotransmitter that acts through N-methyl-D-aspartic acid (NMDA). The NMDA system has been recognized as an important factor affecting cognitive function and neurodegeneration. In depression studies, it is proved that blocking NMDA receptors can increase the plasticity of the brain and strengthen synaptic connections. Recent clinical treatments have also found that the structure of some parts of the limbic system of depression patients has changed, and related functions have been damaged, indicating that the nerves Changes in plasticity may be one of the fundamental mechanisms of depression. In 2000, researchers at Yale University in the United States first discovered the mechanism of action by which the NMDA receptor inhibitor ketamine can quickly and effectively antidepressants. Since then, the National Institute of Mental Health conducted a large-scale double-blind, placebo-controlled clinical study. The rapid antidepressant function of ketamine is confirmed, but due to its serious side effects, it may cause hepatotoxicity, ulcerative cystitis, and especially may cause neurocognitive impairment (for example, can cause dissociation and hallucinations) and addiction, etc. Adverse consequences limit the use of ketamine in the treatment of depression. Despite this, ketamine still sends an encouraging signal: NMDA receptor inhibitors may become a path to develop rapid antidepressant drugs. In this regard, Johnson & Johnson in the United States started early and made the fastest progress. The company's new drug Escetamine is a spiegelmer of ketamine. Studies have shown that this nasal spray formulation can produce a fast-acting antidepressant effect. , But it also has hidden worries that cannot be ignored. It is mainly manifested in the difficulty of patients to get rid of the shadow of possible mental side effects after use. The data released at the annual meeting of the American Psychiatric Association in May 2018 shows that Escetamine may still have "mental dissociation" Serious adverse side effects.

It is an urgent need to develop a new generation of antidepressant drugs with fast-acting antidepressant effects of ketamine but without its adverse side effects. As Tamas Bartfai wrote in "The Future of Drug Discovery": "There will be new antidepressants in this field. Will they be developed? Yes, because there are a large number of unmet medical needs, new drugs will appear. Newcomers will reflect new scientific understandings and use different mechanisms of action" ("The Future of Drug Discovery" P117).

Demand spurs innovation, and this is the technical background of the present invention.

Summary of the invention

The purpose of the present invention is to provide a new use of albiflorin as an N-methyl-D-aspartate receptor (NMDAR) inhibitor, and specifically relates to albiflorin as an N-methyl-D- The use of aspartate receptor (NMDAR) inhibitors for rapid antidepressant use can be used to prepare safe and rapid onset antidepressant drugs. Prior to this, the present inventors first discovered the antidepressant use of paeoniflorin, and then conducted in-depth research on new biological targets and mechanism of action for anti-stress, anti-depression and improving intestinal flora balance during the development of new drugs. It was further discovered and confirmed that paeoniflorin has a rapid antidepressant function as an NMDA receptor.

The albiflorin of the present invention is a monoterpene compound with a molecular formula of C23H28O11, a molecular weight of 480.46, and a molecular structure as shown in the formula. It is a natural active substance derived from the Ranunculaceae plant Paeonia Paeonia The root of lactiflora Pall or Paeonia veitchii Lynch, the root of peony P.suffrsticosa Andrz.

According to the application provided by the present invention, the pharmaceutically acceptable salt of the compound represented by formula (I) can be selected from citrate, hydrochloride, sulfate, malate, tartrate, citrate and phosphoric acid. One or more of the salt.

The present invention discloses that paeoniflorin or a pharmaceutically acceptable salt thereof, or an extract containing paeoniflorin or a pharmaceutically acceptable salt thereof, is an NMDA receptor inhibitor;

The present invention also discloses that the NMDA receptor inhibitor paeoniflorin or a pharmaceutically acceptable salt thereof, or an extract containing paeoniflorin or a pharmaceutically acceptable salt thereof, can rapidly antidepressant by inhibiting the NMDA receptor ；

The present invention further discloses that paeoniflorin or a pharmaceutically acceptable salt thereof, or an extract containing paeoniflorin or a pharmaceutically acceptable salt thereof, can inhibit the expression of NMDA receptor subtype B (GluN2B) Play a role in inhibiting NMDA receptors.

In one aspect, the present invention also provides that paeoniflorin or a pharmaceutically acceptable salt thereof, or an extract containing paeoniflorin or a pharmaceutically acceptable salt thereof, is prepared for rapid treatment of depression by inhibiting NMDA receptors. Use in medicines, foods, health products, food additives, or nutritional supplements that cause symptoms;

Preferably, the NMDA receptor is NMDA receptor subtype B (GluN2B).

The present invention also provides the use of paeoniflorin or a pharmaceutically acceptable salt thereof, or an extract containing paeoniflorin or a pharmaceutically acceptable salt thereof, in the preparation of an NMDA receptor inhibitor;

Preferably, the NMDA receptor is NMDA receptor subtype B (GluN2B).

The present invention also provides that paeoniflorin or a pharmaceutically acceptable salt thereof, or an extract containing paeoniflorin or a pharmaceutically acceptable salt thereof, is used in the preparation of drugs, foods, and foods for inhibiting the activity of NMDA receptors. Use in health products, food additives or nutritional supplements;

Preferably, the NMDA receptor is NMDA receptor subtype B (GluN2B).

In another aspect, the present invention also provides a method for rapid treatment of depression by inhibiting NMDA receptors, the method comprising administering a therapeutically effective amount of paeoniflorin or a pharmaceutically acceptable salt thereof, or containing paeoniflorin Extracts of glycosides or pharmaceutically acceptable salts thereof;

Preferably, the NMDA receptor is NMDA receptor subtype B (GluN2B).

The present invention provides a method for inhibiting NMDA receptors, the method comprising administering a therapeutically effective amount of paeoniflorin or a pharmaceutically acceptable salt thereof, or a compound containing paeoniflorin or a pharmaceutically acceptable salt thereof Extract;

Preferably, the NMDA receptor is NMDA receptor subtype B (GluN2B).

In another aspect, the present invention also provides a composition for the rapid treatment of depression by inhibiting NMDA receptors, which comprises paeoniflorin or a pharmaceutically acceptable salt thereof, or paeoniflorin or a pharmaceutically acceptable salt thereof. Extracts of acceptable salt;

Preferably, the NMDA receptor is NMDA receptor subtype B (GluN2B).

Preferably, the composition is a medicine, food, health care product, food additive or nutritional supplement.

The present invention also provides a composition for inhibiting NMDA receptor, which comprises paeoniflorin or a pharmaceutically acceptable salt thereof, or an extract containing paeoniflorin or a pharmaceutically acceptable salt thereof;

Preferably, the NMDA receptor is NMDA receptor subtype B (GluN2B).

Preferably, the composition is a medicine, food, health care product, food additive or nutritional supplement.

In still another aspect, the present invention also provides paeoniflorin or a pharmaceutically acceptable salt thereof for rapid treatment of depression by inhibiting NMDA receptors, or a compound containing paeoniflorin or a pharmaceutically acceptable salt thereof Extract;

Preferably, the NMDA receptor is NMDA receptor subtype B (GluN2B).

The present invention also provides paeoniflorin or a pharmaceutically acceptable salt thereof as an NMDA receptor inhibitor, or an extract containing paeoniflorin or a pharmaceutically acceptable salt thereof;

Preferably, the NMDA receptor is NMDA receptor subtype B (GluN2B).

Compared with the prior art, the present invention has the following advantages:

1. Compared with conventional antidepressants such as Baiyoujie, the NMDA receptor inhibitor paeoniflorin and its pharmaceutically acceptable salt of the present invention have a rapid antidepressant function;

2. Compared with fast-acting antidepressant drugs such as ketamine, the NMDA receptor inhibitor paeoniflorin and its pharmaceutically acceptable salts of the present invention are safer, and there are no mental aspects such as dissociation and hallucinations. Side effects, there is no hidden danger of addiction.

Brief description of the drawings

Figure 1 shows the sucrose water intake of CUMS model rats after a single dose of paeoniflorin (Alb) and ketamine (Ket), including blank group, paeoniflorin group, ketamine group and chronic stress model group.

Figure 2 shows the number of standing uprights in the opening experiment of CUMS model rats after a single dose of paeoniflorin (Alb) and ketamine (Ket), including blank group, paeoniflorin group, ketamine group and chronic stress model group .

Figure 3 shows the effect of a single dose of ketamine (Ket) on the hippocampal metabolic profile of CUMS model rats, including the blank group, ketamine group and chronic stress model group.

Figure 4 is a graph showing the effect of a single dose of paeoniflorin (Alb) on the hippocampal metabolic profile of CUMS model rats, including the blank group, the paeoniflorin group and the chronic stress model group.

Figure 5 is a graph showing the intake of sucrose water in CUMS model rats given paeoniflorin (Alb) and fluoxetine (Flx) for 7 days, including blank group, paeoniflorin group, ketamine group and chronic stress Excitation model group.

Figure 6 is a graph showing the number of standing uprights in the opening experiment of CUMS model rats given paeoniflorin (Alb) and fluoxetine (Flx) for 7 days, including blank group, paeoniflorin group, fluoxetine group and chronic Stress model group.

Figure 7 is a graph showing the number of times that CUMS model rats were given paeoniflorin (Alb) and fluoxetine (Flx) for 7 days in the opening experiment, including blank group, paeoniflorin group, fluoxetine group and chronic Stress model group.

Figure 8 is a graph showing the effect of paeoniflorin (Alb) administration on the hippocampal metabolism profile of CUMS model rats for 7 days, including the blank group, the paeoniflorin group and the chronic stress model group.

Figure 9 is a graph showing the effect of fluoxetine (Flx) on the hippocampal metabolic profile of CUMS model rats for 7 days, including the blank group, fluoxetine group and chronic stress model group.

Figure 10 is a graph showing the inhibitory effect of paeoniflorin (Alb) on the NMDA receptor subtype GluN2B, which includes blank group, paeoniflorin group, fluoxetine group and chronic stress group.

The best way to implement the invention

The present invention will be further explained below in conjunction with specific implementation cases. However, the following examples are only for illustrating the present invention, not for limiting the scope of the present invention.

Example one

The NMDA receptor inhibitor paeoniflorin (Alb) of the present invention uses ketamine (Ket) as a positive drug for a single-dose one-day administration on chronic stress rat model (CUMS) antidepressant experiment

1. Experimental method

The SD rats were fed under standard conditions for 7 days before the start of the experiment (12 hours: 12 hours, cycle under light-dark conditions; free intake of food and water; temperature: 22-24° C., humidity: 40-60%).

The rats were randomly divided into blank group or CUMS group. The rats in the CUMS group were exposed to a random stressor for 35 days, including 5 minutes of swimming in cold water (10℃), inversion of the day and night photoperiod, 24 hours of food or water lack, 10 minutes of strong light exposure, and 2 minutes of rotator shaking Or 2 minutes tail clip. The rats in the blank group were not disturbed except for touching them once a day (5 minutes). After 4 weeks of stress, depression-like behavior model rats were used to evaluate the efficacy of the drug.

2. Drug administration and experiment

2.1 Drugs

Paeoniflorin (Alb), 95% purity, provided by Beijing Onar Bioengineering Technology Co., Ltd.; Ketamine (Ket), produced by Fujian Gutian Pharmaceutical.

2.2 Experiment

CUMS rats were given a single dose of paeoniflorin (CUMS-Alb, 7 mg/kg, gavage), ketamine (CUMS-Ket, 10 mg/kg, intraperitoneal injection) and normal saline (CUMS-Sal). The rats in the blank group were given normal saline (Ctrl-Sal). Each group has 8 rats. Sucrose Water Preference Test (SPT) was performed 24 hours after administration. An Open Field Test (OFT) was performed 24 hours before and after the administration, and the number of uprights within 4 minutes was calculated.

3. Collection of metabolomics samples

After the behavioral test, the animals were killed by anesthesia, and the hippocampal tissues were collected, frozen in liquid nitrogen quickly and stored at -80°C for use.

4. LC-MS/MS next-generation targeted metabolomics analysis

The hippocampus sample to be tested is ground into powder in liquid nitrogen. The powder (about 50mg) is weighed, mixed with 5μl isotope standard mixture, and extracted with 9 times volume of extraction buffer containing methanol/acetonitrile/acetone/water (30/30/30/10; v/v/v/) . The mixture was placed on ice for 30 minutes, and centrifuged at 16,000 × g and 4°C for 10 minutes.

Use Waters Acquity UPLC system and qtrap 6500 mass spectrometer combined with LC-MS/MS analysis. A synergistic polar RP column (50×2m, 2.5μm, Phenomenex, USA) was used for chromatographic separation at a flow rate of 0.6ml/min at a temperature of 35°C. The mobile phase A is an aqueous solution containing 0.1% formic acid, and the mobile phase B is an acetonitrile solution containing 0.1% formic acid. The main metabolites in the sample are determined.

5. Results

(1) The results of behavioral experiments show that: single-dose intraperitoneal injection of ketamine (Ket, 10mg/kg) and single-dose intragastric administration of paeoniflorin (Alb, 7mg/kg) can completely reverse chronic stress The sucrose water intake of rats was reduced, and no statistical difference was observed between ketamine and paeoniflorin (as shown in Figure 1). A single dose of paeoniflorin also significantly increased the reduction in the number of erections in rats caused by CUMS (as shown in Figure 2), which was similar to the effect of the rapid antidepressant ketamine.

(2) Metabolomics and subsequent cluster analysis showed that the hippocampal metabolic profile between rats administered by single-dose intraperitoneal injection of ketamine (10mg/kg) and saline blank group (CUMS-Sal) was significantly separated (Figure 3) (Shown); Compared with rats in the saline blank group, the hippocampal metabolism profile of the single-dose gavage paeoniflorin group (7mg/kg) was significantly separated, and was closer to the blank blank group than the ketamine group (Figure 4 Shown).

This experiment proves that in a single-dose administration CUMS experiment within one day, the NMDA receptor inhibitor paeoniflorin (Alb) of the present invention has a rapid antidepressant effect similar to ketamine (Ket), and the improvement of the metabolic pathways Lactone glycoside is better than ketamine.

Example two

Antidepressant experiment of NMDA receptor inhibitor paeoniflorin (Alb) of the present invention with fluoxetine (Flx) as a positive drug for 7 days on chronic stress rat model (CUMS)

1. Experimental method

The SD rats were fed under standard conditions for 7 days before the start of the experiment (12 hours: 12 hours, cycle under light-dark conditions; free intake of food and water; temperature: 22-24° C., humidity: 40-60%).

The rats were randomly divided into blank group or CUMS group. The rats in the CUMS group were exposed to a random stressor for 35 days, including 5 minutes of swimming in cold water (10℃), inversion of the day and night photoperiod, 24 hours of food or water lack, 10 minutes of strong light exposure, and 2 minutes of rotator shaking Or 2 minutes tail clip. The rats in the blank group were not disturbed except for touching them once a day (5 minutes). After 4 weeks of stress, depression-like behavior model rats were used to evaluate the efficacy of the drug.

2. Drug administration and experiment

2.1 Drugs

Paeoniflorin, 95% purity, provided by Beijing Onal Bioengineering Technology Co., Ltd.; Fluoxetine, produced by Eli Lilly Suzhou Pharmaceutical Co., Ltd.

2.2 Experiment

For 7 consecutive days, CUMS rats were given saline, fluoxetine and paeoniflorin by gavage 10μl/g; CUMS-fluoxetine group rats (10mg/kg) and CUMS-paeoniflorin group rats (3.5, 7. 14mg/kg). The rats in the blank group were given saline. There are 8 rats in each group. Dosing 1 hour before starting. The sucrose water preference experiment SPT was performed every 7 days (0, 7, 14, 21, 28, and 35 days) during the experiment. The opening experiment OFT was performed 24 hours before and after the administration. Calculate the number of walking and standing activities during the 4-minute period.

3. Collection of metabolomics samples

The administration was administered for 7 days, and the behavioral test was performed 24 hours after the administration. After the test, the animals were anesthetized and the hippocampus tissues were collected, frozen in liquid nitrogen and stored at -80°C for use.

4. LC-MS/MS next-generation targeted metabolomics analysis

The hippocampus sample to be tested is ground into powder in liquid nitrogen. The powder (about 50mg) is weighed, mixed with 5μl isotope standard mixture, and extracted with 9 times volume of extraction buffer containing methanol/acetonitrile/acetone/water (30/30/30/10; v/v/v/) . The mixture was placed on ice for 30 minutes, and centrifuged at 16,000 × g and 4°C for 10 minutes.

Use Waters Acquity UPLC system and qtrap 6500 mass spectrometer combined with LC-MS/MS analysis. A synergistic polar RP column (50×2mm, 2.5μm, Phenomenex, USA) was used for chromatographic separation at a flow rate of 0.6ml/min at a temperature of 35°C. The mobile phase A is an aqueous solution containing 0.1% formic acid, and the mobile phase B is an acetonitrile solution containing 0.1% formic acid. The main metabolites in the sample are determined.

5. Results

(1) The experimental results show that the administration of paeoniflorin can significantly increase the sucrose water intake of the CUMS model rats after 7 days, while the 7 days of fluoxetine administration only slightly increases the sucrose water preference, which is comparable to the model group rats There is no significant difference (p>0.05, Figure 5). Therefore, paeoniflorin has a stronger anti-anhedonia effect than fluoxetine. In addition, after 7 days of administration of paeoniflorin, the chronic stress-induced reduction in uprightness and walking of rats normalized (Figure 6 and Figure 7)

(2) Metabolomics and subsequent cluster analysis showed that there was a significant difference between the paeoniflorin administration group and the saline blank group (CUMS-Sal), and the PLS-DA analysis achieved complete separation (Figure 8); The fluoxetine group and the saline blank group (CUMS-Sal) partially overlap, indicating that the fluoxetine group only partially improved the abnormal metabolism of depression rats, but did not affect or improve the overall metabolism of the hippocampus of rats (Figure 9).

In a 7-day slow stress (CUMS) experiment, the NMDA receptor inhibitor paeoniflorin of the present invention is significantly better than fluoxetine in the rapid antidepressant effect.

Example three

Inhibition of paeoniflorin of the present invention on NMDA receptor subtype GluN2B

1. Method

The behavioral experiment method is the same as in Example 2. After the behavioral experiment was completed, the animals were sacrificed and the hippocampus were collected. All samples were quickly frozen in liquid nitrogen, and then detected by Western blotting.

2. Results

The test results show that the NMDA receptor inhibitor paeoniflorin of the present invention can significantly down-regulate the expression level of NMDA receptor subtype B (GluN2B) (Figure 10).

This experiment proved that paeoniflorin can inhibit the NMDA receptor by inhibiting the expression of NMDA receptor subtype B (GluN2B).

Conclusion and analysis of Examples 1 to 3

Drugs with antidepressant purposes, such as the mainstream antidepressant drug Biyoujie of the monoamine transmitter type. Although it has antidepressant function, it can only produce curative effect after 2-4 weeks after taking the drug. Therefore, the onset of action is slow. The shortcomings and shortcomings of depression drugs. In this regard, the technical background part of this application has been explained clearly. The first sign of the new generation of antidepressant drugs is the ability to quickly fight depression. For example, the rapid antidepressant drug esketamine, which was just approved for registration by the US FDA in March of this year, is a breakthrough treatment drug and has been given priority review for rapid listing.

Although both antidepressants and rapid antidepressants are antidepressant drugs, their uses are very different. This has been a consensus recognized by the global neurological community. In this regard, the applicant has conducted in-depth research and experiments, and Draw the following conclusions.

First of all, the traditional unpredictable long-term stress test is usually carried out simultaneously with the modeling and administration. This modeling cannot prove the rapid antidepressant use of the tested drug. According to the latest global antidepressant research model, it is proved that the rapid antidepressant drugs are administered in a single dose, and the positive reference is the standard rapid antidepressant ketamine. Only through this modelling can it be proved that paeoniflorin has rapid antidepressant effects. As the enlightenment given by the method and conclusion of Example 1, due to the difference in modeling method, administration time and positive drug, the paeoniflorin claimed in this application for rapid antidepressant application is a new application, which is different from the previous one. The published antidepressant use of paeoniflorin.

Secondly, in addition to single-dose administration in chronic stress modeling, another implementation case of this application is administration 7 days after successful modeling. This is also an animal model and drug redesigned for rapid antidepressant use. In this way, the positive drug it compares is the SSRI type of antidepressant Bioyoujie. The experimental results prove that the 7-day administration of paeoniflorin can quickly improve the sucrose water intake of rats, but Bioljie does not have this function. Therefore, this improved modelling and administration method proves that For rapid antidepressant purposes, paeoniflorin is stronger than Baiyoujie.

Furthermore, the applicant also provides single-dose administration and 7-day administration of paeoniflorin to rapidly improve the metabolism of a rat depression model, and the use of paeoniflorin to rapidly antidepressant is proved through the detection of metabolic pathways.

The above description of the specific embodiments of the present invention does not limit the present invention. Those skilled in the art can make various changes or modifications according to the present invention, as long as they do not deviate from the spirit of the present invention, they shall fall within the scope of the appended claims of the present invention.

Claims (9)

Paeoniflorin or a pharmaceutically acceptable salt thereof, or an extract containing paeoniflorin or a pharmaceutically acceptable salt thereof is used in the preparation of drugs, foods, and health products for the rapid treatment of depression by inhibiting NMDA receptors , Food additives or nutritional supplements; Preferably, the NMDA receptor is NMDA receptor subtype B. Use of paeoniflorin or a pharmaceutically acceptable salt thereof, or an extract containing paeoniflorin or a pharmaceutically acceptable salt thereof, in the preparation of an NMDA receptor inhibitor; Preferably, the NMDA receptor is NMDA receptor subtype B. Paeoniflorin or a pharmaceutically acceptable salt thereof, or an extract containing paeoniflorin or a pharmaceutically acceptable salt thereof is used in the preparation of drugs, foods, health products, and food additives for inhibiting the activity of NMDA receptors Or use in nutritional supplements; Preferably, the NMDA receptor is NMDA receptor subtype B. A method for rapid treatment of depression by inhibiting NMDA receptors, the method comprising administering a therapeutically effective amount of paeoniflorin or a pharmaceutically acceptable salt thereof, or comprising paeoniflorin or a pharmaceutically acceptable salt thereof Extract of Preferably, the NMDA receptor is NMDA receptor subtype B. A method for inhibiting NMDA receptors, the method comprising administering a therapeutically effective amount of paeoniflorin or a pharmaceutically acceptable salt thereof, or an extract containing paeoniflorin or a pharmaceutically acceptable salt thereof; Preferably, the NMDA receptor is NMDA receptor subtype B. A composition for the rapid treatment of depression by inhibiting NMDA receptors, which comprises paeoniflorin or a pharmaceutically acceptable salt thereof, or an extract containing paeoniflorin or a pharmaceutically acceptable salt thereof; ； Preferably, the NMDA receptor is NMDA receptor subtype B; Preferably, the composition is a medicine, food, health care product, food additive or nutritional supplement. A composition for inhibiting NMDA receptors, which comprises paeoniflorin or a pharmaceutically acceptable salt thereof, or an extract containing paeoniflorin or a pharmaceutically acceptable salt thereof; Preferably, the NMDA receptor is NMDA receptor subtype B; Preferably, the composition is a medicine, food, health care product, food additive or nutritional supplement. A paeoniflorin or a pharmaceutically acceptable salt thereof for rapid treatment of depression by inhibiting NMDA receptors, or an extract containing paeoniflorin or a pharmaceutically acceptable salt thereof; Preferably, the NMDA receptor is NMDA receptor subtype B. A paeoniflorin or a pharmaceutically acceptable salt thereof used as an NMDA receptor inhibitor, or an extract containing paeoniflorin or a pharmaceutically acceptable salt thereof; Preferably, the NMDA receptor is NMDA receptor subtype B.

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