Use of benserazide hydrochloride in the preparation of anxiolytic drugs

Abstract

The application belongs to the technical field of biological medicine, and specifically discloses application of benserazide hydrochloride in preparation of anxiolytic drugs. The application first finds that benserazide hydrochloride plays an anxiolytic role by regulating the kynurenine metabolic pathway. Animal experiments prove that benserazide hydrochloride can promote the generation of kynurenine and its downstream metabolite 3-hydroxyanthranilic acid, and maintain the stable level of 3-hydroxykynurenine, thereby improving the function of the metabolic pathway and restoring the nervous system homeostasis. Behavioral experiments show that benserazide hydrochloride can increase the exploration behavior of zebrafish and reduce the avoidance behavior, and meanwhile, does not cause inhibition of motor function or sedative effect, and shows good safety and selectivity. The application provides a theoretical basis and a new drug source for the prevention and / or treatment of anxiety.

Description

Technical Field

[0001] This invention relates to the field of biomedical technology, and in particular to the application of benserazide hydrochloride in the preparation of anti-anxiety drugs. Background Technology

[0002] Anxiety disorder is the most common mental disorder, with main clinical symptoms including anxiety, worry, fear, dread, tension, and autonomic nervous system dysfunction. Anxiety disorder severely impairs an individual's psychological, occupational, and social functioning, and imposes a long-term economic burden on families and society. Clinical treatment for anxiety disorder primarily relies on psychotherapy and medication. Psychotherapy has limited effectiveness, while medication has problems such as slow onset of action, drug tolerance, addiction, rebound effects upon withdrawal, and side effects. Many patients do not respond to some medications; therefore, the development of new therapeutic drugs is urgently needed.

[0003] Benserazide hydrochloride (BH) is an inhibitor of aromatic L-amino acid decarboxylases (AADCs). When used in combination with levodopa to form the compound preparation DOPA-BH, it is commonly used clinically for the treatment of Parkinson's disease. Multiple studies have shown that Benserazide hydrochloride may inhibit tumor growth by suppressing hexokinase 2 (HK2), a key enzyme in the glycolytic pathway.

[0004] However, there are currently few research reports on the use of benserazide hydrochloride for the treatment of anxiety disorders. Summary of the Invention

[0005] The purpose of this invention is to address the above-mentioned shortcomings of the prior art by providing an application of benserazide hydrochloride in the preparation of anxiolytic drugs. Benserazide hydrochloride prevents and / or treats anxiety disorders by reducing anxiety behaviors in patients with anxiety disorders.

[0006] To achieve the above objectives, the present invention adopts the following technical solution: A first aspect of the invention is to provide the use of benserazide hydrochloride or a pharmaceutically acceptable salt thereof in the preparation of medicaments for the prevention and / or treatment of anxiety disorders.

[0007] Furthermore, the anxiety disorder is an anxiety disorder associated with abnormalities in the canine uric acid metabolic pathway.

[0008] Furthermore, the abnormality of the canine uric acid metabolic pathway is manifested by an abnormal decrease in canine uric acid and 3-hydroxy-o-aminobenzoic acid levels compared to healthy controls.

[0009] Furthermore, the benserazide hydrochloride can promote the production of kynurenic acid and 3-hydroxy-annaminobenzoic acid in the kynurenic acid metabolic pathway.

[0010] Furthermore, the benserazide hydrochloride can maintain the level of 3-hydroxykynurenic acid in the kynurenic acid metabolic pathway.

[0011] Furthermore, the benserazide hydrochloride can increase an individual's exploratory behavior or reduce avoidance behavior.

[0012] Furthermore, the benserazide hydrochloride, while relieving anxiety symptoms, does not cause motor function inhibition or sedation in individuals.

[0013] Furthermore, the anxiety disorder is selected from generalized anxiety disorder, social anxiety disorder, panic disorder, acute stress disorder, and stress-related pathological avoidance behavior.

[0014] Furthermore, the drug comprises benserazide hydrochloride and pharmaceutically acceptable excipients.

[0015] Furthermore, the dosage form of the drug is at least one of tablets, capsules, granules, oral liquids, injections, and aerosols.

[0016] Compared with the prior art, the beneficial effects of the present invention are: (1) This invention is the first to discover that benserazide hydrochloride exerts its anti-anxiety effect by regulating the kynurenic acid metabolic pathway. Animal experiments have demonstrated that benserazide hydrochloride can promote the production of kynurenic acid and its downstream metabolite 3-hydroxy-anaminobenzoic acid, and maintain a stable level of 3-hydroxykynurenic acid, thereby improving the function of the metabolic pathway and restoring the homeostasis of the nervous system. Behavioral experiments show that benserazide hydrochloride can increase exploratory behavior and reduce avoidance behavior in zebrafish, while not causing motor function inhibition or sedation, demonstrating good safety and selectivity.

[0017] (2) Based on the high conservation of the kynuric acid metabolic pathway in mammals and humans, the benserazide hydrochloride described in this invention has potential anti-anxiety application value in humans and can be used for intervention in generalized anxiety disorder, social anxiety disorder, panic disorder, acute stress disorder and stress-related pathological avoidance behaviors.

[0018] (3) This invention provides a novel, effective and safe anti-anxiety intervention method, providing an operable technical solution for the prevention and treatment of anxiety-related diseases. Attached Figure Description

[0019] Figure 1 In Embodiment 1 of the present invention exosc9The results of the detection of metabolites related to the canineurine pathway in knocked-out adult zebrafish are shown in the figure. A represents the relative abundance of tryptophan; B represents the level of canineurine; C represents the level of 3-hydroxycanine; D represents the level of 3-hydroxy-anaminobenzoic acid; and E represents the level of quinolinic acid (tryptophan relative abundance group, n=3; canineurine level group, n=5; 3-hydroxycanine level group, n=5; 3-hydroxy-anaminobenzoic acid level group, n=5; quinolinic acid level group, n=5). p≤0.05, p≤0.01, ns showed no significant difference). Figure 2 In Example 2 of this invention, benzyl hydrochloride and Linalool were used to... exosc9 - / - Results of anxiety-like behavior tests in juvenile zebrafish. In the figure, A is the result of the time spent in the central area; B is the result of the time spent in the outer area; C is the trajectory heatmap (WT group, n=20). exosc9 - / - Groups, n=28; exosc9 - / - +Benserazide Hydrochloride group, n=23; exosc9 - / - +Linalool group, n=19; p≤0.05; p≤0.01; p≤0.0001); Figure 3 In Example 3 of this invention, benzyl hydrochloride and Linalool were used to... exosc9 - / - Results of tests on anxiety-like behavior and exploratory behavior in adult zebrafish; In the figure, A is the dwell time in the upper region during the new tank diving experiment; B is the latency period for the first entry into the upper region during the new tank diving experiment; C is a schematic diagram of the adult new tank diving experiment; D is a schematic diagram of the adult open field experiment; E is the dwell time in the central region during the open field experiment; F is a trajectory heatmap of the open field experiment (WT group, n=22; WT+Benserazide Hydrochloride group, n=15; WT+Linalool group, n=18). exosc9 - / - Groups, n=23; exosc9 - / - +Benserazide Hydrochloride group, n=17; exosc9- / - +Linalool group, n=18; p≤0.05; p≤0.01; p≤0.001; p≤0.0001; ns (no significant difference). Figure 4 In Example 4 of this invention, benzyl hydrazine hydrochloride and Linalool were used to... exosc9 - / - Results of metabolite level tests related to the kynurenine pathway in adult zebrafish; In the figure, A represents kynurenine level; B represents 3-hydroxykynurenine level; C represents 3-hydroxy-anaminobenzoic acid level (WT group, n=5); exosc9 - / - Groups, n=5; exosc9 - / - +Benserazide Hydrochloride group, n=5; exosc9 - / - +Linalool group, n=5; p≤0.05, p≤0.01, ns showed no significant difference. Detailed Implementation

[0020] To make the objectives, technical solutions, and advantages of the present invention clearer, embodiments of the present invention are described in detail below. Examples of these embodiments are shown in the accompanying drawings, wherein the same or similar reference numerals denote the same or similar elements or elements having the same or similar functions throughout. The embodiments described below with reference to the accompanying drawings are exemplary and are only used to explain the present invention, and should not be construed as limiting the present invention.

[0021] definition In this invention, the term "treatment or prevention" refers to a method aimed at achieving a beneficial or desired clinical outcome. For the purposes of this invention, beneficial or desired clinical outcomes include, but are not limited to, relieving symptoms, reducing disease severity, stabilizing the condition (i.e., preventing deterioration), delaying or slowing disease progression, improving or alleviating the condition, and achieving detectable or undetectable partial or complete remission. Another meaning of "treatment" is extending a patient's survival compared to the expected survival rate without treatment. Therefore, "treatment" is an intervention aimed at altering the pathological process of a disease.

[0022] In this invention, the terms "therapeutic or preventative effective amount," "effective amount," or "sufficient amount" refer to an amount of active agent sufficient to induce a specific biological state, effect, and / or response. Specifically, in this invention, it refers to an amount sufficient to achieve the desired outcome, such as an effective treatment of sepsis, when administered to a subject, including mammals, such as humans. The effective amount of the reagents described herein can vary depending on factors such as the subject's disease state, age, sex, and weight. As those skilled in the art will understand, dosages or treatment regimens can be adjusted to provide an optimal therapeutic response.

[0023] In this invention, the term "anxiety disorder" encompasses the following clinical diagnostic entities and their corresponding preclinical phenotypes: (a) Generalized anxiety disorder It refers to a disorder that meets the DSM-5-TR diagnostic criteria 300.02 (F41.1), whose core feature is excessive anxiety and worry about a variety of events or activities (such as work or academic performance), which the patient has difficulty controlling, and is accompanied by at least three of the following symptoms: restlessness or tension, depression, difficulty concentrating, irritability, muscle tension, and sleep disturbance.

[0024] (b) Social anxiety disorder It refers to a disorder that meets the DSM-5-TR diagnostic criteria 300.23 (F40.10), characterized by a significant and persistent fear of one or more social situations in which the patient fears that their words or actions or the anxiety symptoms they exhibit will lead to negative evaluation.

[0025] (c) Panic disorder It refers to a disorder that meets the DSM-5-TR diagnostic criteria 300.01 (F41.0), characterized by recurrent, unpredictable panic attacks, accompanied by persistent worry about recurrence or behavioral changes.

[0026] (d) Acute stress disorder (ASD) It refers to a disorder that meets the DSM-5-TR diagnostic criteria 308.3 (F43.0), belonging to the category of "trauma and stress-related disorders", characterized by intrusive memories, negative mood, dissociative symptoms, avoidance symptoms and arousal symptoms within 3 days to 1 month after exposure to a traumatic event.

[0027] (e) Stress-related pathological avoidance behaviors This refers to stressor-induced inhibitory phenotypes of exploratory behavior observed in animal models, including but not limited to: In the elevated cross maze experiment, the number of times the arms were opened and / or the time spent in the arms was shortened. The number of times the central region is entered in the open field experiment is reduced and / or the time spent in the central region is shortened. In the novel environment feeding inhibition experiment, the feeding latency was prolonged.

[0028] This phenotype maps to situational avoidance symptoms in human anxiety disorders, but does not constitute a clinical diagnostic entity in itself.

[0029] In this invention, the term "individual" encompasses both humans and animals (mammals, zebrafish, etc.).

[0030] The inventors have discovered for the first time that benserazide hydrochloride has the effect of preventing and / or treating anxiety disorders. Specifically, benserazide hydrochloride prevents and / or treats anxiety disorders by reducing anxiety behaviors in patients with anxiety disorders, thus providing a theoretical basis and a new source of drugs for the prevention and / or treatment of anxiety disorders.

[0031] In some implementation schemes, medication can reduce anxious behaviors in patients with anxiety disorders.

[0032] In some implementations, anxiety disorders include those induced by abnormalities in the kynurenine pathway.

[0033] It is understood that anxiety disorders may also include other types of anxiety disorders existing in the art, and the present invention does not limit this. Furthermore, in the present invention, anxiety disorders preferably include those caused by abnormalities in the kynurenine pathway.

[0034] In this invention, abnormalities in the kynurenic acid metabolic pathway can be identified by detecting the levels of key metabolites in body fluids or tissues. Specifically, kynurenic acid and its downstream metabolite 3-hydroxy-an-aminobenzoic acid are significantly reduced in abnormal states compared to healthy controls. This abnormal reduction suggests impaired function of the kynurenic acid metabolic pathway, which may affect the metabolism of neurotransmitters and neuroprotective effects in the central nervous system, thereby leading to anxious behaviors. Quantitative determination of kynurenic acid and 3-hydroxy-an-aminobenzoic acid can serve as important indicators for evaluating anxiety states and the effectiveness of drug interventions.

[0035] The benserazide hydrochloride provided by this invention can promote the production of kynuric acid and 3-hydroxy-an-aminobenzoic acid in the kynuric acid metabolic pathway. Experimental results show that intervention with benserazide hydrochloride significantly restored the levels of kynuric acid and its metabolites, thereby improving the balance of neurotransmitter metabolism and alleviating anxiety-related behavioral manifestations. This indicates that benserazide hydrochloride exerts a direct anti-anxiety effect by regulating the kynuric acid metabolic pathway.

[0036] The benserazide hydrochloride provided by this invention can also maintain the level of 3-hydroxykynurenic acid in the kynurenic acid metabolic pathway. As a key downstream product of kynurenic acid metabolism, the homeostasis of 3-hydroxykynurenic acid is crucial for the redox balance and neuroprotection of the central nervous system. Through the regulatory effect of benserazide hydrochloride, excessive decreases or abnormal fluctuations in 3-hydroxykynurenic acid can be prevented, thereby achieving overall regulation of the kynurenic acid metabolic pathway, which is beneficial for enhancing anti-anxiety effects and reducing the occurrence of anxiety behaviors.

[0037] This invention further demonstrates through behavioral observation that benserazide hydrochloride can increase exploratory behavior and reduce avoidance behavior in zebrafish, significantly improving anxiety-related behavioral performance. Simultaneously, benserazide hydrochloride does not cause motor function inhibition or sedation during the relief of anxiety symptoms, exhibiting good safety and selectivity.

[0038] Numerous studies have confirmed that anxiolytic compounds screened in zebrafish models have shown good translational consistency in subsequent mammalian models (such as the mouse elevated cruciate maze and rat social avoidance test) and human clinical trials. Therefore, the experimental results from zebrafish models can be reliably applied to anxiolytic effects in humans and other mammals. Those skilled in the art can reasonably expect that the anxiolytic effects of benserazide hydrochloride described in this invention in zebrafish models, and its characteristic of not causing motor function inhibition while alleviating anxiety symptoms, are also applicable to other mammalian individuals, including humans.

[0039] This invention provides a novel technical solution for safe and effective anti-anxiety intervention by regulating the canine uric acid metabolic pathway through benserazide hydrochloride, combined with behavioral improvement effects, and has potential clinical application value.

[0040] This invention also provides an anti-anxiety drug containing benserazide hydrochloride as an active ingredient. The drug comprises a therapeutically effective amount of benserazide hydrochloride and pharmaceutically acceptable excipients. The excipients are selected from one or more of diluents, binders, disintegrants, lubricants, solvents, and stabilizers. Through scientific formulation, this invention ensures the stability and bioavailability of benserazide hydrochloride in the formulation, enabling it to effectively cross biological barriers and act on the kynurenine metabolic pathway of the central nervous system.

[0041] The drugs of this invention can be prepared into various dosage forms according to clinical needs. Oral solid dosage forms (such as tablets, capsules, and granules) ensure the stable release of active ingredients in the gastrointestinal tract by controlling the disintegration time; oral liquids facilitate precise adjustment of dosage, especially suitable for groups with swallowing difficulties; injections are used for rapid intervention in acute anxiety or panic disorders; aerosols are used for nasal or pulmonary administration, designed to shorten the onset time and improve targeting.

[0042] The following detailed description, with reference to specific embodiments, illustrates the application of benserazide hydrochloride or its pharmaceutically acceptable salts provided by the present invention in the preparation of drugs for the prevention and / or treatment of anxiety disorders.

[0043] The zebrafish strain used in this invention: WT wild-type zebrafish, exosc9 - / - Mutant zebrafish (anxious type). This includes wild-type WT zebrafish and... exosc9- / - The mutant zebrafish (anxious type) was purchased by the Institute of Hydrobiology, Chinese Academy of Sciences.

[0044] The concentration of benzylhydrazine hydrochloride used was 25 μM (administered to zebrafish in water).

[0045] Example 1 Anxious type Exosc9 Gene knockout zebrafish dogs exhibited abnormal levels of metabolites related to the urinary tract pathway.

[0046] Experimental materials: WT zebrafish, exosc9 - / - Mutant zebrafish (anxious type).

[0047] exosc9 - / - Mutant Zebrafish (Anxious Type): Based on zebrafish exosc9 The exon1 region of the gene is knocked out, removing 11 bases, resulting in normal... exosc9 The gene expression lacks the 362nd amino acid, resulting in the loss of normal expression. exosc9 Gene function.

[0048] First, all zebrafish were acclimatized to ensure stable growth; the experiment was divided into a WT group and a... exosc9 - / - Groups, with 3 biological replicates per group.

[0049] Next, take WT, exosc9 - / - Metabolite analysis was performed on zebrafish containing mutant 3 mpf.

[0050] Metabolite detection experimental procedures: Zebrafish at 3 mpf were collected. First, the zebrafish were anesthetized on ice. After the fish stopped struggling, brain tissue was dissected. The isolated brain tissue samples were processed according to the metabolite detection kit instructions. The relative abundance of tryptophan, kynurenine, 3-hydroxykynurenine, 3-hydroxy-an-aminobenzoic acid, and quinolinic acid levels were detected using an ELISA reader. The data were analyzed using a t-test. Results are shown below. Figure 1 As shown.

[0051] from Figure 1 It can be seen that, compared with the WT group, exosc9 - / - The relative abundance of tryptophan in zebrafish was significantly increased (e.g. Figure 1 (As shown in A); kynurenine levels were significantly reduced (e.g., Figure 1 (As shown in B); 3-hydroxykynurenine levels were significantly reduced (e.g., as shown in B). Figure 1 (as shown in C); the level of 3-hydroxy-o-aminobenzoic acid was significantly reduced (e.g., as shown in C). Figure 1 (As shown in D); quinolinic acid levels were significantly elevated (e.g., as shown in D). Figure 1(As shown in E). The results indicate that... exosc9 Knockout leads to a significant abnormal accumulation of metabolites related to the urinary tract in zebrafish dogs, resulting in metabolic imbalance in the pathway.

[0052] Example 2 Benserazine hydrochloride for the prevention and treatment of juvenile anxiety disorder induced by kynurenine pathway abnormalities in zebrafish.

[0053] In this embodiment, zebrafish with anxiety induced by abnormal kynurenine pathway ( exosc9 - / - The mutant zebrafish was treated as follows: 1) Benserazide Hydrochloride Treatment Group: In Example 1 exosc9 - / - Mutant zebrafish (anxious) embryos were treated with a dose of 25 μM for one week; 2) Linalool treatment group: In Example 1 exosc9 - / - Mutant zebrafish (anxious) embryos were treated with a dose of 4 μM for one week.

[0054] Next, the anxiety behaviors of zebrafish in the different treatment groups were tested to evaluate the preventive and therapeutic effects of benserazide hydrochloride on juvenile anxiety induced by kynurenine pathway abnormalities in zebrafish.

[0055] Specifically, open field experiments were conducted on zebrafish treated with benzyl hydrochloride for 7 days, using the WT group and... exosc9 - / - The control group was used as the control group, and the results were as follows: Figure 2 As shown.

[0056] The open-field test method for juvenile fish is as follows: The zebrafish juvenile open field test was used to assess anxiety behavior in zebrafish. Zebrafish reaching 7 days post-flood (dpf) were placed in 6-well plates filled with E3 medium, with one juvenile zebrafish in each well. The ambient temperature was set to 28°C using a temperature control system, allowing the juvenile zebrafish acclimatization period of 5 minutes. After acclimatization, the swimming trajectory and speed of the zebrafish were recorded for a total of 10 minutes. Each well's circular observation area was divided into an inner and outer region, and the time the zebrafish spent in each region was recorded.

[0057] The time zebrafish spend in the central region and the time they spend in the outer region are recorded as follows: Figure 2 As shown.

[0058] from Figure 2As can be seen from this, compared to the WT group, exosc9 - / - The time spent in the central region by the anxious zebrafish was significantly reduced. After treatment with benserazide hydrochloride and Linalool: exosc9 - / - The time spent in the central region by anxious zebrafish was significantly increased, and the benserazide hydrochloride group showed the best effect (e.g., Figure 2 (as shown in A in the diagram). exosc9 - / - The time spent in the outer region by the anxious zebrafish was significantly reduced (e.g. Figure 2 (as shown in B in the image). exosc9 - / - The anxious zebrafish also showed a significant increase in their exploration trajectory towards the central area (e.g. Figure 2 (As shown in C). The results indicate that treatment with benserazide hydrochloride improved the anxiety behavior of juvenile zebrafish.

[0059] Example 3 Prevention and treatment of anxiety disorder in adult zebrafish induced by kynurenine pathway abnormalities.

[0060] In this embodiment, anxiety disorder induced by kynurenine pathway abnormalities was observed in adult zebrafish ( exosc9 - / - The mutant zebrafish was treated as follows: 1) Benserazide Hydrochloride Treatment Group: 3 mpf in Example 1 exosc9 - / - The mutant zebrafish (anxious type) were treated with a dose of 25 μM for one week; 2) Linalool treatment group: 3 mpf in Example 1 exosc9 - / - The mutant zebrafish (anxious type) were treated with a dose of 4 μM for one week.

[0061] Next, the anxiety behaviors of zebrafish in the different treatment groups were tested.

[0062] Specifically, zebrafish treated with benzyl hydrochloride (1 week) and Linalool (1 week) underwent novel aquarium diving and open-field experiments, respectively, using the WT group, exosc9 - / - The control group was used as the control group, and the results were as follows: Figure 3 As shown.

[0063] The experimental testing method for adult fish diving in a new type of aquarium is as follows: The zebrafish used in the experiment were placed in a transparent tank (28cm × 20cm × 5cm) that they had never been exposed to before. Before the anxiety behavior test, dechlorinated tap water was added to the tank, and the water level was divided into three equal parts: upper, middle, and lower. To ensure consistent experimental conditions, square light panels were installed on the back and bottom of the tank to provide uniform lighting and maintain a constant background environment. During the experiment, the zebrafish were placed in the tank, and their behavior was immediately recorded using a side-mounted camera. Each zebrafish was recorded for 10 minutes, and the experiment was conducted daily from 9:00 AM to 5:00 PM. The open-field test method for adult fish is as follows: A transparent acrylic fish tank measuring 40×40×20 cm was used as the experimental setup. During the experiment, a zebrafish was placed in the open experimental tank and allowed to adapt for 3 minutes. Then, a camera was used to track and record the zebrafish's trajectory over 5 minutes. The experiment was conducted daily from 9:00 to 15:00.

[0064] from Figure 3 As can be seen, in the novel aquarium exploration test, a reduced time spent in the upper region by zebrafish indicates anxiety-like behavior. After treatment with both the benserazide hydrochloride group and the Linalool group, the time spent in the upper region by adult anxious zebrafish was significantly prolonged, with the benserazide hydrochloride treatment showing a better effect (e.g., ...). Figure 3 As shown in A); the latency period for the first entry into the upper region was significantly shortened (e.g., as shown in A). Figure 3 As shown in B); the time spent in the central area increased significantly (e.g., as shown in B). Figure 3 As shown in E), the results indicate that anxiety behavior improved after treatment with benserazide hydrochloride. The heatmap also illustrates the effects of benserazide hydrochloride treatment. exosc9 - / - Anxiety-like behaviors in the zebrafish were improved (e.g. Figure 3 (as shown in F) Finally, the metabolite levels of adult zebrafish from the different treatment groups were measured to evaluate the preventive and therapeutic effects of benserazide hydrochloride on zebrafish with anxiety induced by kynurenine pathway abnormalities.

[0065] Specifically, for the aforementioned WT group, exosc9 - / - Zebrafish in the treatment groups (group A, group Benserazide Hydrochloride, and group Linalool) underwent behavioral testing, and their brains were harvested as described in Example 1. The levels of kynurenine pathway metabolites were then measured, and the results were as follows: Figure 4 As shown.

[0066] from Figure 4 As can be seen from this, compared to the WT group, exosc9 - / -The kynurenine level in the model group zebrafish was significantly reduced, while the kynurenine level in the anxious zebrafish was significantly restored after treatment with benserazide hydrochloride; although the Linalool treatment group also upregulated the kynurenine level, the improvement was significantly weaker than that in the benserazide hydrochloride group, and there was no statistical significance (e.g. Figure 4 (As shown in A); compared to group WT, exosc9 - / - The 3-hydroxykynurenine level was significantly reduced in the model group, while the 3-hydroxykynurenine level did not change significantly after treatment with benserazide hydrochloride. This indicates that benserazide hydrochloride does not intervene in the basal level of this metabolite during pathway repair, but only maintains its homeostasis (e.g., ...). Figure 4 (as shown in B in the figure); compared with the WT wild-type group, exosc9 - / - The model group of zebrafish showed a significant decrease in 3-hydroxy-annaminobenzoic acid (3-hydroxy-2-aminobenzoic acid), consistent with the trend in kynurenine levels. This further confirms that anxiety in EXOSC9-deficient zebrafish leads to abnormal overall metabolic flux in the kynurenine pathway, with inhibition of upstream to midstream metabolic processes. After treatment with benserazide hydrochloride, 3-hydroxy-2-aminobenzoic acid levels significantly rebounded, returning to levels close to those in the WT group. In contrast, the Linalool treatment group showed no significant regulatory effect (e.g., ...). Figure 4 (as shown in C).

[0067] In summary, this invention is the first to discover that benserazide hydrochloride has the effect of preventing and / or treating anxiety disorders. Furthermore, animal experiments have demonstrated that benserazide hydrochloride prevents and / or treats anxiety disorders by reducing anxiety behaviors in zebrafish.

[0068] For any points not covered above, existing technologies shall apply.

[0069] Although specific embodiments of the present invention have been described in detail by way of examples, those skilled in the art should understand that the above examples are for illustrative purposes only and are not intended to limit the scope of the invention. Those skilled in the art can make various modifications or additions to the described specific embodiments or use similar methods to replace them, without departing from the direction of the invention or exceeding the scope defined by the appended claims. Those skilled in the art should understand that any modifications, equivalent substitutions, improvements, etc., made to the above embodiments based on the technical essence of the present invention should be included within the protection scope of the present invention.

Claims

1. The use of benserazide hydrochloride or a pharmaceutically acceptable salt thereof in the preparation of medicines for the prevention and / or treatment of anxiety disorders.

2. The application according to claim 1, characterized in that, The anxiety disorder mentioned is an anxiety disorder related to abnormalities in the canine uric acid metabolic pathway.

3. The application according to claim 2, characterized in that, The abnormality in the canine uric acid metabolic pathway was manifested by an abnormally low level of canine uric acid and 3-hydroxy-o-aminobenzoic acid compared to healthy controls.

4. The application according to claim 1, characterized in that, The benserazide hydrochloride can promote the production of kynurenic acid and 3-hydroxy-annaminobenzoic acid in the kynurenic acid metabolic pathway.

5. The application according to claim 1, characterized in that, The benserazide hydrochloride can maintain the level of 3-hydroxykynurenic acid in the kynurenic acid metabolic pathway.

6. The application according to claim 1, characterized in that, The benserazide hydrochloride can increase an individual's exploratory behavior or reduce avoidance behavior.

7. The application according to claim 1, characterized in that, The benserazide hydrochloride relieves anxiety symptoms without causing motor dysfunction or sedation.

8. The application according to claim 1, characterized in that, The anxiety disorders mentioned are selected from generalized anxiety disorder, social anxiety disorder, panic disorder, acute stress disorder, and stress-related pathological avoidance behavior.

9. The application according to any one of claims 1-8, characterized in that, The drug contains benserazide hydrochloride and pharmaceutically acceptable excipients.

10. The application according to claim 9, characterized in that, The dosage form of the drug is at least one of tablets, capsules, granules, oral liquids, injections, and aerosols.

Images