Use of hippuric acid for the preparation of a medicament for the prevention and / or treatment of depression

Abstract

The application discloses application of hippuric acid in preparation of a medicine for preventing and / or treating depression, and belongs to the technical field of biological medicine. The hippuric acid or pharmaceutically acceptable salt thereof has significant and multi-target antidepressant pharmacological activity through chronic mild stress depression animal model experiment. Specifically, in terms of improving core depressive symptoms, the sugar water preference experiment result shows that the hippuric acid can effectively reverse CUMS-induced hedonic deficiency of mice, and significantly improves the sucrose preference rate, and the forced swimming experiment proves that the hippuric acid can significantly shorten the immobility time of mice and relieve behavioral despair; in terms of improving anxiety-like behavior, the mine field experiment data show that after the hippuric acid intervention, the number of times of entering the central area, the residence time and the total activity distance of the depressive model mice are all significantly increased, which indicates that the hippuric acid can effectively improve the spontaneous activity reduction caused by chronic stress.

Description

Technical Field

[0001] This invention relates to the field of biomedical technology, and in particular to the use of hippuric acid in the preparation of medicaments for the prevention and / or treatment of depression. Background Technology

[0002] Currently used antidepressants (such as selective serotonin reuptake inhibitors) have drawbacks, including slow onset of action, significant individual variability in efficacy, and noticeable side effects. In particular, they lack a clear and effective effect on improving cognitive impairment associated with depression. Therefore, developing novel antidepressants with multiple targets, low toxicity, and the ability to simultaneously improve mood symptoms and cognitive function is of significant clinical importance.

[0003] In recent years, the widespread application of metabolomics technology has provided new perspectives for revealing potential biomarkers and pathological mechanisms of depression. Hippuric acid, a glycine conjugate of benzoic acid, is one of the most abundant organic acids in mammalian urine and represents the final metabolite of toluene detoxification. Its metabolic process in vivo is as follows: toluene is oxidized to benzyl alcohol by hepatic cytochrome P450 enzymes, then converted to benzoic acid by alcohol dehydrogenase. Benzoic acid combines with glycine to form hippuric acid, which is ultimately excreted in urine. Independent metabolomics studies have found that hippuric acid exhibits significant changes in age-related diseases and is closely related to the degree of cognitive impairment. Studies have reported that urinary hippuric acid levels in healthy individuals increase significantly with age, but in pathological states of cognitive impairment, urinary hippuric acid levels decrease, suggesting that hippuric acid metabolic imbalance may be involved in the pathological process of cognitive degeneration.

[0004] It is worth noting that existing metabolomics evidence suggests that hippuric acid has significant research value in depression. Our previous search of metabolomics databases revealed that hippuric acid was the only metabolite significantly elevated in both chronic unpredictable mild stress (CUMS) mouse models of depression and urine samples from patients with depression, compared to their respective control groups. This suggests that hippuric acid may play a crucial regulatory role in the progression of depression.

[0005] However, to date, there are no reports, either domestically or internationally, on the direct use of hippuric acid or its pharmaceutically acceptable salts in the preparation of drugs for the prevention and treatment of depression. Current technologies only explore hippuric acid as a biomarker of toluene exposure or a potential prognostic biomarker for depression; they have not revealed whether exogenous hippuric acid supplementation possesses antidepressant pharmacological activity, nor have they elucidated its specific efficacy in improving core symptoms of depression such as anhedonia and behavioral hopelessness, anxiety-like behaviors, and cognitive impairment.

[0006] This invention addresses the shortcomings of existing technologies by demonstrating, for the first time, through experiments using an animal model of chronic mild stress-induced depression, that hippuric acid or its pharmaceutically acceptable salts possess significant and multi-target antidepressant pharmacological activity. Experimental results show that, in improving core depressive symptoms, hippuric acid effectively reverses CUMS-induced anhedonia, significantly increases sucrose preference, shortens immobility time in the forced swimming test, and alleviates behavioral despair. Regarding the improvement of anxiety-like behaviors, hippuric acid intervention significantly increased the number of entries, dwell time, and total distance traveled in the central area of ​​the open field test in depressed model mice, indicating its effective ability to improve the reduction in spontaneous activity caused by chronic stress. Most importantly, this invention demonstrates unique advantages over traditional antidepressants in improving cognitive impairment in depression: a novel object recognition experiment confirmed that hippuric acid significantly improves the recognition memory index, and a water maze experiment confirmed that it increases the number of platform crossings and target quadrant paths in spatial exploration, effectively repairing recognition memory impairment and hippocampus-dependent spatial memory damage.

[0007] Therefore, this invention provides a novel candidate drug molecule for clinical use that combines mood improvement and cognitive function repair, and has good clinical translational value and market application prospects. Summary of the Invention

[0008] The purpose of this invention is to provide the use of hippuric acid in the preparation of medicaments for the prevention and / or treatment of depression, in order to solve the problems existing in the prior art.

[0009] To achieve the above objectives, the present invention provides the following solution: One of the technical solutions of this invention is the application of hippuric acid in the preparation of drugs for the prevention and / or treatment of depression.

[0010] The second technical solution of the present invention is the application of hippuric acid in the preparation of drugs for the prevention and / or treatment of depressive-like behaviors caused by chronic stress.

[0011] The third technical solution of this invention is the application of hippuric acid in the preparation of drugs that improve cognitive impairment associated with depression.

[0012] Based on the above technical solution, the present invention has the following technical effects: This invention demonstrates, through experiments using a chronic mild stress-induced depression animal model, that hippuric acid or its pharmaceutically acceptable salts possess significant and multi-target antidepressant pharmacological activity. Specifically, in improving core depressive symptoms, the sucrose preference test showed that hippuric acid effectively reversed CUMS-induced anhedonia in mice and significantly increased sucrose preference rate. The forced swimming test also confirmed that it significantly shortened immobility time and alleviated behavioral despair. Regarding the improvement of anxiety-like behavior, the mine field test data showed that hippuric acid intervention significantly increased the number of times mice entered the central region, their dwell time, and their total activity distance, indicating that it can effectively improve the reduction in spontaneous activity caused by chronic stress. This invention exhibits unique advantages over traditional antidepressants in improving cognitive impairment in depression. The new object recognition test and water maze test results respectively confirmed that hippuric acid can significantly improve the recognition memory index and increase the number of platform crossings and target quadrant paths in spatial exploration, effectively repairing recognition memory impairment and hippocampus-dependent spatial memory damage. This invention provides a novel candidate drug molecule with a novel mechanism of action that addresses both mood improvement and cognitive function repair, possessing good clinical translational value and market application prospects. Attached Figure Description

[0013] Figure 1 This is the result of a sugar water preference experiment.

[0014] Figure 2 These are the results of experiments conducted at the mine.

[0015] Figure 3 The results of the experiment on recognizing new objects show...

[0016] Figure 4 The results are from the water maze experiment.

[0017] Figure 5 The results are from a forced swimming experiment. Detailed Implementation

[0018] Unless otherwise specified, the technical solutions described in this invention are all conventional solutions in the field, and the reagents or raw materials used are all purchased from commercial channels or are publicly available unless otherwise specified.

[0019] This invention provides the use of hippuric acid in the preparation of medicaments for the prevention and / or treatment of depression.

[0020] This invention also provides the use of hippuric acid in the preparation of medicaments for the prevention and / or treatment of depressive-like behaviors caused by chronic stress.

[0021] This invention also provides the use of hippuric acid in the preparation of medicaments for improving cognitive impairment associated with depression.

[0022] In some specific implementations, the drug uses hippuric acid as the sole active ingredient.

[0023] In some specific implementations, the drug is in the form of an oral formulation.

[0024] In some specific implementations, the oral formulation is a tablet, capsule, granule, or oral liquid.

[0025] In some specific implementations, the effective dose of hippuric acid is 1-50 mg / kg / day.

[0026] In some specific implementations, the effective dose of hippuric acid is 10 mg / kg / day.

[0027] Example 1 1. Laboratory animals C57BL / 6J mice, 8 weeks old and weighing 18-22g, were purchased from Beijing Huafukang Biotechnology Co., Ltd.

[0028] 2. Experimental grouping and drug treatment Twenty-four 8-week-old male C57BL / 6J mice were selected and divided into three groups: a control group, a chronic mild stress (CUMS) group, and a CUMS + hippuric acid (HA) group, with eight mice in each group. Four weeks after the CMS model was established, the mice in the drug treatment group were administered 10 mg / kg hippuric acid by gavage daily for four consecutive weeks under the modeling conditions.

[0029] 3. Experimental Methods Establishment of the CUMS animal model: Mice used in the experiment were acclimatized to the environment for one week before the experiment. The stress methods used in this experiment mainly included the following: tail clamping, restraint, light exposure, cold water swimming, oven drying, tilted cages, moist bedding, fasting, water deprivation, and noise stimulation. During the CMS modeling period, animals were exposed to 2-4 stress methods daily, with each stress method administered randomly and for at least 3-4 hours. After the daily stress period, all animals were placed in clean cages and returned to their original feeding conditions.

[0030] The criteria for successful establishment of the CUMS model in mice include: core indicators such as: ① anhedonia, marked by a significant decrease in the sugar water preference rate in the sugar water preference test, which is one of the most core features of the CUMS model; ② behavioral despair, marked by a significant increase in immobility time in the forced swimming test (FST); ③ anxiety-like behavior, marked by a significant decrease in the time spent in the central region or the distance of movement in the open field test (OFT).

[0031] After successful modeling, 8-week-old C57 mice were administered 10 mg / kg / day of hippuric acid by gavage for 4 weeks, while the control group was given the same dose of dmso.

[0032] 4. Sugar Water Preference Experiment Adaptation phase for mice: Two identical water bottles were used, one filled with drinking water and the other with a 1% sucrose solution. These were placed in the same cage simultaneously, and their horizontal positions were swapped every 12 hours to eliminate positional preference. After adaptation, all fluids were removed, and the mice were deprived of water for 12 hours (during which time they were allowed to eat normally).

[0033] Mouse testing phase: Fresh 1% sucrose solution and drinking water were reconstituted and the initial weight was accurately recorded. The water bottles were placed symmetrically in the mouse cages to start the test. After 12 hours, the positions of the water bottles were changed and the test was continued for another 12 hours. After 24 hours, the final liquid consumption was measured and recorded again.

[0034] Sugar water preference rate: (sugar water consumption / sugar water consumption + drinking water consumption) × 100%.

[0035] The results of the sugar water preference experiment showed that ( Figure 1 CUMS depressed mice showed a significantly reduced sucrose preference (P < 0.05), indicating that they had obvious depressive symptoms; hippurate improved the depressive symptoms in CUMS depressed mice.

[0036] 5. Mine Field Experiment The results of the open field experiment show that ( Figure 2 The number of times the mice entered the central region, the time spent in the central region, and the total distance traveled in the central region were significantly reduced in CUMS depressed mice (P < 0.05), indicating that their spontaneous movement was significantly reduced and their anxiety-depression-like behavior was increased. Hippurate improved the depressive symptoms of CUMS depressed mice.

[0037] 6. New Object Recognition The results of the new object recognition experiment show that ( Figure 3 The total exploration time and number of recognition memory index (NOI) counts in CUMS depressed mice were significantly reduced (P < 0.05), indicating a significant recognition memory impairment. Hippurate improved the recognition memory impairment in CUMS depressed mice.

[0038] 7. Water Maze Experiment The Morris water maze experiment results show that ( Figure 4 The number of times CUMS depressed mice entered the platform, the latency in the target quadrant, and the swimming distance in the target quadrant were significantly reduced (P<0.05), indicating that they had significant spatial memory impairment; hippurate improved the spatial memory impairment in CUMS depressed mice.

[0039] 8. Forced swimming The results of the forced swimming experiment showed that ( Figure 5The core manifestation of the CUMS depressed mouse model was a significant increase in immobility time, accompanied by a decrease in active struggling behaviors (such as swimming and climbing), suggesting an increase in hopeless behaviors. Hippurate improved the hopeless and depressive symptoms in CUMS depressed mice.

[0040] Obviously, the above embodiments of the present invention are merely examples for clearly illustrating the present invention, and are not intended to limit the implementation of the present invention. For those skilled in the art, other variations or modifications can be made based on the above description. It is neither necessary nor possible to exhaustively describe all embodiments here. Any modifications, equivalent substitutions, and improvements made within the spirit and principles of the present invention should be included within the scope of protection of the claims of the present invention.

Claims

1. Application of hippuric acid in the preparation of drugs for the prevention and / or treatment of depression.

2. Application of hippuric acid in the preparation of drugs for the prevention and / or treatment of depressive-like behaviors caused by chronic stress.

3. Application of hippuric acid in the preparation of drugs to improve cognitive impairment associated with depression.

4. The application according to any one of claims 1-3, characterized in that, The drug uses hippuric acid as its sole active ingredient.

5. The application according to any one of claims 1-3, characterized in that, The drug is an oral formulation.

6. The application according to claim 5, characterized in that, The oral preparation is a tablet, capsule, granule, or oral liquid.

7. The application according to any one of claims 1-3, characterized in that, The effective dose of hippuric acid is 1-50 mg / kg / day.

8. The application according to claim 7, characterized in that, The effective dose of hippuric acid is 10 mg / kg / day.

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