CN115212195B - Application of malic acid in preparation of medicines for preventing and/or treating depression - Google Patents
Application of malic acid in preparation of medicines for preventing and/or treating depression Download PDFInfo
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- CN115212195B CN115212195B CN202210688850.XA CN202210688850A CN115212195B CN 115212195 B CN115212195 B CN 115212195B CN 202210688850 A CN202210688850 A CN 202210688850A CN 115212195 B CN115212195 B CN 115212195B
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- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 title claims abstract description 55
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 title claims abstract description 47
- 235000011090 malic acid Nutrition 0.000 title claims abstract description 47
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- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
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- 229960001785 mirtazapine Drugs 0.000 description 1
- RONZAEMNMFQXRA-UHFFFAOYSA-N mirtazapine Chemical compound C1C2=CC=CN=C2N2CCN(C)CC2C2=CC=CC=C21 RONZAEMNMFQXRA-UHFFFAOYSA-N 0.000 description 1
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- 229960002748 norepinephrine Drugs 0.000 description 1
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 1
- 229940127221 norepinephrine reuptake inhibitor Drugs 0.000 description 1
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- 229960002296 paroxetine Drugs 0.000 description 1
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- 239000003772 serotonin uptake inhibitor Substances 0.000 description 1
- 229960002073 sertraline Drugs 0.000 description 1
- VGKDLMBJGBXTGI-SJCJKPOMSA-N sertraline Chemical compound C1([C@@H]2CC[C@@H](C3=CC=CC=C32)NC)=CC=C(Cl)C(Cl)=C1 VGKDLMBJGBXTGI-SJCJKPOMSA-N 0.000 description 1
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- 239000013589 supplement Substances 0.000 description 1
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- 229960004688 venlafaxine Drugs 0.000 description 1
- PNVNVHUZROJLTJ-UHFFFAOYSA-N venlafaxine Chemical compound C1=CC(OC)=CC=C1C(CN(C)C)C1(O)CCCCC1 PNVNVHUZROJLTJ-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
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- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Biomedical Technology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Psychiatry (AREA)
- Pain & Pain Management (AREA)
- Epidemiology (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention belongs to the technical field of medicines, and particularly relates to application of malic acid in preparation of medicines for preventing and/or treating depression. Animal experiments show that after modeling of chronic social frustration stress, the glucose water preference of mice given with malic acid is obviously higher than that of control mice; in social interaction experiments, the group given malic acid had a susceptibility to depression of about one-half that of the control group. From the results, malic acid has obvious effects of preventing and improving mouse depression-like behaviors caused by social frustration. Therefore, the malic acid can be used for preparing the medicines for preventing and/or treating depression and has good application prospect.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to application of malic acid in preparation of medicines for preventing and/or treating depression.
Background
Depression is a mental disorder characterized by sustained emotional depression as the main clinical feature, the most common type of mental disorder in modern people. Clinically, the mood is low and the reality is too careless, the mood is low and subsides for a long time, from the beginning of smoldering to the last of sadness, spewing, pain, pessimistic and aversion, the feeling of living is hopefully afflicting itself every day, negatively, evading, and finally, the feeling of suicidal tendency and behavior is even more. Meanwhile, patients also suffer from somatic symptoms such as chest distress and shortness of breath, and bring great economic burden to society and families.
Currently, the treatment of depression mainly includes medication, physical therapy and psychological therapy. Among them, drug therapy is a major therapeutic measure for depression. First-line antidepressants currently in clinical use include mainly selective 5-hydroxytryptamine reuptake inhibitors (representing the drugs fluoxetine, paroxetine, sertraline, fluvoxamine, citalopram and escitalopram), 5-hydroxytryptamine and norepinephrine reuptake inhibitors (representing the drugs venlafaxine and duloxetine), norepinephrine and specific 5-hydroxytryptamine antidepressants (representing the drugs mirtazapine), and the like.
However, there are still two problems with these existing therapeutic drugs for depression: firstly, the antidepressant commonly used at present has long onset time, 40-60% of response rate, less than 50% of remission rate and high recurrence rate. Secondly, most antidepressants applied clinically at present have larger side effects. In addition, most of the existing medicines are medicines for treating depression, but few medicines for preventing depression exist at present. Therefore, there is still a need to develop a greater variety of preventive or therapeutic drugs for depression, providing more options for clinical prevention and treatment of depression.
Malic acid is an organic acid with a sour taste, which is naturally found in a variety of fruits and vegetables. Meanwhile, malic acid is also one of byproducts of human metabolism. The structural formula of malic acid is as follows:
in the prior art, malic acid is commonly used as a food additive to provide sourness; meanwhile, the compound feed additive is added into supplements, and can also be used for relieving chronic fatigue and fibromyalgia and improving exercise capacity.
However, the effect of malic acid on depression and its molecular mechanism have not been reported at present.
Disclosure of Invention
Aiming at the problems in the prior art, the invention provides the application of malic acid in preparing medicaments for preventing and/or treating depression, and provides more choices for medicament treatment of depression.
Use of malic acid or a pharmaceutically acceptable salt thereof, or a derivative thereof, for the manufacture of a medicament for the prevention and/or treatment of depression.
Preferably, the malic acid is L-malic acid.
The invention also provides a medicament for preventing and/or treating depression, which is prepared from malic acid or pharmaceutically acceptable salt or derivative thereof as an active ingredient and pharmaceutically acceptable auxiliary materials or auxiliary ingredients.
Preferably, the malic acid is L-malic acid.
Preferably, the dosage form of the medicament is a solid preparation, a semisolid preparation, a liquid preparation or a gas preparation.
By "pharmaceutically acceptable" is meant that the carrier, vehicle, diluent, adjuvant, and/or salt thereof is generally chemically or physically compatible with the other ingredients comprising the pharmaceutical dosage form, and physiologically compatible with the recipient.
"salts" are acidic and/or basic salts formed with inorganic and/or organic acids and/or bases of a compound or stereoisomer thereof, and also include zwitterionic salts (inner salts) and also include quaternary ammonium salts, for example alkylammonium salts. These salts may be obtained directly in the final isolation and purification of the compounds. Or by mixing the compound, or a stereoisomer thereof, with a suitable amount (e.g., equivalent) of an acid or base. These salts may be obtained by precipitation in solution and collected by filtration, or recovered after evaporation of the solvent, or by lyophilization after reaction in an aqueous medium.
According to animal experiments, after the depression modeling society is frustrated, the sugar water preference of mice given with malic acid is obviously higher than that of a control; in social interaction experiments, the group given malic acid had a susceptibility to depression of about one-half that of the control group. From this, it is clear that malic acid has a remarkable preventive and ameliorating effect on depression-like behavior caused by social frustration. In addition, since malic acid is a natural product and is a metabolite in the human body itself, malic acid also has high safety in use as a drug. Therefore, the malic acid can be used for preparing the medicines for preventing and/or treating depression and has good application prospect.
It should be apparent that, in light of the foregoing, various modifications, substitutions and alterations can be made herein without departing from the spirit and scope of the invention as defined by the appended claims.
The above-described aspects of the present invention will be described in further detail below with reference to specific embodiments in the form of examples. It should not be understood that the scope of the above subject matter of the present invention is limited to the following examples only. All techniques implemented based on the above description of the invention are within the scope of the invention.
Drawings
FIG. 1 is a schematic illustration of the experimental procedure of example 1;
FIG. 2 is the experimental results of the sugar water preference experiment in example 1;
FIG. 3 is the experimental results of the social interaction experiment in example 1;
fig. 4 is a graph showing the results of the social interaction experimental depression susceptibility in example 1.
Detailed Description
The technical scheme of the invention is further described by the following specific examples:
EXAMPLE 1 malic acid role in controlling depression
This example investigated the effect of malic acid addition to feed on a chronic social frustrating stress (CSDS) mouse model. Most depression-related stresses are social in nature because of their social nature, including environmental stress, life events, and interpersonal frustration. Therefore, compared with other animal models of depression, the chronic social frustrating stress mouse model can better simulate the actual process of depression caused by social factors, has lasting behavioral and biological changes, and is one of animal models with better research on depression. Through the experiments of the embodiment, the prevention and treatment effects of malic acid on depression can be demonstrated.
1. Experimental animal
C57BL/6J mice (8 weeks old, weight 18-22 g) were fed under constant laboratory conditions (12 hours/12 hours light and dark cycle, room temperature 23.+ -. 2 ℃ C., relative humidity 55.+ -. 10%). Clear water and mouse feed are sufficient. All animal treatments and experimental procedures were approved by the ethics committee.
2. Experimental method
1. Experimental procedure
Experimental procedure As shown in FIG. 1, 8 week old C57BL/6J mice were acclimatized, subjected to Baseline tests of sugar water and body weight, subjected to chronic social frustration stimulation for 10 days after exclusion of mice with daily physical size and no sugar water preference, and subsequently subjected to depressive behavior tests (Day, day; baseline, baseline test; treatents, normal feed or 2% malic acid feeding; CSDS/CON, chronic social frustration stress or control treatment).
2. Experimental grouping
The C57BL/6J mice were divided into four groups, namely:
normal feed+con group (n=10), experimental group fed with a rat maintenance feed (SPF grade), i.e. a feed containing 18% protein and 4% fat sterilized by irradiation with 60 Co-gamma rays and not subjected to CSDS;
normal feed+csds group (n=10), experimental group fed with a mice maintenance feed (SPF grade), i.e. a feed containing 18% protein and 4% fat sterilized by irradiation with 60 Co-gamma rays and subjected to CSDS;
group 2% malic acid+con (n=18), experimental group fed with a rat maintenance feed (SPF grade), i.e. a feed containing 18% protein and 4% fat sterilized by irradiation with 60 Co-gamma rays, supplemented with 2% (w/w) L-malic acid and not subjected to CSDS;
group 2% malic acid+csds (n=14) the experimental group fed with a 2% (w/w) L-malic acid added to a rat maintenance feed (SPF grade), i.e. a feed containing 18% protein and 4% fat sterilized by irradiation with 60 Co-gamma rays and subjected to CSDS.
3. Chronic social frustrating stress
Before social frustration, male CD1 mice of 4-6 months of age with strong aggressiveness are screened, so that the social frustration strength of model C57BL/6J mice is ensured. For screening of single CD-1 mice, the whole screening process lasts for 3 days, 1 time per day, 1C 57BL/6J mice are placed into a feeding cage of the CD-1 mice every day, and the mice are taken out after 3 minutes; the different C57BL/6J mice were changed daily for 3 days. The aggression of screening CD-1 mice was mainly referred to two criteria: (1) CD-1 was challenged to C57BL/6J mice for at least two consecutive days in a 3 day (3 min per day) screen; (2) the latency of the initial challenge was within 1 minute.
The day before the start of molding, social frustrating test cages (with spacer) were prepared and screened CD-1 mice were placed in one cage of the isolation barrier one night in advance. C57BL/6J mice were placed as "invaders" into the screened CD1 mouse cages daily after the start of the molding and allowed to contact for 5-10min, called contact stress. In the contact process of the two, the C57BL/6J mice are challenged by the CD1 mice, so that the mice show the behavior of avoidance, fear and the like. After the two were contacted, the C57BL/6J mice and CD1 mice were separated using a clear plexiglass plate with holes and left for 24 hours as an indirect psychological stress. The above operation was repeated continuously for 10 days. Control group C57BL/6J: 2 mice of the same age group were selected, and the experiment was repeated continuously for 10 days with reference to the experiment of the experimental group (it can be understood that the CD-1 mice in the experimental group were replaced with the control C57BL/6J mice) by replacing different experimental cages each day.
4. Social interaction experiments
After 24 hours from the end of social frustration, all groups of C57BL/6J mice were placed individually in the social interaction open field in sequence, and allowed to adapt to the environment for 1 hour before detection. In the video recording stage, a camera system is started to record the track tracking of the C57BL/6J mice in the open field: track tracking of CD1-1 free mice was performed for 2.5 minutes; a new aggressive CD1-1 mouse (which is not used in the social frustration stage) is put into the organic glass cover at the side wall of the open field at the middle interval of 30 seconds; track following 2.5 minutes after CD1-1 mice was performed. The software records and analyzes the index detected by the experiment, and is mainly as follows: a. animal overall trajectory and total travel; b. the number of times the animal enters the different areas (mainly social areas, corner areas are recorded as needed) and the dwell time.
5. Sugar water preference experimental mice were first acclimatized to 1% sugar water for 4 days. The mice were subjected to 12 hours of water deprivation, after which the sugar water and clear water were again placed on a feeding rack, and the sugar water and clear water intake of the mice were recorded over 12 hours. Sugar preference = sugar water intake ≡ (sugar water intake + clear water intake) ×100%.
3. Experimental results
As shown in FIG. 2, the sugar preference value of the normal feed+CSDS group is remarkably reduced compared with that of the normal feed+CON group, and the sugar preference value of the 2% malic acid+CSDS group is not remarkably different, so that the 2% malic acid administration has remarkable improvement effect on the reduction of the sugar preference (hedonic deficit) of mice caused by social frustration (Sucrose preference (%), sugar preference percentage; CSDS, chronic social frustration stress; CON, control treatment; vehicle, normal feed; mal,2% malic acid).
As shown in FIG. 3, the interaction Time of the normal feed+CSDS group was significantly shortened when the challenged mice existed, while the interaction Time of the 2% malic acid+CSDS group was not significantly different, thus it was seen that the administration of 2% malic acid had a significant improvement effect on the reduction of social interaction Time (social avoidance) of mice caused by social frustration (in the figure: time in IZ, time in the interaction zone; vehicle, normal feed; mal,2% malic acid; CON, control treatment; CSDS, chronic social frustrating stress; absent, challenged mice did not exist; present, challenged mice existed).
As shown in fig. 4, the depression susceptibility (depression incidence) was doubled in the 2% malic acid+csds group compared to the normal feed+csds group, and thus it was seen that the administration of 2% malic acid had a depression resistant effect (in the figure: mice%, mice ratio; vehicle, normal feed; mal,2% malic acid; response, depression resistance; depression sensitivity).
According to the embodiment, the malic acid can improve the syrup preference of the CSDS mouse model and improve the social avoidance phenomenon of the CSDS mouse model, so that the malic acid can prove that the malic acid has obvious prevention and improvement effects on depression-like behaviors caused by social frustration. Therefore, the malic acid can be used for preparing the medicines for preventing and/or treating depression and has good application prospect.
Claims (1)
1. Use of malic acid or a pharmaceutically acceptable salt thereof as sole active ingredient in the manufacture of a medicament for the prevention and/or treatment of depression, characterized in that: the malic acid is L-malic acid.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210688850.XA CN115212195B (en) | 2022-06-17 | 2022-06-17 | Application of malic acid in preparation of medicines for preventing and/or treating depression |
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| Application Number | Priority Date | Filing Date | Title |
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| CN202210688850.XA CN115212195B (en) | 2022-06-17 | 2022-06-17 | Application of malic acid in preparation of medicines for preventing and/or treating depression |
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| Publication Number | Publication Date |
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| KR100780333B1 (en) * | 2006-05-08 | 2007-11-28 | 김성진 | Composition containing an extract of Rubi Fructus for preventing and treating anxiety and depression |
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