CN115212195A - Application of malic acid in preparation of medicine for preventing and/or treating depression - Google Patents
Application of malic acid in preparation of medicine for preventing and/or treating depression Download PDFInfo
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- CN115212195A CN115212195A CN202210688850.XA CN202210688850A CN115212195A CN 115212195 A CN115212195 A CN 115212195A CN 202210688850 A CN202210688850 A CN 202210688850A CN 115212195 A CN115212195 A CN 115212195A
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- 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
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- 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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Abstract
The invention belongs to the technical field of medicines, and particularly relates to application of malic acid in preparation of a medicine for preventing and/or treating depression. Animal experiments show that after the chronic society defeats stress modeling, the sweet water preference of a mouse given malic acid is obviously higher than that of a control mouse; in social interaction experiments, the depression susceptibility of the group given malic acid is about one half of that of the control group. Therefore, malic acid has obvious effects of preventing and improving the depression-like behaviors of the mice caused by social frustration. Therefore, the malic acid can be used for preparing the medicament for preventing and/or treating the 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 a medicine for preventing and/or treating depression.
Background
Depression is a psychologic disorder characterized primarily by persistent mood swings, and is the most common type of mental disorder in modern people. Clinically, the mood is low and the reality is too happy, the mood is low and subsided for a long time, the feeling is from sultriness at the beginning to the final sadness, the people feel alive every day and hopefully afflict themselves, negative, escape and even have suicide tendency and behavior. Meanwhile, patients also suffer from somatization symptoms such as chest distress and shortness of breath, which brings huge economic burden to society and families.
At present, the treatment methods for depression mainly include drug therapy, physical therapy and psychological therapy. Among them, drug therapy is the main therapeutic measure for depression. The first-line antidepressants currently used clinically mainly include 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 antidepressant drugs (representing the drug mirtazapine), and the like.
However, there are still two problems with the existing depression treatment drugs: firstly, the antidepressant commonly used at present has long onset time, the reaction rate is 40-60%, the remission rate is less than 50%, and the recurrence rate is high. Secondly, most of the current clinically applied antidepressants have large side effects. In addition, most of the existing drugs are drugs for treating depression, and few drugs capable of preventing depression are available at present. Therefore, there is still a need to develop more kinds of drugs for the prevention or treatment of depression, providing more options for the 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 the 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 a sour taste; at the same time, it can be added into supplement for relieving chronic fatigue and fibromyalgia and improving exercise ability.
However, the action 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 the medicament for preventing and/or treating depression, and provides more choices for the medicament treatment of depression.
Application of malic acid or pharmaceutically acceptable salt or derivative thereof in preparing medicines for preventing and/or treating depression.
Preferably, the malic acid is L-malic acid.
The invention also provides a medicament for preventing and/or treating depression, which is prepared by taking malic acid or pharmaceutically acceptable salt thereof or derivatives thereof as an active ingredient and adding 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 semi-solid preparation, a liquid preparation or a gas preparation.
By "pharmaceutically acceptable" is meant a carrier, cargo, diluent, excipient, and/or salt thereof, which is generally chemically or physically compatible with the other ingredients comprising the pharmaceutical dosage form, and which is physiologically compatible with the recipient.
"salts" are acid and/or base salts of a compound or a stereoisomer thereof with inorganic and/or organic acids and/or bases, and also include zwitterionic (inner) salts, as well as quaternary ammonium salts, such as alkylammonium salts. These salts can be obtained directly in the final isolation and purification of the compounds. Or by mixing the compound, or a stereoisomer thereof, with a certain amount of an acid or a base, as appropriate (e.g., an equivalent amount). These salts may form precipitates in the solution which are collected by filtration, or they may be recovered by evaporation of the solvent, or they may be prepared by reaction in an aqueous medium followed by lyophilization.
Animal experiments show that after the society of depression modeling is frustrated, the sweet water preference of a mouse given malic acid is obviously higher than that of a control; in social interaction experiments, the depression susceptibility of the group given malic acid is about one half of that of the control group. Therefore, malic acid has obvious effects of preventing and improving depressive behavior caused by social frustration. In addition, because malic acid is a natural product and is a metabolite in the human body, malic acid is highly safe to use as a drug. Therefore, the malic acid can be used for preparing the medicament for preventing and/or treating the depression and has good application prospect.
Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.
The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Drawings
FIG. 1 is a schematic flow chart of the experiment 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 shows the results of the social interaction test for depression susceptibility in example 1.
Detailed Description
The technical solution of the present invention is further illustrated by the following specific examples:
example 1 Effect of malic acid in controlling Depression
This example investigates the effect of malic acid addition to feed on a chronic social frustration stress (CSDS) mouse model. Most depression-related stresses are social in nature, as they have social characteristics, including environmental stress, life events, and personal frustration. Therefore, compared with other animal models of depression, the mouse model of chronic social frustration stress can better simulate the real process of depression caused by social factors, has lasting behavioral and biological changes, and is one of the animal models with better depression research. Through the experiment of the embodiment, the prevention and treatment effect of malic acid on depression can be proved.
1. Laboratory animal
C57BL/6J mice (8 weeks of age, 18-22g body weight) were fed under constant laboratory conditions (12 hours/12 hours light-dark cycle, room temperature 23 + -2 deg.C, relative humidity 55 + -10%). The clear water and the mouse feed are sufficient. All animal handling and experimental procedures were approved by the ethical committee.
2. Experimental method
1. Experimental procedure
Experimental procedure As shown in FIG. 1, 8-week-old C57BL/6J mice were acclimatized, subjected to a Baseline test for sugar water and body weight, and subjected to a chronic social contusion test for a period of 10 days after exclusion of mice with too small natural physique and a preference for sugar-free water, followed by a depressive behavior test (Day, day; baseline, baseline test; trends, normal diet or 2% malic acid feeding; CSDS/CON, chronic social contusion stress or control treatment in the figure).
2. Experiment grouping
C57BL/6J mice were divided into four groups, namely:
normal feed + CON group (n = 10), experimental group fed with rat maintenance feed (SPF grade), i.e. feed containing 18% protein and 4% fat sterilized by 60 Co-gamma irradiation and not subjected to CSDS;
a normal feed + CSDS group (n = 10), an experimental group fed with a rat maintenance feed (SPF grade), i.e., a feed containing 18% protein and 4% fat sterilized by 60 Co-gamma irradiation and subjected to CSDS;
2% malic acid + CON group (n = 18), experimental group fed with 2% (w/w) L-malic acid added to a feed containing 18% protein and 4% fat sterilized by irradiation of 60 Co-gamma rays (SPF grade) in rats and mice without CSDS;
group of 2% malic acid + CSDS (n = 14) experimental group of CSDS was carried out with 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 60 Co-gamma irradiation.
3. Chronic social frustrating stress
Before social frustration, 4-6 months old male CD1 mice with strong aggressivity are screened, and the social frustration strength of the model C57BL/6J mice is ensured. For the screening of a single CD-1 mouse, the whole screening process lasts for 3 days, 1 time per day, 1C 57BL/6J mouse is placed into a breeding cage of the CD-1 mouse per day, and the mouse is taken out after 3 minutes; the C57BL/6J mice were changed daily for a total of 3 days. Screening of CD-1 mice for aggressive behavior is based primarily on two criteria: (1) CD-1 was challenged in a 3 day (3 min per day) screen on C57BL/6J mice for at least two consecutive days; (2) the latency of the initial challenge is within 1 minute.
The social frustration experimental cage (with padding) was prepared the day before the start of molding and the screened CD-1 mice were placed in cages on one side of the isolation barrier one night in advance. After the molding is started, the C57BL/6J mouse is taken as an invader to be placed into a screened CD1 mouse cage every day, and the mouse is exposed for 5-10min, which is called as contact stress. During the contact, the C57BL/6J mice are attacked by the CD1 mice, so as to show evasion, fear and other behaviors. After both were contacted, C57BL/6J mice and CD1 mice were separated by a transparent plexiglass plate with a hole and left for 24 hours as an indirect psychological stress. The above operations were continuously repeated for 10 days. Control C57BL/6J: 2C 57BL/6J mice of the same age group were selected, and the procedure was repeated for 10 consecutive days, with reference to the experiment of the experimental group (which may be understood as replacing the CD-1 mice in the experimental group with the control C57BL/6J mice), with different experimental cages each day.
4. Social interaction experiment
After 24 hours after the social frustration is finished, all groups of C57BL/6J mice are respectively put into a social interactive open field in turn and are allowed to adapt to the environment for 1 hour before detection. And in the video recording stage, starting a camera system to record the track tracking of the C57BL/6J mouse in the open field: firstly, carrying out 2.5-minute trajectory tracking on a CD 1-free mouse; the interval between the two mice is 30 seconds, and a brand-new offensive CD1-1 mouse (which is not used in the stage of social frustration) is placed in the organic glass cover on the side wall of the open field; follow up of the trajectory with CD1-1 mice was done for an additional 2.5 minutes. Software records and analyzes the indexes detected by the experiment, mainly as follows: a. overall trajectory and total travel of the animal; b. the number of times the animal entered different areas (mainly social, corner areas are recorded as needed) and the stay time.
5. Sugar water preference experimental mice were first acclimatized to 1% sugar water for 4 days. The mice were deprived of water for 12 hours, after which time the sugar water and clear water were again placed on the feeding rack and the sugar water and clear water intake of the mice was recorded over a 12 hour period. Sugar water preference = sugar water intake ÷ (sugar water intake + fresh water intake) × 100%.
3. Results of the experiment
As shown in FIG. 2, the sugar preference values of the normal diet + CSDS group were significantly decreased compared to the normal diet + CON group, while the sugar preference values of the 2% malic acid + CSDS group were not significantly different, and thus, it was found that the administration of 2% malic acid had a significant improvement effect on the decrease in sugar preference (anhedonia) of mice caused by social withdrawal (in the figure: sugar preference (%), percentage of sugar preference (%), CSDS, chronic social withdrawal stress; CON, control treatment; vehicle, normal diet; mal,2% malic acid).
As shown in FIG. 3, the interaction Time was significantly shortened in the presence of challenge mice in the normal diet + CSDS group compared to the normal diet + CON group, and the interaction Time was not significantly different in the 2% malic acid + CSDS group, so that it was found that the administration of 2% malic acid significantly improved the reduction in social interaction Time (social avoidance) in mice caused by social frustration (in the figure: time in IZ, time in the interaction zone; vehicle, normal diet; mal,2% malic acid; CON, control treatment; CSDS, chronic social frustration stress; absent, absence of challenge mice; present, presence of challenge mice).
As shown in FIG. 4, the depression susceptibility (depression incidence) was doubled in the 2% malic acid + CSDS group compared to the normal diet + CSDS group, and thus it was found that the administration of 2% malic acid had a depression-resistant effect (Mice%, ratio of Mice; vehicle, normal diet; mal,2% malic acid; resilient, depression-resistant; susceptible, depression-sensitive).
The above examples show that malic acid can improve the sugar water preference of the CSDS mouse model and improve the social avoidance phenomenon of the CSDS mouse model, and thus, the malic acid can prove to have obvious prevention and improvement effects on depression-like behaviors caused by social frustration. Therefore, the malic acid can be used for preparing the medicament for preventing and/or treating the depression and has good application prospect.
Claims (5)
1. Application of malic acid or pharmaceutically acceptable salt thereof, or derivatives thereof in preparing medicines for preventing and/or treating depression.
2. Use according to claim 1, characterized in that: the malic acid is L-malic acid.
3. A medicament for preventing and/or treating depression, characterized by: the malic acid or pharmaceutically acceptable salt or derivative thereof is used as an active ingredient, and pharmaceutically acceptable auxiliary materials or auxiliary ingredients are added to prepare the malic acid.
4. A medicament as claimed in claim 3, wherein: the malic acid is L-malic acid.
5. A medicament as claimed in claim 3, wherein: the dosage form of the medicament is solid preparation, semi-solid preparation, liquid preparation or gas preparation.
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| CN117016484B (en) * | 2023-09-19 | 2024-04-05 | 中国人民解放军军事科学院军事医学研究院 | Construction method and application of anxiety-like mouse model |
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