CN117797137A - Application of morin in preparation of antidepressant drugs - Google Patents

Abstract

The invention relates to the technical field of medicine preparation, and particularly discloses application of morin in preparation of antidepressant medicines, wherein the influence of morin on behavior of a depressive mouse is researched by establishing a chronic Wen Heying induced depression model and a corticosterone induced depression model, and the improvement of morin on the behavior of the mouse like depression is found, which is manifested in that the preference rate of syrup is increased, and the immobility time of forced swimming and tail suspension experiments is shortened. The morin in the invention can obviously increase the preference rate of the sugar water of mice at the dosage of 40mg/kg and 80mg/kg, shortens the immobility time of forced swimming and tail suspension experiments, and has the potential for preparing antidepressant drugs.

Description

Application of Morin in Preparing Antidepressant Drugs

Technical field

The present invention relates to the technical field of drug preparation, and specifically relates to the application of morin in the preparation of antidepressant drugs.

Background technique

Depression is the most common mental illness nowadays, with continuous and long-term low mood as the main clinical feature. It is the most important type of mental illness in modern people.

Clinically, patients are depressed and unhappy with reality, and their mood is depressed for a long time, from being unhappy at the beginning to being heartbroken at the end, with inferiority, pain, pessimism, and world-weariness. They feel that every day of living is torturing themselves in despair, being negative, escaping, and finally even having suicidal tendencies and behaviors. Patients suffer from somatization symptoms. Chest tightness and shortness of breath. They just want to lie in bed every day and don't want to move. They have obvious anxiety. More serious cases will have schizophrenia symptoms such as auditory hallucinations, persecution delusions, and multiple personalities. Each episode of depression lasts for at least 2 weeks, a year, or even several years, and most cases tend to relapse.

The cause of depression is not very clear, but it is certain that many biological, psychological and social environmental factors are involved in the pathogenesis of depression. Biological factors mainly involve genetics, neurobiochemistry, neuroendocrine, nerve regeneration, etc.; psychological susceptibility qualities that are closely related to depression are premorbid personality traits, such as depressive temperament. Stressful life events in adulthood are important triggers for clinically significant depressive episodes. However, these factors do not work alone, emphasizing the interaction between genetics and environmental or stress factors, as well as the timing of the occurrence of this interaction, which has an important impact on the occurrence of depression.

The diagnosis of depression should mainly be based on medical history, clinical symptoms, disease course, physical examination and laboratory tests. The diagnosis of typical cases is generally not difficult. The internationally accepted diagnostic standards generally include ICD-10 and DSM-IV. In China, ICD-10 is mainly used, which refers to the first episode of depression and recurrent depression, excluding bipolar depression. Patients often have typical symptoms such as depressed mood, loss of interest and pleasure, low energy, or feelings of fatigue. Other common symptoms are ① reduced ability to concentrate and pay attention; ② reduced self-evaluation; ③ thoughts of self-guilt and worthlessness (even in mild attacks); ④ belief that the future is bleak and pessimistic; ⑤ thoughts of self-harm or suicide. or behavior; ⑥ sleep disturbance; ⑦ decreased appetite. The course of illness lasts for at least 2 weeks.

The treatment of depressive episodes should achieve three goals: ① improve the clinical cure rate, minimize the disability rate and suicide rate, the key is to completely eliminate clinical symptoms; ② improve the quality of life and restore social function; ③ prevent relapse. The principles of depression treatment mainly include: ① individualized treatment; ② gradually increase the dose, use the minimum effective dose as much as possible, minimize adverse reactions, and improve medication compliance; ③ sufficient dose and sufficient course of treatment; ④ single medication as much as possible, if the effect is not good, consider conversion treatment, enhancement treatment or combination treatment, but pay attention to drug interactions; ⑤ informed consent before treatment; ⑥ closely observe changes in the condition and adverse reactions during treatment and deal with them in time; ⑦ can be combined with psychological treatment to increase the efficacy; ⑧ actively treat other physical diseases, substance dependence, anxiety disorders, etc. that co-occur with depression.

Medication is the mainstay of treatment for moderate to severe depressive episodes. Currently, the first-line antidepressants in clinical use mainly include selective serotonin reuptake inhibitors (SSRI, representing the drugs fluoxetine, paroxetine, sertraline, fluvoxamine, citalopram and escitalopram) , serotonin and norepinephrine reuptake inhibitors (SNRI, represented by the drugs venlafaxine and duloxetine), norepinephrine, and specific serotonergic antidepressants (NaSSA, represented by the drug mirtazone equality. The use of traditional tricyclic and tetracyclic antidepressants and monoamine oxidase inhibitors has been significantly reduced due to their serious adverse reactions.

Currently, drugs for depression are relatively single and their therapeutic effects are not ideal. Therefore, it is extremely important to find new ingredients that can be used to prepare depression drugs, which is of great significance to the prevention and treatment of depression.

Contents of the invention

In order to solve the technical problem that antidepressant drugs are single and the therapeutic effect is not obvious, the present invention provides the application of morin in the preparation of antidepressant drugs. The morin in the present invention can be used at doses of 40 mg/kg and 80 mg/kg. It significantly increases the sugar water preference rate of mice and shortens the immobility time in forced swimming and tail suspension experiments. Morin has the potential to be used in the preparation of antidepressant drugs.

The invention provides the application of morin in the preparation of antidepressant drugs. The structural formula of the morin is as follows:

Further, the morin is used to prepare antidepressant drugs in mice.

Further, the dosage of morin is 20-80 mg/kg according to the body weight of the mouse.

Further, the dosage of morin is 40-80 mg/kg according to the mouse body weight.

Further, the dosage of morin according to the mouse body weight is 40 mg/kg.

Further, the dosage of morin according to the mouse body weight was 80 mg/kg.

Further, the medicine is any pharmaceutically acceptable pharmaceutical dosage form made of morin as an active ingredient and any pharmaceutical auxiliary material or pharmaceutical excipient.

Further, the dosage forms include granules, tablets, granules, soft gel pills, capsules, drops, ointments or injections.

Compared with the prior art, the beneficial effects of the present invention are:

1. The present invention established a chronic mild stress depression model to study the effect of morin on chronic stress-induced depression-like behavior in mice. It was found that the morin medium-dose group (40 mg/kg) and the morin high-dose group (80 mg/kg ) significantly increased the sugar water preference rate of experimental mice and shortened the immobility time of forced swimming and tail suspension experiments, indicating that medium-dose morin and high-dose morin have antidepressant effects;

2. The present invention also induces depressive-like behavior in mice through corticosterone, and uses morin for oral administration. It is found that both the morin medium-dose group (40mg/kg) and the morin high-dose group (80mg/kg) significantly increased The sugar water preference rate shortened the immobility time in forced swimming and tail suspension experiments, indicating that morin has antidepressant effects.

Detailed ways

Specific embodiments of the present invention will be described in detail below, but it should be understood that the protection scope of the present invention is not limited by the specific embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without any creative work fall within the scope of protection of the present invention. The experimental methods described in the various embodiments of the present invention are conventional methods unless otherwise specified. The materials, reagents, etc. used in the following examples can be obtained from commercial sources unless otherwise specified.

Example 1: Application of morin in the preparation of antidepressant drugs.

1. Establishment of the chronic mild stress depression model

1. Materials and methods

a. Experimental animal preparation

70 SPF grade C57BL/6N male mice, weighing 18-22g, were adaptively fed for 7 days, during which sufficient drinking water and feed were provided;

b. Reagent/drug preparation

morin, fluoxetine, 0.9% sodium chloride solution (normal saline), 1% (w/v) sucrose solution, and purified water;

The chemical formula of morin is C15H10O7, CAS No.: 480-16-0, molecular weight: 302.24, and the structural formula of morin is:

2. Model construction method

(1) During the adaptive feeding period, three consecutive sugar water preference baseline measurements were performed, and mice with abnormal sugar water preference were eliminated (binge drinking: total intake > 2 times the average total intake of mice; underdrinking: total intake <1/2 of the average total intake of mice; sugar water preference ratio <60%), after the end, all remaining mice will be randomly divided into normal group and chronic stimulation group, and ensure that the sugar water preference ratio of each group is consistent;

(2) The normal group was fed normally and did not receive any stimulation; the chronic stimulation group was fed in a single cage and received chronic mild stimulation;

Stimulation factors: The chronic stimulation group was subjected to water and food deprivation, dirty cages, tilted cages, strobes, noise, overnight lighting twice, intermittent lighting, empty bottles, restraint, day and night reversal and ice water swimming stimulation; the specific process is as follows:

a. Food and water deprivation (24h): water and food deprivation for 24h;

b. Dirty cage (24h): Add 200mL of water into the cage to create a humid environment;

c. Inclined cage (45°): Place the cage at an angle of 45°;

d. Stroboscopic (150 flash/min): flash stimulation in a dark environment;

e. Noise (90±5dB): continuous playback of noise;

f. Lighting twice throughout the night: Do not turn off the lights at night, and illuminate continuously for 24 hours;

g. Intermittent lighting (interval 2h): switch the light on and off every 2h;

h. Empty bottle (1h): After fasting and water fasting, give an empty bottle;

i. Restraint (3h): Stuff the mouse into a 50mL centrifuge tube and fix it;

j. Day and night are reversed: turn off the lights during the day and turn on the lights at night;

k. Ice water swimming (4℃, 5min): Put the mice into 4℃ cold water and swim for 5min;

All stimulation processes a to k above were carried out independently and continuously. The stimulation order was randomly adjusted every week. The stimulation was continued for 12 weeks, and the mouse body weight was measured every week.

2. Experimental grouping and administration

After 8 weeks of continuous stimulation, the sugar water preference was measured, and stimulation-tolerant mice were eliminated based on the sugar water preference ratio (there was no significant change in the sugar water preference ratio before and after stimulation). According to the principle of consistent sugar-water preference ratio, the remaining mice in the chronic stimulation group were randomly divided into the model group, the morin low-dose group (20 mg/kg), the morin medium-dose group (40 mg/kg), and the morin high-dose group. (80mg/kg), positive control group (fluoxetine, 20mg/kg), 10 animals in each group. All drugs were dissolved in 0.9% sodium chloride solution in the form of suspension, and 10 mL/kg was administered intragastrically. The mice in the model group and the normal group were intragastrically administered with an equal volume of 0.9% sodium chloride solution for 4 weeks. Chronic mild stimulation was given during administration.

3. Behavioral measurement methods

1. Sugar water preference test (Sucrose preference test, SPT)

(1)Sugar water adaptation.

Before the measurement, all mice were fed in single cages, with one bottle of 1% (w/v) sucrose solution and one bottle of pure water in each cage to adapt for 48 hours. During this period, the positions of the sugar water and pure water bottles were exchanged every 12 hours to avoid conditioned conditions in the mice. Location preference.

(2)Formal SPT.

After the adaptation, the mice were deprived of food and water for 12 hours, and then given one bottle each of weighed and labeled new sucrose water and pure water. After 12 hours, all sugar water bottles and pure water bottles were quickly weighed and recorded. According to the formula: sugar water preference Ratio (%) = [sugar water intake/(sugar water intake + pure water intake)] × 100% to calculate the sugar water preference ratio of mice.

(3) Forced swimming test (FST)

Place the mouse in a cylindrical barrel with a height of 25cm and an inner diameter of 14cm. Add tap water with a height of 15cm and a temperature of 23±2°C. Make sure that the tail of the mouse cannot touch the bottom of the barrel. Use a camera to record the activities within 6 minutes. Observe and Record the mouse's immobility time within the next 4 minutes.

(4) Tail suspension test (TST)

Paste the tail of the mouse on the crossbar and hang it upside down on the table. Use a camera to record the activity within 6 minutes. Observe and record the immobility time of the mouse within the next 4 minutes.

4. Experimental results

Table 1 Effect of morin on depressive-like behavior in mice induced by chronic stress (Mean ± SEM, n = 10)

Note: Compared with the normal group, ##p<0.01; compared with the model group, *p<0.05, **p<0.01

Compared with the normal group, the sugar water preference rate of mice in the model group was significantly reduced, and the immobility time in the forced swimming and tail suspension tests was significantly prolonged, indicating that the model was successfully established. Compared with the model group, both the morin medium-dose group (40mg/kg) and the morin high-dose group (80mg/kg) significantly increased the sugar water preference rate and shortened the immobility time in forced swimming and tail suspension experiments, indicating that the medium-dose Morin and high doses of morin have antidepressant effects.

Example 2: Application of morin in the preparation of antidepressant drugs.

1. Establishment of the corticosterone-induced depression model

1. Materials and methods

a. Experimental animal preparation

60 male ICR mice, weighing 18-22g;

b. Reagent/drug preparation

Morin, fluoxetine, corticosterone, 0.9% sodium chloride solution (physiological saline), 1% (w/v) sucrose solution and pure water.

2. Experimental grouping and administration

Male ICR mice were randomly divided into 6 groups, with 10 mice in each group (n=10). The 6 groups of mice were respectively normal group, corticosterone group, fluoxetine group (20mg/kg), and morin low-dose group (20mg /kg), morin medium-dose group (40mg/kg), and morin high-dose group (80mg/kg). The administration method of fluoxetine and morin was intragastric administration, and corticosterone (40 mg/kg) was injected subcutaneously 30 minutes after administration. The administration volume was 10 mL/kg. The normal group was given the same amount of normal saline. After 21 days of continuous injection, behavioral experiments were conducted.

3. Behavioral measurement methods

1. Sugar water preference test (Sucrose preference test, SPT)

(1)Sugar water adaptation.

Before the measurement, all mice were fed in single cages, with one bottle of 1% (w/v) sucrose solution and one bottle of pure water in each cage to adapt for 48 hours. During this period, the positions of the sugar water and pure water bottles were exchanged every 12 hours to avoid conditioned conditions in the mice. Location preference.

(2)Formal SPT.

After the adaptation, the mice were deprived of food and water for 12 hours, and then given one bottle each of weighed and labeled new sucrose water and pure water. After 12 hours, all sugar water bottles and pure water bottles were quickly weighed and recorded. According to the formula: sugar water preference Ratio (%) = [sugar water intake/(sugar water intake + pure water intake)] × 100% to calculate the sugar water preference ratio of mice.

(3) Forced swimming test (FST)

Place the mouse in a cylindrical barrel with a height of 25cm and an inner diameter of 14cm. Add tap water with a height of 15cm and a temperature of 23±2°C. Make sure that the tail of the mouse cannot touch the bottom of the barrel. Use a camera to record the activities within 6 minutes. Observe and Record the mouse's immobility time within the next 4 minutes.

(4) Tail suspension test (TST)

Paste the tail of the mouse on the crossbar and hang it upside down on the table. Use a camera to record the activity within 6 minutes. Observe and record the immobility time of the mouse within the next 4 minutes.

IV. Experimental Results

Table 2 Effects of mulberry pigment on depressive-like behavior induced by corticosterone in mice (Mean±SEM, n＝10)

Note: Compared with the normal group, #p<0.05, ##p<0.01; compared with the model group, *p<0.05, **p<0.01

Compared with the normal group, the sugar water preference rate of mice in the corticosterone group was significantly reduced, and the immobility time in the forced swimming and tail suspension tests was significantly prolonged, indicating that the depression model was successfully established. Compared with the corticosterone group, both the morin 40 and 80 mg/kg groups significantly increased the sugar water preference rate and shortened the immobility time in the forced swimming and tail suspension tests, indicating that they have antidepressant effects.

Although the preferred embodiments of the present invention have been described, those skilled in the art will be able to make additional changes and modifications to these embodiments once the basic inventive concepts are apparent. Therefore, it is intended that the appended claims be construed to include the preferred embodiments and all changes and modifications that fall within the scope of the invention.

Obviously, those skilled in the art can make various changes and modifications to the present invention without departing from the spirit and scope of the invention. In this way, if these modifications and variations of the present invention fall within the scope of the claims of the present invention and equivalent technologies, the present invention is also intended to include these modifications and variations.

Claims (8)

1. The application of morin in the preparation of antidepressant drugs, characterized in that the structural formula of morin is as follows: 2. Application of morin in the preparation of antidepressant drugs according to claim 1, characterized in that the morin is used to prepare antidepressant drugs in mice. 3. The application of morin according to claim 1 in the preparation of antidepressant drugs, characterized in that the dosage of morin according to the body weight of mice is 20-80 mg/kg. 4. The application of morin in the preparation of antidepressant drugs according to claim 3, characterized in that the dosage of morin according to the body weight of mice is 40-80 mg/kg. 5. The application of morin in the preparation of antidepressant drugs according to claim 4, characterized in that the dosage of morin according to the body weight of mice is 40 mg/kg. 6. The application of morin in the preparation of antidepressant drugs according to claim 4, characterized in that the dosage of morin according to the body weight of mice is 80 mg/kg. 7. The use of mulberry pigment in the preparation of an antidepressant drug according to claim 1, characterized in that the drug is any pharmaceutical dosage form that is pharmaceutically permitted and is prepared from mulberry pigment as an active ingredient and any pharmaceutical auxiliary material or pharmaceutical excipient. 8. The application of morin in preparing antidepressant drugs according to claim 7, characterized in that the dosage form includes granules, tablets, granules, soft gel pills, capsules, dropping pills, ointments or injection.