CN118416068A

CN118416068A - Application of berbamine in preparation of antidepressant drugs

Info

Publication number: CN118416068A
Application number: CN202410896319.0A
Authority: CN
Inventors: 张志玲; 翟所迪
Original assignee: Peking University Third Hospital Peking University Third Clinical Medical College
Current assignee: Peking University Third Hospital Peking University Third Clinical Medical College
Priority date: 2024-07-05
Filing date: 2024-07-05
Publication date: 2024-08-02

Abstract

Berbamine (Berbamine) is a dibenzyl isoquinoline alkaloid extracted from plants. At present, research on berbamine in the antidepressant field is not reported yet. The natural source and relatively low toxicity of berbamine make it a powerful candidate for the development of novel antidepressants. The application relates to application of berbamine or pharmaceutically acceptable salt thereof in preparation of a preparation for depression. The application exploits the clinical new indication application of the berbamine, and can be used for treating and relieving depressive mood disorder or depression. The inventor judges the anti-depression effect of the berbamine hydrochloride by the animal tail suspension and forced swimming immobility time in a classical depression animal model, and the result shows that the immobility time of a depression model mouse is shortened compared with the immobility time of a treatment group without gastric lavage in the treatment process of 2.5-10 mg/kg of gastric lavage, and especially the anti-depression effect is optimal in the mice of 5 mg/kg of berbamine hydrochloride.

Description

Application of berbamine in preparation of antidepressant drugs

Technical Field

The invention relates to the field of medicines, in particular to application of berbamine in preparation of antidepressant medicines.

Background

Depression is a common mental disorder disease and is a global public health problem characterized by sustained sad mood, loss of interest, loss of appetite, sleep disorders and other symptoms, and severe people can develop pessimistic pessimistic mood and suicidal behavior, affecting the quality of life of millions of people. According to Saveanu RV in Etiology of depression: GENETIC AND environmental factors the results disclosed in one article of text indicate that the suicide rate of depression patients is as high as 14%.

Although a variety of antidepressants are currently available, such as selective 5-HT reuptake inhibitors (SSRIs), tricyclic antidepressants, etc., for example: a new application of morphine disclosed in Chinese patent application with publication number of CN 115671106A. Animal test results prove that morphine can obviously raise the erection times, sugar water consumption, weight and horizontal crossing number of a rat depression model, improve the blood 5-HT level of rats and quickly achieve the anti-depression effect. Currently, chemical medicines on the market mainly select escitalopram, fluoxetine, mirtazapine, paroxetine, sertraline, citalopram, duloxetine, milnacipran, amitriptyline and the like for treating depression, but the medicines have the problems of multiple contraindications, obvious side effects, easy recurrence after stopping the medicine, lower effective rate, poor patient compliance and the like.

These drugs vary in therapeutic effect and have delayed onset of action, often accompanied by adverse effects such as weight gain, sexual dysfunction or therapeutic resistance. Therefore, finding new antidepressant treatment strategies is an important research direction in the field of psychomedicine.

At present, chinese herbal medicines and plant extract products thereof are also one of main research directions for developing antidepressant medicines. For example, st.John's wort extract, morinda root oligosaccharide, amber extract, etc. have been marketed. The natural products have efficacy on different types of depressed patients through different mechanisms of action.

The publication "Behavioral and Biochemical Evaluation of Anti-Depressive and Oxidative Stress-Ameliorating Effects of Amber Extract in Adult Male ICR Mice"（https://doi.org/10.3390/nutraceuticals3020017） of Nutraceuticals proposes: amber is a terpenoid-containing resin from pine. The research proves that the amber has the biological activities of anti-stress, anti-Alzheimer's disease or neuroprotection, anti-inflammatory, lipid-lowering and the like. Amber extract can prevent or control stress-induced depression by modulating the HPA axis system and reducing the levels of key stress hormones (such as ACTH and corticosterone). In addition, amber extract improvement results in an increase in the level of antidepressant neurotransmitters (dopamine and serotonin).

Because depression belongs to mental diseases, the medicine taking period and recurrence risk of depression both enable the medicine intake of patients to be larger than that of common diseases. Therefore, natural product drugs with strong pertinence, less adverse reactions and relatively less damage to the liver and kidney are one of the main directions in the field of antidepressant research.

The patent application with publication number CN110464744A discloses a Xinjiang black Berberis extract, a preparation method and application thereof, wherein the Xinjiang black Berberis extract comprises the following active ingredients: 2.70-4.56 mg/g of magnaline, 5.87-15.93 mg/g of berberine, 4.42-6.01 mg/g of ferulic acid, 0.24-0.56 mg/g of african stephanine, 2.17-3.80 mg/g of jateorhizine, 2.89-4.66 mg/g of palmatine and 4.13-6.99 mg/g of berberine. Antibacterial experiments prove that the berberis thunbergii root extract can inhibit the growth of staphylococcus aureus, escherichia coli and pseudomonas aeruginosa and has good antibacterial activity; meanwhile, the berberis thunbergii root extract can change the permeability of staphylococcus aureus, pseudomonas aeruginosa and escherichia coli cell membranes, damage the integrity of the cells and obviously increase the extracellular ATP concentration. The embodiment of the application also records the curative evaluation of the interference effect of the berberis thunbergii root on the Irritable Bowel Syndrome (IBS) and the research experiment based on the mechanism of the brain intestinal movement, takes excitatory neuron CHAT, cytokine interleukin IL-6, tumor necrosis factor TNF-alpha, gastrointestinal hormone 5-HT, neuropeptide CGRP and c-FOS gene expression nuclear protein as research indexes, and the result shows that the berberis thunbergii root extract can relieve the abdominal pain and diarrhea manifestations of an IBS model rat; the action mechanism of the brain and intestine movement shows that: the berberis thunbergii root can down regulate the expression of ghatt, c-FOS, CGRP, 5-HT3R, 5-HT4R in brain and colon tissues, however, this document speculates that the berberis thunbergii root can treat IBS by acting on ghatt peptide and thereby affecting the central nervous system without data.

It is well known that IBS patients may develop clinical manifestations like depressive disorders, which often fluctuate due to disease effects, unlike depression, especially primary depression. Thus, the above-mentioned patent application publications are not directed to any technical details related to depression. The compositions disclosed in the above patents contain a plurality of components which may be effective for depression, and the action mechanism is not clear when the compositions act on depression caused by irritable bowel syndrome due to different substance types and substance components in the mixture.

Furthermore, there are differences in one aspect due to the understanding of those skilled in the art; on the other hand, since the applicant has studied a lot of documents and patents while making the present invention, the text is not limited to details and contents of all but it is by no means the present invention does not have these prior art features, but the present invention has all the prior art features, and the applicant remains in the background art to which the right of the related prior art is added.

Disclosure of Invention

The present invention aims at researching one new treating scheme for depression, especially with natural berbamine product.

Berbamine (Berbamine) is a dibenzyl isoquinoline alkaloid extracted from a variety of berberis plants. Berbamine has been used clinically for leukopenia caused by various reasons, and can also be used for preventing leukopenia after cancer radiotherapy and chemotherapy. In recent years, scientific research began to reveal potential applications of berbamine in the neuroscience field, including anti-neuropathic pain, alzheimer's disease. Preliminary studies have shown that berbamine can have a positive effect on the central nervous system through a variety of mechanisms, such as improving neuroinflammatory states, promoting nerve cell growth and repair, and the like. However, no research on berberine as a single active ingredient in the antidepressant field has been reported at present. The natural source and relatively low toxicity of berbamine make it a powerful candidate for the development of novel antidepressants.

One aspect of the present application relates to the use of berbamine or a pharmaceutically acceptable salt, hydrate or precursor thereof for the preparation of a formulation for depression. In particular to the application of berberine or pharmaceutically acceptable salt, hydrate or precursor thereof in preparing a preparation for pathological depression. Preferably, the application relates to the application of berbamine or pharmaceutically acceptable salt, hydrate or precursor thereof in preparing a preparation for acute depression, as shown by the experimental results of mouse tail suspension in the examples.

The application exploits the new application of the berbamine, which can be used for treating and relieving the depressed mood disorder or depression. The inventor judges the anti-depression effect of the berbamine through animal tail suspension and forced swimming experiment immobility time in a classical depression animal model, and the result shows that the immobility time of a depression model mouse is shortened compared with the immobility time of a treatment group without gastric lavage in the treatment process of 2.5-10 mg/kg, and the effect is optimal especially in the mice of a berbamine group of 5 mg/kg. The above results demonstrate that berbamine has the function of treating and alleviating depressive mood disorders or depression. The application also provides a preparation form which can be realized. The berbamine can be used as an active ingredient, is applied to antidepressant drug compositions, and provides more choices for treating depressive mood disorders.

According to a preferred embodiment, the depression comprises major depression, bipolar depression, psychotic depression, reactive depression, climacteric depression, secondary depression, post partum depression, seasonal depression.

According to a preferred embodiment, the pharmaceutically acceptable salt of berbamine comprises berbamine hydrochloride.

According to a preferred embodiment, the chemical formula of berbamine for use in the treatment of depressed mood is as follows:

（Ⅰ）。

The diagnosis criteria for depressive disorder related to the Chinese mental disorder classification and diagnosis criteria (CCMD-3) are as follows:

[ symptom criteria ] is mainly mental depression, and there are at least 4 items:

(1) Loss of interest, unpleasant sensation;

(2) Reduced energy or tiredness;

(3) Psychomotor retardation or agitation;

(4) Too low self-assessment, self-responsibility, or feelings of guilt;

(5) Difficulty in association or reduced subjective thinking ability;

(6) Repeatedly appearing die for's thoughts or suicidal and self-damaging behaviors;

(7) Sleep disorders such as insomnia, wakefulness, or hypersomnia;

(8) Appetite reduction or significant weight loss;

(9) Hyposexuality.

According to the experimental verification of related mice, the berberine or the pharmaceutically acceptable salt thereof has the function of improving mental retardation or agitation, energy decline or fatigue caused by depression.

Another aspect of the application relates to a pharmaceutical composition. The pharmaceutical composition comprises one of the following combinations: a. berbamine; b. one of berbamine and a pharmaceutically acceptable salt thereof; c. berbamine and various medicaments for treating depression or depression-associated diseases. Preferably, the antidepressant drug comprises a traditional Chinese medicine.

According to a preferred embodiment, the pharmaceutical composition is preferably administered orally.

According to a preferred embodiment, the pharmaceutical composition dosage forms comprise tablets, capsules, granules, oral solutions, sustained-release oral preparations, powders, injections, aerosols and other dosage forms, i.e. the pharmaceutical composition is in the form of tablets, capsules, granules, oral solutions, sustained-release oral preparations, powders, injections, aerosols and other dosage forms.

According to a preferred embodiment, the dosage of berbamine hydrochloride for animal use is 1-10 mg/kg/day. Preferably, the dosage of the berbamine hydrochloride is 1-2.5 mg/kg/day. Preferably, the dosage of the berbamine hydrochloride is 2.5-5 mg/kg/day. Preferably, the dosage of the berbamine hydrochloride is 5-10 mg/kg/day. Preferably, the dosage of berbamine hydrochloride is 2.5 mg/kg/day. More preferably, the dosage of berbamine hydrochloride is 5 mg/kg/day. Preferably, the dosage of berbamine hydrochloride is 10 mg/kg/day. In the present application, the unit mg/kg/day of the dosage of berbamine hydrochloride means the dosage of berbamine hydrochloride (mg) per kg body weight of mice per day.

According to the prior known berbamine toxicological data: the half-lethal dose (LD 50) of berbamine hydrochloride tablet mice orally administered was 1500 mg/kg. In the dog subacute toxicity experiment, 30-120 mg/kg/day of berbamine hydrochloride is orally taken, the total experiment is taken for 30 days, 30 mg/kg/day is orally taken at first, and 120 mg/kg/day is changed after 15 days. Anorexia occurred only at large doses (60 mg/kg/day), but continued administration was not affected, and recovery was possible after withdrawal. No abnormalities were seen in blood regulation, BSP excretion and serum urea nitrogen. In the experiments of rats, the administration is carried out 3 times a week, 250 mg/kg each time, and the administration is carried out for 5 months, the animal body weight is the same as that of the animals in the paired groups, and no abnormal changes are found in the liver, the kidney, the spleen and the like in pathological examination, so that the long-term toxicity of the berberine is proved to be very low. According to the dosage of the drug instruction, the maximum daily dosage of the berbamine is not more than 300 mg. From the data in the examples, the better the intervention effect on the depression effect of the mice was accompanied by the increase of the administration amount of berbamine. Based on this, the daily dosage of berberine in the preparation for human use is not more than 300 mg.

According to a preferred embodiment, the pharmaceutical composition comprises a pharmaceutically acceptable carrier, diluent, preservative, solubilizer, stabilizer, disintegrant, binder, lubricant, wetting agent, emulsifier, sweetener, colorant, flavoring agent, salt, buffer, coating agent or antioxidant. The diluent may be starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, glucose, urea, calcium carbonate, kaolin, microcrystalline cellulose, aluminum silicate, etc. The binder and lubricant may be water, glycerol, polyethylene glycol, ethanol, propanol, starch slurry, dextrin, syrup, mel, glucose solution, acacia syrup, gelatin slurry, sodium carboxymethyl cellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone, etc. The disintegrating agent can be dry starch, alginate, agar powder, brown algae starch, sodium bicarbonate and citric acid, calcium carbonate, polyoxyethylene, sorbitol fatty acid ester, sodium dodecyl sulfonate, methylcellulose, ethylcellulose, etc.

According to a preferred embodiment, the antidepressant drug with synergistic effect to be administered in combination with berbamine comprises an serum-elevating 5-hydroxytryptamine or norepinephrine antidepressant drug or the like. Preferably, the antidepressant drug with synergistic effect for administration in combination with berbamine comprises one or more of citalopram, fluoxetine, mirtazapine, paroxetine, sertraline, escitalopram, duloxetine, milnacipran, amitriptyline.

According to a preferred embodiment, the drug to be combined with berbamine comprises a drug having analgesic, anti-alzheimer's disease, anti-parkinson's disease, anxiolytic or sleep-aiding functions. Preferably, the analgesic drug comprises one or more of a non-steroidal anti-inflammatory drug, pregabalin, gabapentin, duloxetine. Preferably, the anti-alzheimer's disease drug comprises one or more of memantine, donepezil, lenkanesab, mannite sodium. Preferably, the antiparkinsonism drug comprises one or more of selegiline, rasagiline, mecobab, dopa hydrazine, benzomarirope, pramipexole, ropinirole. Preferably, the anxiolytic or hypnotic drug comprises one or more of alprazolam, esmolam, diazepam, lorazepam, clonazepam, buspirone, aripiprazole, quetiapine, olanzapine, and epipiprazole.

In particular, in clinical application, the combined administration has been a popular treatment scheme for patients with depression accompanied by various symptoms, and according to the pharmacological toxicity research disclosed by berberine, the symptoms of anxiety and insomnia caused by depression are synchronously treated by combining the berberine through treatment means known in the prior art, so that the influence of the accompanying symptoms on the life quality of the patients can be reduced while the treatment of the depression is provided for the patients. Especially, the berbamine belongs to a natural product, has low toxic and side effects on human bodies, has low influence on liver and kidney functions, and has the natural advantage of being shared with a compound drug when being used in combination.

In particular, in terms of clinical application, combination therapy has been a popular treatment regimen in patients with various neuropsychiatric diseases accompanied with depression symptoms, and according to the pharmacological toxicity studies disclosed for berberine, simultaneous treatment of depression symptoms mainly caused by alzheimer's disease, antiparkinsonism and pain can be performed by combining berberine through treatment means known in the prior art, and the influence of the associated depression symptoms on the life quality of the patients can be reduced while providing anti-alzheimer's disease, antiparkinsonism and pain treatment to the patients. Especially, the berbamine belongs to a natural product, has low toxic and side effects on human bodies, has low influence on liver and kidney functions, and has the natural advantage of being shared with a compound drug when being used in combination.

According to a preferred embodiment, the medicament for treating depression or a concomitant depression disease comprises a Chinese medicament or a Chinese patent medicament having an antidepressant effect. Preferably, the medicament for treating depression or a concomitant depression disease comprises one or more of a san johnsoni extract, a morinda officinalis oligosaccharide, an amber extract.

Specifically, the extract of san johnsonii exerts an antidepressant effect by inhibiting the reabsorption of presynaptic membrane norepinephrine, 5-hydroxytryptamine and dopamine; the morinda root oligosaccharide plays an anti-depression role by increasing the 5-HT and DA levels of the forehead cortex; the amber extract exerts antidepressant effects by reducing the release of HPA hyperthyroidism-modulating stress hormone. They exert synergistic antidepressant effects when used in combination with berbamine.

In another aspect, the application relates to a combination regimen comprising at least one Chinese patent drug and one chemical. The combined medication has the effect of improving the treatment of depression. The combined administration scheme can also reduce the influence of long-term administration on the side effects of human bodies.

According to a preferred embodiment, the antidepressant compound comprises a serum-enhancing 5-hydroxytryptamine or norepinephrine, among others. Depression patients may also be accompanied by psychological symptoms such as anxiety, self-crime, etc. and physical symptoms such as sleep and appetite disorders when producing depressed emotions, and drugs directed only to depressed emotions are not able to solve such symptoms. A combination regimen that is personalized for different symptoms is clinically used.

Based on this, the present application provides a combination regimen comprising at least berberine for alleviating or treating depression and one medicament for the concomitant symptoms of a patient suffering from depression.

Drugs for the accompanying symptoms of depression patients include atypical antipsychotics, anxiolytics or drugs that rapidly alleviate significant anxiety symptoms and accompanying sleep disorders in depression patients in a short period of time. Atypical antipsychotics include aripiprazole, quetiapine sustained release tablets, olanzapine or epipiprazole, and the like. The anxiolytic comprises buspirone, tandospirone. Buspirone can improve cognitive function in anxiety patients. The drug for rapidly relieving the remarkable anxiety symptoms and the accompanying sleep disorder of the depression patients in a short period can be benzodiazepine drugs.

According to a preferred embodiment, the pharmaceutical composition has the function of combating depressive sleep disorders.

Considering that the current pathogenesis of depression is complex, the clinical treatment method for depression (especially for depression patients with abnormal behaviors affecting life quality) often adopts a multi-drug combination treatment mode, such as antidepressant chemicals and traditional Chinese medicines; antidepressants and mood stabilizers; antidepressants and antipsychotics; antidepressants, anxiolytics, etc.

In the existing market, berberine belonging to tertiary amine alkali is known to have the advantages of good intestinal absorption, high safety and low toxic and side effects. Berbamine has been formed into a good stable dosage form. Thus, the present application provides for the co-administration of berbamine-based antidepressant drugs in combination with the pharmacological effects of berbamine, especially for patients with sleep disorders due to anxiety.

Drawings

FIG. 1 is a diagram showing the motor ability of a behavioural test dosing mouse;

FIG. 2 shows the immobility time of tail suspension experiments of behavioural test dosing mice;

FIG. 3 shows the time period for forced swimming of the behavioural test dosing mice.

Detailed Description

The following detailed description refers to the accompanying drawings.

The following examples are only for further explanation of the beneficial effects of berberine in the present application, and should not be used to limit the scope of the present application. The specific meaning of the terms in the present application will be understood by those of ordinary skill in the art in specific detail. The experimental procedures described in the examples below are conventional, unless otherwise specified. The reagents and the like used in the following examples are commercially available unless otherwise specified. The terms "comprising" and "having" and any variations thereof, are intended to cover a non-exclusive inclusion. For example, a process, method, apparatus, article, or device that comprises a list of steps is not limited to the elements or modules listed but may alternatively include additional steps not listed or inherent to such process, method, article, or device.

By "pharmaceutically acceptable salts" as used herein is meant those salts which are, within the scope of sound medical judgment, suitable for contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit/risk ratio, such as those prepared by increasing the solubility of the drug or for enhancing its stability, and are commonly referred to as sodium or potassium salts. Specifically, in order to precipitate the berberine of the tertiary amine type alkaloid in the solution so as to facilitate preparation and storage, the berberine hydrochloride is mainly adopted in clinic at present.

In the present invention, the "berbamine" may be a compound represented by formula I in pure form, or a compound represented by formula I having a purity of more than 90%, or may be an extract of a berberidaceae plant containing 1 to 99 wt% of berbamine. More preferably, the "berbamine" may be an extract of a berberidaceae plant of 5-99 wt% berbamine. The preparation method of berbamine can be extracted from plants or chemically synthesized by methods known to those skilled in the art.

The pharmaceutically acceptable salt refers to salts generated by the reaction of a compound and inorganic acid, organic acid, alkali metal or alkaline earth metal and the like. These salts include, but are not limited to, (1) salts formed with the following mineral acids: such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid; (2) Salts with organic acids such as acetic acid, oxalic acid, succinic acid, tartaric acid, methanesulfonic acid, maleic acid, or arginine. Other salts include salts with alkali or alkaline earth metals (such as sodium, potassium, calcium or magnesium) in the form of esters, carbamates, or other conventional "prodrugs".

The term "precursor" refers to a salt or solution of a compound having the structure of formula (I) or a compound having the structure of formula (I) that undergoes a metabolic or chemical reaction in a patient when administered by an appropriate method.

The invention can also comprise isomers and racemates of berbamine with depression treatment effect. The isomer, racemate compounds of berbamine have one or more asymmetric centers. The above compounds may exist as racemic mixtures, individual enantiomers, individual diastereomers, diastereomeric mixtures, cis-or trans-isomers.

Statistics for data processing referred to in the present application: GRAPHPAD PRISM Version 5 (GraphPad Software, inc., la Jolla, CA, USA) software was used for statistical analysis. Data are all expressed in mean+ -SEM, using One-way ANOVA with One-way analysis of variance, p <0.05 being statistically significant.

The application evaluates the antidepressant effect of the berberine (Berbamine, BBM) by counting the time of the FST immobility through a Forced Swimming Test (FST). The application evaluates the antidepressant effect of the berbamine by counting the time of TST immobility through a Tail Suspension Test (TST).

Example 1

Preparation of a mouse model of LPS-induced depression.

Lipopolysaccharide (LPS) -induced mouse model is a common animal model that mimics human depression. LPS is a cell wall constituent of gram-negative bacteria capable of eliciting inflammatory responses by activating the immune system, thereby mimicking the pathological processes associated with depression in animals.

C57BL/6J mice, male, 18-22 g, purchased from animal experiment center of North Damedical department, SPF grade animals, placed 5-6 per cage, kept at constant temperature and constant humidity, day-light lamps with light and shade of every 12 h alternately, and fed water freely, and experiments were performed after 1 week of adaptation to the environment.

Dosage and configuration: LPS was formulated with physiological saline at a dose of 1 mg/kg and a dosing volume of 0.01: 0.01 ml/g.

Grouping: the C57 mice were randomly divided into 6 groups, which were a blank control group, a model group, a low-dose group of berbamine hydrochloride, a medium-dose group of berbamine hydrochloride, a high-dose group of berbamine hydrochloride, and a duloxetine positive drug group, respectively. The mice of the model group, the low-dose group of the berberine hydrochloride, the medium-dose group of the berberine hydrochloride, the high-dose group of the berberine hydrochloride and the duloxetine positive drug group were given 1 mg/kg LPS in a single abdominal cavity.

Example 2

Implementation of a mouse behavioural experimental model.

Dosage and configuration: the berbamine hydrochloride is prepared by using physiological saline, and the administration dosage is 2.5 mg/kg, 5mg/kg, 10 mg/kg and the administration volume is 0.01 ml/g. Duloxetine hydrochloride is prepared with physiological saline, and the administration dosage is 9 mg/kg and the administration volume is 0.01 ml/g.

Grouping: the C57 mice were randomly divided into 6 groups, which were a blank control group, a model group, a low-dose group of berbamine hydrochloride, a medium-dose group of berbamine hydrochloride, a high-dose group of berbamine hydrochloride, and a duloxetine positive drug group, respectively. The mice of the model group, the low-dose group of the berberine hydrochloride, the medium-dose group of the berberine hydrochloride, the high-dose group of the berberine hydrochloride and the duloxetine positive drug group were given 1 mg/kg LPS in a single abdominal cavity. After 22 hours, the berberine hydrochloride is administrated by low-dose group lavage with 10 mg/kg of berberine hydrochloride. The berberine hydrochloride is administered by intragastric administration of 20 mg/kg. The berberine hydrochloride is administered by high dose group lavage at 40 mg/kg. Duloxetine 9 mg/kg was given to duloxetine positive drug group by intragastric administration. And (5) performing exercise capacity, tail suspension and forced swimming experiments after 2 hours.

First motion capability detection

A box of size 42 x 42cm and a monitoring camera were used. Mice were placed individually in the center of the box and were free to explore for 6 minutes, with 1 st minute being acclimated and 5 minutes of activity after mice were recorded. After each test, the excrement was cleaned and wiped with alcohol to remove odors. The total movement distance of the mice was counted.

As shown in fig. 1, there was no difference in total range of movement between groups of mice, which was substantially 20 m. The relevant results show that the berbamine hydrochloride does not affect the exercise capacity or the physical state of the mice in the depression state or the normal state.

(II) tail suspension experiment

The mice were held on the suspension by an adhesive tape located approximately 2 cm from the tail tip to keep the head of the mice 15 cm from the ground. Mice were hung for 1 minute before testing, and the immobility time of the mice was counted for 5 minutes. Immobility is defined as the mice being suspended upside down and kept stationary.

As shown in fig. 2, the related experimental results show that:

Untreated model mice for depression had a suspension time of 89 s.2.5 The suspension time of the berbamine hydrochloride in mg/kg is 70 s after the administration by gastric lavage. The suspension time of 5 mg/kg of berbamine hydrochloride after gastric administration was 48 s.10 The suspension time of the berbamine hydrochloride in mg/kg is 48 s after the administration by gastric lavage. The suspension time of duloxetine after administration by gastric lavage was 40 s. The related results show that the berbamine hydrochloride can obviously inhibit the increase of the LPS-induced mice tail suspension immobility time. In particular, mice were kept stable for a period of time after gastric lavage administration of 5 mg/kg of berbamine hydrochloride.

(III) forced swimming experiment

The procedure used for this experiment was the same as that described in Maciel et al (2013). The experiment was carried out with a cylinder (diameter 18.5 cm, height 25 cm).

The cylinder was filled with water to a height of 17 cm a. The water is kept at 23-25 ℃. The immobility of the mice in water is defined as no movement other than that required to keep the heads of the mice above water. Each mouse was forced to swim for 6 minutes and the time to stay motionless in seconds for 4 minutes after quantifying the mice.

As shown in fig. 3, the related experimental results show that:

The untreated model mice for depression had a forced swimming immobility time of 45 s.2.5 The forced swimming immobility time of the berberine hydrochloride of mg/kg after the administration by gastric lavage is 28 s. The forced swimming immobility time after 5 mg/kg of berberine hydrochloride is 27 s.10 The forced swimming immobility time of the berberine hydrochloride of mg/kg after the administration by gastric lavage is 36 s. The forced swimming immobility time after duloxetine administration by gastric lavage is 19 s. The related results show that the berbamine hydrochloride can significantly inhibit the significant increase of the LPS-induced forced swimming immobility time of mice.

After 5 mg/kg of berbamine hydrochloride is administrated by stomach irrigation, the forced swimming immobility time of the mice is shortest, and after 10 mg/kg of berbamine hydrochloride is administrated by stomach irrigation, the forced swimming immobility time of the mice is increased compared with the forced swimming immobility time of 5 mg/kg of berbamine hydrochloride group mice. Thus, 5 mg/kg of berbamine hydrochloride is administered by gavage as the optimal dose.

The results show that the berbamine hydrochloride has the function of resisting mouse depression mood disorder, in particular to the berbamine hydrochloride with the dosage of 2.5-5 mg/kg.

It should be noted that the above-described embodiments are exemplary, and that a person skilled in the art, in light of the present disclosure, may devise various solutions that fall within the scope of the present disclosure and fall within the scope of the present disclosure. It should be understood by those skilled in the art that the present description and drawings are illustrative and not limiting to the claims. The scope of the invention is defined by the claims and their equivalents. The description of the invention includes various inventive concepts such as "preferably," "according to a preferred embodiment," or "optionally," all means that the corresponding paragraph discloses a separate concept, and the applicant reserves the right to filed a divisional application according to each inventive concept. Throughout this document, the word "preferably" is used in a generic sense to mean only one alternative, and not to be construed as necessarily required, so that the applicant reserves the right to forego or delete the relevant preferred feature at any time.

Claims

1. Use of berbamine or a pharmaceutically acceptable salt thereof in the preparation of a formulation for use in depression.

2. The use according to claim 1, wherein the depression comprises major depression, bipolar depression, psychotic depression, reactive depression, climacteric depression, secondary depression, post partum depression, seasonal depression.

3. A pharmaceutical composition for depression, characterized in that it comprises one of the following combinations:

a. Berbamine;

b. One of berbamine and a pharmaceutically acceptable salt thereof;

c. berbamine and various medicaments for treating depression or depression-associated diseases.

4. The pharmaceutical composition of claim 3, wherein the pharmaceutically acceptable salt of berbamine comprises berbamine hydrochloride.

5. A pharmaceutical composition according to claim 3, wherein the berbamine or a pharmaceutically acceptable salt thereof has a function of improving psychomotor retardation or agitation, hypofunction or fatigue caused by depression.

6. The pharmaceutical composition of claim 3, wherein the berbamine is administered at a dose of 300 mg/day or less.

7. The pharmaceutical composition of claim 3, wherein the pharmaceutical composition comprises a pharmaceutically acceptable carrier, diluent, preservative, solubilizer, stabilizer, disintegrant, binder, lubricant, wetting agent, emulsifier, sweetener, colorant, flavoring agent, salt, buffer, coating agent, or antioxidant.

8. A pharmaceutical composition according to claim 3, wherein the pharmaceutical composition is in the form of tablets, powders, granules, capsules, oral liquids, sustained release formulations, injections, aerosols and other external preparations.

9. The pharmaceutical composition according to claim 3, wherein the pharmaceutical composition comprises a drug having synergistic/analgesic/anti-Alzheimer's disease/anti-Parkinson's disease/anxiolytic/sleep-aiding functions in combination with berbamine,

The drug which is used in combination with the berberine and has synergistic function comprises the drug with the function of increasing serum 5-hydroxytryptamine, norepinephrine or dopamine;

the drug which is used in combination with the berberine and has analgesic function comprises one or more of nonsteroidal anti-inflammatory drug, pregabalin, gabapentin and duloxetine;

The drug which is used in combination with the berbamine and has the capability of resisting Alzheimer disease comprises one or more of memantine, donepezil, lenkanamab and mannite sodium;

The drug which is used in combination with the berbamine and has the capacity of resisting parkinsonism comprises one or more of selegiline, rasagiline, mecobab, dopa hydrazine, benzomarirope, pramipexole and ropinirole;

The drug which is used in combination with the berbamine and has anxiolytic or sleep-aiding function comprises one or more of alprazolam, escitalopram, diazepam, lorazepam, clonazepam, buspirone, aripiprazole, quetiapine, olanzapine and epipiprazole.

10. The pharmaceutical composition according to claim 3, wherein the drug for treating depression or depression-associated diseases comprises a Chinese medicine or a Chinese patent medicine having an antidepressant effect.