CN114272229A - Application of schisanhenol and derivatives thereof in preparation of medicines for treating depression and prepared antidepressant medicines - Google Patents

Abstract

The invention provides application of schisanhenol and derivatives thereof in preparing medicaments for treating depression and prepared antidepressant medicaments. The application dosage is 0.01-30mg of schisanhenol or derivatives thereof per kilogram of body weight, and the antidepressant effect can be produced within 60 minutes after administration. After 5 days of administration, both low and high doses produced significant antidepressant effects. The research result of the invention shows that in the tail suspension experiment of a mammal mouse, the schisanhenol or the derivative thereof has the effect of quickly resisting depression and is more effective than the conventional antidepressant drug imipramine. The invention adopts forced swimming experiment and mouse tail suspension experiment as drug screening experiment, and simultaneously carries out mouse Open field experiment (Open field test) to test the autonomous activity of the mouse and avoid the interference of central stimulant. The antidepressant drug has the advantages of obvious antidepressant effect, quick response, small dosage, small side effect and the like, and is expected to become a new antidepressant drug with high speed, high efficiency and a new mechanism.

Description

Application of schisanhenol and derivatives thereof in preparation of medicines for treating depression and prepared antidepressant medicines

Technical Field

The invention belongs to the technical field of medicines, and relates to application of schisanhenol (Hernandezine) and derivatives thereof in preparation of medicines for treating depression and prepared antidepressant medicines.

Background

Major Depressive Disorder (MDD) is a serious, recurrent disabling psychotic disorder. About 3 billion depression patients worldwide. The incidence of depression in china is 4.2%, with about 5600 ten thousand patients suffering depression. Depression is the second leading cause of life loss (years) due to disability, and has become a major public health problem that urgently needs to be solved. Depression is clinically manifested as depressed mood, hyposis, and even pessimistic and boredom, with suicide attempts or behaviors. The current first-line clinical antidepressants mainly comprise selective 5-hydroxytryptamine reuptake inhibitors, 5-hydroxytryptamine and norepinephrine reuptake inhibitors and the like, but the drugs have slow effect, narrow action spectrum and are easy to relapse after drug withdrawal. Despite the use of multiple antidepressant medications, about 30% of patients become refractory Depression (TRD). Patients with this type of refractory depression present a higher risk of social burden and risk of suicide. Therefore, the search for new antidepressant drugs with good compliance, few side effects and novel pharmacological mechanisms has great clinical requirements, and is also a hot spot of international research at present.

Schisanhenol (schizanenol; Gomisin K3; (+) -Gomisin K3; NSC 330515) is also known as (+) -Gomisin K3, deoxyschizandrin. A biphenyl cyclooctene lignin component extracted and separated from various schisandra plants.

The molecular formula of schisanhenol is C₂₃H₃₀O₆The molecular weight is 402.48, the melting point is 132-133 ℃, and the water-soluble chitosan-chitosan composite material can be dissolved in solvents such as ethanol, diethyl ether, ethyl acetate and DMSO and is almost insoluble in water. ExistingResearch shows that schisanhenol has an antioxidant effect, can inhibit cell damage caused by various chemical inducements, has an obvious protective effect on cell mitochondrial swelling and membrane fluidity reduction, has the activities of resisting fibrinolysis, inhibiting platelet aggregation and dilating blood vessels, has therapeutic and protective effects on cerebral infarction and cerebral function and morphology, and is a candidate medicament for treating ischemic cerebral apoplexy.

The subacute toxicity experiment proves that the schisanhenol has no obvious influence on the functions of bone marrow, liver, kidney and the like of rats. At present, schisanhenol as an active ingredient for preventing and treating depression is not reported.

Disclosure of Invention

The invention aims to provide application of schisanhenol and derivatives thereof in preparing medicaments for treating depression, and the medicaments have the advantages of remarkable anti-depression effect, quick response, small dosage, small side effect and the like.

The invention provides application of schisanhenol of a formula (I) or derivatives thereof in preparing a medicament for treating depression,

further, the derivatives include: sodium salt or potassium salt of schisanhenol, etc.

Further, the dosage is 0.01-30mg of schisanhenol or its derivatives per kg of body weight.

The invention also provides an anti-depression drug, which comprises the following components: schisanhenol or its derivatives, and pharmaceutically acceptable auxiliary components.

The medicinal components also comprise medicinal components which have positive effects on treating depression after being simultaneously applied.

Further, the pharmaceutical ingredients having a positive effect on the treatment of depression after the simultaneous administration include: monoamine oxidase inhibitor MAOI, tricyclic antidepressant TCA, selective serotonin reuptake inhibitor SSRI, serotonin and norepinephrine reuptake inhibitor SNRI, noradrenergic and specific 5-HT receptor antagonist NASSA, 5-HT antagonist and reuptake inhibitor, or melatonin and 5-HT2C receptor antagonist.

Further, the tricyclic antidepressants (TCAs) include amitriptyline, imipramine, chlorpromazine, doxepin, clomipramine, and the like; such Selective Serotonin Reuptake Inhibitors (SSRIs) are for example: fluoxetine (banseolute), paroxetine (tyloxamine), fluvoxamine (lansoprazole), sertraline (levofloxacin), citalopram (citalopram, siberian), escitalopram (escitalopram), etc.; the Serotonin and Norepinephrine Reuptake Inhibitors (SNRI), e.g., venlafaxine, duloxetine, etc.; the noradrenergic and specific 5-HT receptor antagonists (NASSA), e.g., mirtazapine, etc.; the 5-HT antagonist and reuptake inhibitor: such as nefazodone and trazodone; the melatonin and 5-HT2C receptor antagonists: such as agomelatine.

Further, the pharmaceutical ingredients which have a positive effect on the treatment of depression after simultaneous administration are herbs such as: john's wort, and tianeptine, Vortioxetine (also known as Vortioxetine), Bupropion (bupapion), and the like.

Further, the pharmaceutical ingredients which have positive effects on treating depression after simultaneous administration are as follows: ketamines, including S-ketamine or ketamine nasal feeds.

Further, the effective dose of the medicine is 0.01-30mg of schisanhenol and derivatives thereof per kilogram of body weight.

The above medicinal preparation is in the form of powder, granule, tablet, capsule, pill, solution, suspension or injection.

The schisanhenol is white granular crystal or white crystal powder, HRESI-MS M/z [ M + H ]]⁺403.21152, it is suggested that its molecular formula is C₂₃H₃₀O₆。

¹H NMR(400MHz,CDCl3)δH 6.57(1H,s,H-4),6.36(1H,s,H-11),5.71(1H,s,-OH),3.90(3H,s,-OCH3),3.89–3.86(9H,m,-OCH3×3),3.63(3H,s,-OCH3),2.57(dd,J＝13.6,7.4Hz,1H),2.47(dd,J＝13.6,1.9Hz,1H),2.28(dd,J＝13.3,9.5Hz,1H),2.05(d,J＝12.8Hz,1H),1.92–1.76(m,2H),1.58(s,1H),0.99(3H,d,H-8,J＝6.8Hz),0.74(3H,d,H-7,J＝7.1Hz).。

¹³C NMR (100MHz, CDCl3) Δ C153.2 (C-3),151.3(C-1),150.6(C-12),146.8(C-14),139.8(C-2),139.8(C-5),134.3(C-10),133.8(C-13),121.2(C-16),116.9(C-15),107.8(CH, C-4),107.3(CH, C-11),61.1(OCH3, C-2),61.0(OCH 2, C-1),55.9(OCH3, C-3),55.8(OCH3, C-12),40.9(CH, C-7),39.2(CH2, C-9),35.7(CH2, C-6),33.7(CH, C-8),21.8(CH3, C-18), CH 12.18 (CH-78, C-368). Determined as schisanhenol.

The medicament can be administered in unit dosage form, and the administration dosage form can be liquid dosage form or solid dosage form. For example, the liquid dosage form can be true solution, colloid, microparticle, emulsion, or suspension. Other dosage forms such as tablet, capsule, dripping pill, aerosol, pill, powder, solution, suspension, emulsion, granule, suppository, lyophilized powder for injection, etc.

The administration route can be intestinal or parenteral, such as oral, intramuscular, subcutaneous, nasal, oral mucosal, cutaneous, peritoneal or rectal.

The route of administration of the drug of the present invention may be administration by injection. The injection includes intravenous injection, intramuscular injection, subcutaneous injection, intradermal injection, acupoint injection, etc.

The medicine of the present invention may be prepared into common preparation, slow released preparation, controlled releasing preparation, targeting preparation and various particle medicine feeding system.

In order to prepare the unit dosage form into tablets, various carriers well known in the art can be widely used. In the vector: diluents and absorbents such as starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, glucose, urea, calcium carbonate, kaolin, microcrystalline cellulose, aluminum silicate, and the like; wetting agents and binders such as water, polyethylene glycol, ethanol, propanol, starch slurry, dextrin, syrup, honey, glucose solution, acacia slurry, gelatin slurry, sodium carboxymethyl cellulose, shellac, methyl cellulose, potassium phosphate, polyvinylpyrrolidone, etc.; disintegrating agents such as dried starch, alginate, agar powder, brown algae starch, sodium bicarbonate and citric acid, calcium carbonate, polyoxyethylene sorbitol fatty acid ester, sodium dodecylsulfate, methyl cellulose, ethyl cellulose, etc.; disintegration inhibitors such as sucrose, glyceryl tristearate, cacao butter, hydrogenated oil and the like; absorption accelerators such as quaternary ammonium salts, sodium lauryl sulfate and the like; lubricants, for example, talc, silica, corn starch, stearate, boric acid, liquid paraffin, polyethylene glycol, and the like. The tablets may be further formulated into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer and multi-layer tablets.

For making the administration units into pills, a wide variety of carriers well known in the art can be used. In the vector: for example, diluents and absorbents such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oils, polyvinylpyrrolidone, Gelucire, kaolin, talc, and the like; binders such as acacia, tragacanth, gelatin, ethanol, honey, liquid sugar, rice paste or batter, etc.; disintegrating agents, such as agar powder, dried starch, alginate, sodium dodecylsulfate, methylcellulose, ethylcellulose, etc.

For making the administration unit into a suppository, various carriers well known in the art can be widely used. In the vector: such as polyethylene glycol, lecithin, cocoa butter, higher alcohols, higher alcohol enzymes, gelatin, semisynthetic glyceroses, and the like.

To encapsulate the administration units, the active ingredient is mixed with the various carriers described above, and the mixture thus obtained is placed in hard gelatin capsules or soft gelatin capsules. Or making into microcapsule, suspending in aqueous medium to form suspension, or making into hard capsule or injection.

For example, the composition of the present invention is formulated into an injectable preparation, such as a solution, a suspension solution, an emulsion, a lyophilized powder, which may be aqueous or non-aqueous, and may contain one or more pharmaceutically acceptable carriers, diluents, binders, lubricants, preservatives, surfactants or dispersants. For example, the diluent may be selected from water, ethanol, polyethylene glycol, 1, 3-propanediol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitol fatty acid enzyme, etc. In addition, for the preparation of isotonic injection, sodium chloride, glucose or glycerol may be added in an appropriate amount to the preparation for injection, and conventional cosolvents, buffers, pH adjusters and the like may also be added. These adjuvants are commonly used in the art.

In addition, if desired, colorants, preservatives, flavors, flavorings, sweeteners, or other materials may also be added to the pharmaceutical preparation.

The dose of the pharmaceutical composition of the present invention to be administered depends on many factors, such as the nature and severity of the disease to be prevented or treated, the sex, age, body weight, character and individual response of the patient or animal, the administration route, the number of administrations, etc., and thus the therapeutic dose of the present invention can be widely varied. Generally, the dosage of the compounds of the present invention used is well known to those skilled in the art. The actual effective amount of the drug contained in the final preparation of the medicinal composition can be properly adjusted according to the requirement of the effective amount of the drug so as to achieve the treatment of obesity, abnormal glucose tolerance, hyperlipidemia, diabetes, complications thereof and other diseases; and the use of chronic inflammation, insulin resistance, cerebrovascular disease and atherosclerosis in relation to the above mentioned diseases.

In general, for a patient weighing about 75 kg, the compounds of the present invention are administered in a daily dose of 0.001mg/kg body weight to 200mg/kg body weight, preferably 1mg/kg body weight to 100mg/kg body weight. The above-mentioned dosage may be administered in a single dosage form or divided into several, e.g., two, three or four dosage forms, which is limited by the clinical experience of the administering physician and the dosage regimen. The compounds or compositions of the present invention may be administered alone or in combination with other therapeutic or symptomatic agents.

The invention provides an anti-depression drug, which comprises two stages of prevention and treatment. The dosage of the anti-depression drug is as follows: 0.01-30mg of schisanhenol and its derivatives are provided per kg of body weight per day. The administration mode of the anti-depression drug is oral administration, nasal spray, instillation or injection; the subject to be administered is a mammal, including a human.

The anti-depression drug provided by the invention is a drug administration dosage of 0.01-30mg of schisanhenol and derivatives thereof per kilogram of body weight; the antidepressant effect can be achieved within 60 minutes after administration. After 5 days of administration, both low and high doses produced significant antidepressant effects. The medicine has the advantages of remarkable antidepressant effect, quick action, small dosage, small side effect and the like. In the forced swimming test of mammal mice, the schisanhenol and the derivatives thereof have more obvious antidepressant effect than the conventional antidepressant drug imipramine.

Compared with the prior art, the invention has the beneficial technical effects that:

1. the invention provides application of schisanhenol or derivatives thereof in preparing anti-depression drugs. The research result of the invention shows that in the tail suspension experiment of a mammal mouse, the schisanhenol or the derivative thereof has the effect of quickly resisting depression and is more effective than the conventional antidepressant drug imipramine.

2. The invention adopts forced swimming experiment and mouse tail suspension experiment as drug screening experiment. Forced swimming experiments and mouse tail suspension experiments are two common animal behavior despair depression model experiments, and can better ensure the reliability of screening results. Forced swimming experiments in mice have been used for screening of many antidepressants. Moreover, most of the antidepressants with clinical treatment effects are also proved to be effective in reducing immobility time in forced swimming experiments.

By immobile, it is meant that "the animal stops struggling in water, or is in a floating state, only exposing nostrils to keep breathing, and only having small limb movements to keep the head floating on the water". Drugs to be screened were administered prior to the assay. Animals cannot escape from the harsh environment due to downstream swimming in a forced state, resulting in despair behavior of the animals. The model method is simple, convenient and reliable, and is widely used for screening and evaluating the antidepressant. The tail suspension experiment of the mouse is that the mouse does not struggle under the tail suspension state and presents a special quiet immobility state, and the antidepressant can obviously shorten the duration time of the immobility state. During the test, the tail of the mouse is fixed and suspended upside down. The tail of the mouse is not twisted and folded. And recording the immobility time. The immobility indexes are as follows: animal limbs and trunk struggle without twisting. The tail suspension experiment is sensitive to various antidepressants, and avoids the interference of temperature and animal movement dysfunction in the swimming experiment, so that the results of the forced swimming experiment can be effectively verified and supplemented when some mice are used for screening the antidepressants.

3. Shows stronger antidepressant effect than imipramine. In a tail suspension experiment of a mouse animal model, it is found that the depression symptom of a high-dose group mouse (10mg/kg) of schisanhenol and derivatives thereof starts to be relieved 60 minutes after injection, namely, the activity is more and more frequent compared with a blank control group, and the immobility time is obviously shortened. After 5 days of injection, the time of suspending tail and immobility of the tail is obviously shortened by schisanhenol and derivatives thereof. Schisanhenol and its derivatives show stronger antidepressant effect than imipramine at a dose (10mg/kg) lower than that of imipramine (15 mg/kg).

4. The invention also carries out an Open field test (Open field test) of the mouse to check the autonomous activity of the mouse and avoid the interference of central stimulant. Since the shortening of the immobility time of animals in classical animal models of depression may be due to the central excitatory action of the drug, the present invention also simultaneously performs mouse open-field experiments. The result shows that the high concentration of the schisanhenol and the derivatives thereof have no significant influence on the autonomous activity of mice compared with the control group, so that the possibility of causing mania by stimulant can be eliminated, and the schisanhenol and the derivatives thereof are proved to have significant antidepressant effect.

5. The antidepressant medicament taking the schisanhenol or the derivative thereof as the effective component is expected to become a new antidepressant medicament with high speed, high efficiency and a new mechanism.

Drawings

The drawings in the present application are intended to provide further explanation of the application, and the illustrative embodiments and description of the application are intended to explain the application and are not to be construed as limiting the application.

FIG. 1, schisanhenol structure formula

FIG. 2 of schisanhenol¹H NMR

FIG. 3 of schisanhenol¹³C NMR

FIG. 4 MS of schisanhenol

FIG. 5 Effect of schisanhenol injection on mouse Tail suspension experiment one hour later

Ordinate: tail suspension experiment mice immobility time(s), abscissa: from left to right, a DMSO control group, a WWZF low dose group (WW-L, 5mg/kg), a WWZF high dose group (WW-H, 10mg/kg), a normal saline control group, and a imipramine positive control group (15mg/kg) were sequentially arranged.

As a result: c57BL/6 male mice showed significant antidepressant effects in the mice tail suspension experiments 60 minutes after intraperitoneal injection of different doses of WWZF (10mg/kg) in the high dose group (animals per group N6-10, ANOVA test p < 0.05, p < 0.01).

FIG. 6 Effect of schisanhenol injection on mouse swimming test 5 days later

Ordinate: forced swimming test mice immobility time(s), abscissa: from left to right in sequence: DMSO control group, WWZF low dose group (WWZF-L, 5mg/kg), WWZF high dose group (WWZF-H, 10mg/kg), normal saline control group, imipramine positive control group (IMI, 15mg/kg),

as a result: five days after the C57BL/6 male mice are subjected to intraperitoneal injection of WWZF with different doses, the compound shows extremely remarkable anti-depression effect in a forced swimming experiment of the mice. This antidepressant effect is more pronounced than that of the traditional antidepressant drug imipramine (N-8-10, p < 0.05, p < 0.01 for t test in each group of animals).

Detailed Description

To further illustrate the present invention, the following detailed description of the invention is given by way of specific examples, which are purely illustrative and intended to describe the invention in detail and not intended to limit the exemplary embodiments according to the application.

Schisanhenol, CAS number: 69363-14-0, trade name: bailingwei J & K, available from Beijing Bighe Spectrum detection technology, Inc.

Example 1:

taking 150g of schisanhenol and a proper amount of auxiliary materials, sieving, uniformly mixing, and encapsulating to prepare 1000 schisanhenol capsules. Obtaining the content of schisanhenol according to quantitative analysis, and taking the content as the basis of the dosage.

Example 2:

diluting schisanhenol 150g with water, and flavoring with stevioside to obtain 10% liquid preparation, and making into schisanhenol oral liquid. Obtaining the content of schisanhenol according to quantitative analysis, and taking the content as the basis of the dosage.

Example 3:

adding water for injection into Schisandra chinensis sodium phenolate, fine filtering, bottling, and sterilizing to obtain injection.

Example 4:

schisandra chinensis phenol potassium salt is dissolved in sterile water for injection, added with excipient, stirred to dissolve, filtered by a sterile suction filter funnel, then subjected to sterile fine filtration, subpackaged in 2 ampoules, freeze-dried at low temperature, sterilized, sealed by melting to obtain the powder injection.

Example 5:

adding excipient into schisanhenol according to the weight ratio of the schisanhenol to the excipient of 9:1, and preparing into powder.

Example 6:

adding excipient into schisanhenol according to the weight ratio of schisanhenol to excipient of 1:5-1:10, granulating and tabletting.

Example 7:

schisandra phenol sodium salt is prepared into oral liquid according to a conventional oral liquid preparation method.

Example 8:

adding excipient into schisanhenol according to the weight ratio of the schisanhenol to the excipient of 5:1, and making into capsule, granule or electuary.

Example 9:

adding excipient into the schisanhenol potassium salt according to the weight ratio of the schisanhenol potassium salt to the excipient of 3:1, and preparing into capsules, granules or electuary.

Example 10:

schisandra chinensis phenol sodium salt 46.6 g, added with starch 600 g, lactose 200 g, menthol 3 g, carboxymethyl starch sodium 152 g, made into buccal tablet, as functional food.

Test example 1 Effect of schisanhenol on animal Depression model Tail suspension test

Experimental animals: c57BL/6 mice, male, 30-40 grams in weight, supplied by sbefu (beijing) biotechnology limited, license number: SCXK (Jing) 2019-. The animals are raised in cages with the light and shade period of 12h/12h, the room temperature of 20-22 ℃, the water is free, and the feed is provided by the Huada protein experimental animal center.

Experimental drugs: schisanhenol is extracted from institute of pharmaceutical sciences of Chinese academy of medicine, and its chemical purity and structural analysis are shown in FIGS. 2, 3 and 4. Imipramine hydrochloride (Imipramine hydrochloride) is a product of Sigma company, the product number is I7379, and the batch number is O56K 1380.

Experimental equipment: a cross bar; rubberized fabric; a camera (a mobile phone); JUNSO multifunctional timer.

The experimental steps are as follows: male C57BL/6 mice were acclimatized for one week and divided into 5 groups of 6-8 mice each. The two groups are respectively a dimethyl sulfoxide DMSO control group (DMSO is dissolved in normal saline), a schisanhenol low-dose group (schisanhenol-L is dissolved in DMSO at 5mg/kg), a schisanhenol high-dose group (schisanhenol-H is dissolved in DMSO at 10mg/kg), a traditional antidepressant drug imipramine positive control group (15mg/kg imipramine is dissolved in normal saline), and a normal saline control group. The medicine is administrated by intraperitoneal injection at 10 am according to 0.1ml/10g body weight, and after 60 minutes of injection, tail suspension experiments are carried out on 6-8 mice in each group; in the tail suspension experiment of the mouse, the tail of the mouse is stuck on a horizontal cross bar at a position 2 cm away from the tail tip by using an adhesive tape, so that the animal is in an inverted hanging state, and the head of the animal is 15 cm away from a table top. The observation time was 6 minutes and the cumulative immobility time was recorded over 4 minutes.

The immobility indexes are as follows: neither the animal's limbs nor body struggles.

The statistical method comprises the following steps: the results are expressed as mean ± SE and three samples were tested by ANOVA. The average comparison of the two samples (imipramine and saline) was performed using the t-test.

The depression symptom of the mice in the schisanhenol high-dose group starts to be relieved 60 minutes after injection, namely struggle movement is more and more frequent compared with a blank control group, and the immobility time is obviously shortened. The activity of the imipramine positive control group and the physiological saline control group is not enhanced to be obvious within 60 minutes after injection. The results observed after 60 minutes of injection, as shown in FIG. 5, the immobility time of the mice in the low-dose and high-dose groups of schisanhenol was reduced from 163.20 + -5.27 s to 130.5 + -7.35 s (P < 0.05) and 138.4 + -4.76 in comparison with the DMSO control group.

The result shows that the schisanhenol can take effect within a short time and can resist depression despair symptoms caused by forced tail suspension of mice.

Test example 2 Effect of schisanhenol on forced swimming test of animal depression model

Experimental animals: c57BL/6 mice, male, offered by sbefu (beijing) biotechnology limited, license number: SCXK (Jing) 2019-. The animals are raised in cages one week before the experiment, the light and shade period is 12h/12h, the room temperature is 20-22 ℃, the water is freely eaten, and the feed is provided by the Huada protein experimental animal center.

Experimental drugs: schisanhenol. The positive control Imipramine hydrochloride (Imipramine hydrochloride) is a product of Sigma company, the product number is I7379, and the batch number is O56K 1380.

An experimental instrument: glass cylinder (height 40cm, diameter 14 cm); a mouse open box (the length and the width are 50cm, the height is 40cm, and the bottom is 16 equal parts); a thermometer; JUNSO multifunctional timer.

The experimental steps are as follows: drug preparation same tail suspension experiment. Animal drug injection: c57BL/6 mice, age 7 weeks, weigh 30-40 grams, acclimate for one week and begin the experiment. Animals were randomly grouped into 5 groups of 8-10 animals each. Intraperitoneal injections were started at 10 am each day. The injection amount is 0.3 ml/30 g, the injection is performed intraperitoneally once a day, and a forced swimming experiment is started five days after the injection.

Forced swimming experiment: each group of C57BL/6 mice was placed individually vertically into a plexiglas cylinder (40cm height by 14cm diameter) at a water depth of 25cm and a water temperature of 21-23 ℃. The administration group and the control group were recorded for 6 minutes, and the cumulative immobility time in the following 4 minutes was compared for each group of mice.

And (3) judging the motionless time: the mouse floats on the water surface, does not try to climb out of the cylinder, and only does some action which is necessary to keep the head of the mouse on the water surface.

The statistical analysis method comprises the following steps: the results are expressed as means ± SE and the comparison of the mean of the two samples is performed by t-test.

As shown in FIG. 6, compared with DMSO control group, the immobility time of the mice in the schisanhenol high-dose group and the low-dose group is significantly reduced within 4 minutes of forced swimming, and the immobility time of the mice in the schisanhenol low-dose group and the schisanhenol high-dose group is reduced to 24.50 +/-4.50 s (p is less than 0.01) and 27.00 +/-3.65 from 58.13 +/-14.00 s, which are respectively reduced by 57.85% and 53.55% compared with that in 1% DMSO control group. The immobility time of mice treated by the traditional antidepressant drug imipramine (15mg/kg) is reduced from 75.54 +/-6.06 s to 57.17 +/-5.66 s, which is reduced by 24.32%, and the anti-depression effect of schisanhenol is stronger compared with imipramine.

Test example 3 mouse open-field test

Since the reduction in immobility time in classical animal models of depression is probably due to the central excitatory action of the drug, we performed a mouse open field experiment to examine the central excitatory properties of schisanhenol.

The experimental results show that the mice enter the open box for the next 5 minutes of 6 minutes, counted by ANY-maze software, the total distance of movement in the open box is not changed significantly (Anova, p > 0.05, N ═ 21) after the schisanhenol is treated with high dose (18.26 +/-3.34 m) and low dose (17.31 +/-2.19 m) compared with the control group (16.62 +/-4.32 m), so that the possibility of inducing mania can be eliminated, and the schisanhenol indeed has a remarkable anti-depression effect.

Finally, the above embodiments are only intended to illustrate the technical solutions of the present invention and not to limit the present invention, and although the present invention has been described in detail with reference to the preferred embodiments, it will be understood by those skilled in the art that modifications or equivalent substitutions may be made on the technical solutions of the present invention without departing from the spirit and scope of the technical solutions, and all of them should be covered by the claims of the present invention.

Claims (10)

1. The application of schisanhenol of formula (I) or derivatives thereof in preparing medicaments for treating depression,

2. the use according to claim 1, wherein the derivative comprises: sodium or potassium schisanhenol salt.

3. The use according to claim 1, wherein the dose is 0.01-30mg of schisanhenol or a derivative thereof per kg of body weight.

4. An anti-depression drug, wherein the drug comprises the following components: schisanhenol or its derivatives, and pharmaceutically acceptable auxiliary components.

5. The antidepressant as in claim 4, wherein said pharmaceutical components further comprise pharmaceutical components having a positive effect on the treatment of depression after the simultaneous administration.

6. The antidepressant as claimed in claim 5, characterized in that said pharmaceutical ingredients with a positive effect on the treatment of depression after the simultaneous administration comprise: monoamine oxidase inhibitor MAOI, tricyclic antidepressant TCA, selective serotonin reuptake inhibitor SSRI, serotonin and norepinephrine reuptake inhibitor SNRI, noradrenergic and specific 5-HT receptor antagonist NASSA, 5-HT antagonist and reuptake inhibitor or melatonin and 5-HT2C receptor antagonist.

7. The anti-depression drug of claim 6, wherein said tricyclic antidepressant comprises: amitriptyline, imipramine, chlorpromazine, doxepin or clomipramine; the selective serotonin reuptake inhibitor comprises: fluoxetine, paroxetine, fluvoxamine, sertraline, citalopram or escitalopram; the serotonin and norepinephrine reuptake inhibitor comprises: venlafaxine or duloxetine; the noradrenergic and specific 5-HT receptor antagonist NASSA comprises mirtazapine; the 5-HT antagonist and reuptake inhibitor comprises: nefazodone or trazodone; the melatonin and 5-HT2C receptor antagonists include: agomelatine.

8. An antidepressant drug according to claim 5, characterized in that said pharmaceutical ingredients having a positive effect on the treatment of depression after the simultaneous administration comprise herbs which are St.

9. The antidepressant drug according to claim 5, characterized in that said pharmaceutical composition having a positive effect on the treatment of depression after the simultaneous administration comprises ketamine, which is S-ketamine or ketamine nasal feed.

10. The antidepressant as claimed in claim 3, 4, 5, 6, 7, 8 or 9, characterized in that said pharmaceutical form is a powder, granules, tablets, capsules, pills, solutions, suspensions or injections.

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