Use of seco-strychnoside in preparation of antidepressant drugs

Abstract

The application belongs to the technical field of biological medicine, and specifically discloses application of seco-oxymatrine in preparation of an antidepressant, wherein the antidepressant further contains a pharmaceutically acceptable carrier; the antidepressant is one of an oral preparation, an inhalant and an injection; the oral preparation is one of a suspension, an emulsion, a solution, a powder, a tablet, a granule and a capsule. When seco-oxymatrine is used as an effective component of the antidepressant, the depressive behavior of a LPS-induced depressive model mouse can be effectively improved.

Description

Technical Field

[0001] This invention relates to the field of biomedicine, specifically to the application of oxidized strychnine in the preparation of antidepressant drugs. Background Technology

[0002] The clinical manifestations of depression are mainly persistent low mood, accompanied by sleep disturbances and loss of interest, and it is a common mental illness. In recent years, with the increasing pressure of social life, the incidence of depression has also shown an upward trend. Depression has become an important cause of reduced quality of life, increased family burden, and interference with the treatment of other diseases. However, current treatments for depression mainly rely on selective serotonin reuptake inhibitors (SSRIs), selective serotonin-norepinephrine reuptake inhibitors (SSRIs), and fast-acting antidepressants. These drugs have adverse effects such as short half-life, slow onset of action, drug interactions, and drug tolerance. Therefore, finding a new and effective antidepressant is an urgent problem to be solved and has become a pressing need for the treatment of depression.

[0003] Loganin (LOG) is one of the active ingredients in the traditional Chinese medicine Strychnos nux-vomica, and has been shown to have various pharmacological effects, such as anti-inflammatory and antioxidant properties. Vogeloside (VOG) is an iridoid compound isolated from the roots of *Brucea javanica*, and has exhibited antitumor, anti-inflammatory, antioxidant, and antibacterial pharmacological activities, showing potential for cardiovascular protection and antidiabetic treatment. Epivogeloside (EPI) and VOG are a pair of chiral compounds with similar chemical skeletons, and both also possess certain anti-inflammatory and antioxidant activities. EPI has been shown to be used in the preparation of drugs for treating myocardial fibrosis and has anti-myocardial ischemia-reperfusion injury effects. Secoxyloganin (SL) is a characteristic chemical component of *Lonicera japonica*, *Lonicera macrantha*, and their closely related species, belonging to the iridoid class of compounds. Currently, there is limited research on the pharmacological effects of secoxyloganin. SL, LOG, VOG, and EPI all possess similar diterpenoid core skeletons, containing multiple cyclic structures and linked with multiple functional groups such as hydroxyl and methoxy groups. However, there are currently no reports on the use of these four compounds (SL, LOG, VOG, and EPI) for antidepressant purposes, especially regarding the deoxidation of strychnine. Summary of the Invention

[0004] To address the shortcomings of existing technologies, the purpose of this invention is to provide the application of oxidized strychnine in the preparation of antidepressant drugs.

[0005] To achieve the above objectives, the present invention provides the following technical solution:

[0006] Application of oxidized strychnine in the preparation of antidepressant drugs.

[0007] The antidepressant uses strychnine as its active ingredient and contains one or more pharmaceutically acceptable carriers, excipients, and diluents.

[0008] The antidepressant is one of the following: oral, inhaled, or injectable formulations.

[0009] The oral preparation is one of the following: suspension, emulsion, solution, powder, tablet, granule, or capsule.

[0010] Due to the adoption of the above technical solutions, the beneficial effects of the present invention include:

[0011] When strychnine is used as an active ingredient in antidepressants, it can effectively improve depressive-like behaviors in lipopolysaccharide (LPS)-induced depression models in mice, and this effect is significantly superior to its structural analogs (including strychnine, strychnine hemiacetal lactone, and epistrychnine hemiacetal lactone). Therefore, strychnine has a significant ameliorative effect on depressive behaviors and can be used to prepare drugs for the prevention and treatment of depression. Attached Figure Description

[0012] Figure 1 The graph shows the effects of each test drug on the open field behavior of model mice. Figure 1 A shows the time map of the central region in the model mice under different drugs. Figure 1 B shows the number of times the model mice entered the central region under different drugs.

[0013] Figure 2 The images show the movement trajectories of model mice under different drug conditions.

[0014] Figure 3 The graph shows the effects of each test drug on the tail suspension test behavior of model mice. Figure 3 A shows the immobility time of model mice under different drugs. Figure 3 B shows the number of immobility cycles in the model mice under different drugs.

[0015] Figure 4 The graph shows the effects of each test drug on the forced swimming behavior of model mice. Figure 4 A shows the immobility time of model mice under different drugs. Figure 4 B shows the number of immobility cycles in the model mice under different drugs. Detailed Implementation

[0016] The substantive content of the present invention will be described in detail below with reference to animal experiments and accompanying drawings. However, those skilled in the art should know that the scope of protection of the present invention is not limited by the following content.

[0017] 1. Laboratory animals

[0018] C57 / 6J mice, SPF grade, male, 8 weeks old, were all provided by Beijing Vital River Laboratory Animal Technology Co., Ltd. After entering the laboratory, the mice had free access to food and water, maintained at a temperature of 21±1℃ and humidity of 50%±5%, with a 12h / 12h light-dark cycle. During the rearing period, the animals' health was monitored twice daily, and no adverse events were observed. All animal experimental procedures followed the US NIH's "Guideline for the Care and Use of Laboratory Animals" and the Animal (Scientific Procedures) Act, 1986, as amended (SI2012 / 3039). The research protocol was approved by the Laboratory Animal Welfare and Ethics Committee of Shandong First Medical University (Shandong Academy of Medical Sciences).

[0019] 2. Animal grouping and drug treatment

[0020] C57 / 6J mice were randomly divided into 7 groups of 8 mice each: control group, LPS group (model group), LPS+SL (20 mg / kg) group, LPS+LOG (20 mg / kg) group, LPS+VOG (20 mg / kg) group, LPS+EPI (20 mg / kg) group, and LPS+Flu (20 mg / kg) group. Mice were treated by gavage according to the above groupings and drug dosages, once daily for 14 consecutive days. The control group and LPS model group were given the same volume of 1X phosphate-buffered saline (PBS, pH=7.4, catalog number: BL302A, manufacturer: Beijing Lanjieke Technology Co., Ltd.) by gavage for 14 days. All LPS treatment groups were then intraperitoneally injected with LPS (2 mg / kg / time, once daily for 2 consecutive days) to establish a mouse model of depression. The control group was injected with the same volume of 1X PBS.

[0021] 3. Behavioral testing

[0022] Open field test, tail suspension test, and forced swimming test are commonly used behavioral methods for detecting depression models. In the open field test, a decrease in the time mice spend in the central area and the number of times they enter the central area indicates a reduction in free exploration behavior. In the tail suspension test and forced swimming test, the longer the mice remain suspended and immobile, the more immobile they are, indicating a state of despair. Analysis of the behaviors exhibited by the mice in these behavioral tests shows that the model mice exhibit depression-like behaviors.

[0023] 3.1 Open Field Experiment

[0024] The XR-SuperMaze animal behavior video tracking and analysis system was used for testing. The open field box dimensions were L×W×H=50cm×50cm×50cm, and the camera sampling rate was 15 frames / second. Each mouse was observed for 6 minutes. The animal's activity was recorded by a computer using an infrared camera system and a video synthesizer. The time and number of times the mouse entered the central area within 6 minutes were recorded and analyzed. After each test, the box was wiped with 75% alcohol to reduce the influence of odor on the mice.

[0025] 3.2 Tail Suspension Experiment

[0026] Using medical tape, the tip of the mouse's tail was suspended about 30 cm above the plane, keeping it vertical with its head facing the camera. The time the mice remained still with their tails suspended was recorded for 6 minutes. After recording and analysis, the time the mice remained still with their tails suspended was calculated 4 minutes later.

[0027] 3.3 Forced Swimming Experiment

[0028] The mice were placed in an acrylic cylinder filled with 20 cm of water at a temperature of 24°C. The water droplets inside and outside the container were wiped clean. Each mouse was forced to swim for 6 minutes, and the time each mouse remained still during the last 4 minutes of forced swimming was recorded.

[0029] 3.4 Statistical Analysis

[0030] Statistical analysis was performed using GraphPad Prism 9.0 software. All data are expressed as mean ± standard deviation (SD). For comparisons of two independent samples, Student's t-test was used if variances were homogeneous; otherwise, Welcht's test was used. One-way ANOVA was used for comparisons among multiple groups. Fisher's LSD test was performed if variances were homogeneous; otherwise, Tamhane's T² test was used. The significance level was set at P < 0.05.

[0031] 4. Experimental Results

[0032] In open field experiments, such as Figure 1 As shown, compared with the control group, ###P<0.001, indicating that the time spent in the central region and the number of times mice entered the central region were significantly reduced in the LPS group compared with the control group. Compared with the LPS group, the drug groups (LPS+SL, LPS+LOG, LPS+VOG, LPS+EPI, and LPS+Flu) showed **P<0.01 and ***P<0.001, indicating that compared with the drug groups, treatment with strychnine and fluoxetine significantly increased the time spent in the central region and the number of times mice entered the central region. Figure 2 Select a representative image of one mouse from each group.

[0033] In the tail suspension experiment, such as Figure 3 As shown, compared with the Control group, #P<0.05, ###P<0.001; compared with the LPS group, *P<0.05, ***P<0.001; compared with the LPS group, &P<0.05. This indicates that compared with the Control group, the LPS group mice had increased suspension immobility time and number of immobilities; compared with the LPS group, the drug groups showed decreased suspension immobility time after treatment with oxidized strychnine, strychnine, and fluoxetine; and compared with the LPS group mice, the LPS+SL group showed a trend towards reducing the number of suspension immobilities after treatment with oxidized strychnine.

[0034] In the forced swimming experiment, such as Figure 4 As shown, compared with the Control group, ##P < 0.01, ###P < 0.001; compared with the LPS group, *P < 0.05, **P < 0.01, ***P < 0.001; compared with the LPS+SL group, &P < 0.05. This indicates that compared with the Control group, the model mice in the LPS group had increased suspension immobility time and number of immobilities; compared with the LPS group, the suspension immobility time of mice treated with oxidized strychnine, strychnine, and fluoxetine was reduced; compared with the LPS group, the LPS+SL group showed a trend of reducing the number of suspension immobilities in the model mice after oxidized strychnine treatment.

[0035] Furthermore, in the tail suspension test and forced swimming test, the LPS+LOG group had a significantly longer period of immobility compared to the LPS+SL group (see [link to LPS+LOG group]). Figure 3 A and Figure 4 A); In open field, tail suspension, and forced swimming tests, strychnine hemiacetal lactone and epistrychnine hemiacetal lactone did not significantly improve central zone time, central zone frequency, and suspension immobility time in model mice.

[0036] In summary, oxidized strychnine significantly improved LPS-induced depressive-like behavior in mice. Compared with strychnine, oxidized strychnine hemiacetal lactone, and epi-oxidized strychnine hemiacetal lactone, oxidized strychnine showed a significant advantage in reducing depressive-like behavior in a mouse depression model. Therefore, oxidized strychnine can be used to prepare antidepressant drugs, which can also contain pharmaceutically acceptable carriers. These antidepressant drugs can be administered orally, inhaled, or injected. The oral dosage form can be a suspension, emulsion, solution, powder, tablet, granule, or capsule.

[0037] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. However, any modifications, alterations, and variations made by those skilled in the art without departing from the scope of the present invention based on the disclosed technical content are equivalent embodiments of the present invention. Furthermore, any modifications, alterations, and variations made to the above embodiments based on the essential technology of the present invention are still within the protection scope of the present invention.

Claims

1. Application of oxidized strychnine in the preparation of antidepressant drugs.

2. The application according to claim 1, characterized in that, The antidepressant uses strychnine as its active ingredient and contains a pharmaceutically acceptable carrier.

3. The application according to claim 2, characterized in that, The carrier is a diluent.

4. The application according to claim 1 or 2, characterized in that, The antidepressant is one of the following: oral, inhaled, or injectable formulations.

5. The application according to claim 4, characterized in that, The oral preparation is one of the following: suspension, emulsion, solution, powder, tablet, granule, or capsule.

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