CN107865920B

CN107865920B - Application of heart nourishing tablet in preparation of medicine for treating depression

Info

Publication number: CN107865920B
Application number: CN201610860733.1A
Authority: CN
Inventors: 叶冠; 赵亚红; 毕晓莹; 张海; 薛丹; 高越; 柴逸峰; 刘彦君; 洪毅; 高莉
Original assignee: Shanghai Medicine Group Qingdao Guofeng Pharmaceutical Co ltd; Shanghai Phaarmaceuticals Holding Co ltd
Current assignee: Shanghai Medicine Group Qingdao Guofeng Pharmaceutical Co ltd; Shanghai Phaarmaceuticals Holding Co ltd
Priority date: 2016-09-28
Filing date: 2016-09-28
Publication date: 2020-06-30
Anticipated expiration: 2036-09-28
Also published as: CN107865920A

Abstract

The invention provides application of a heart nourishing tablet in preparing a medicament for treating depression. The pharmacodynamic test shows that the heart nourishing tablet has obvious effect on treating the depression. Therefore, the heart nourishing tablet can be used for preparing the medicament for treating the depression and has good development and application prospects.

Description

Application of heart nourishing tablet in preparation of medicine for treating depression

Technical Field

The invention relates to the field of medicines, in particular to application of a heart nourishing tablet consisting of thirteen medicinal materials of astragalus, codonopsis pilosula, salvia miltiorrhiza, kudzuvine root, epimedium herb, hawthorn, rehmannia root, Chinese angelica, coptis, vinegar-processed corydalis tuber, lucid ganoderma, ginseng and honey-fried licorice root in preparing a medicine for treating depression.

Background

Depression is a common mental disorder that can cause mental and physical harm. Depression is characterized by depressed mood, loss of pleasure, or even pessimistic boredom, with suicidal attempts or behaviors accompanied by fatigue, inattention, sleep disturbance, cognitive, speech dysfunction, etc. Depression seriously afflicts the daily lives and learning of patients and is one of the sources of heavy burden to the family and society. According to the world health organization statistics, about 3.5 million people suffer from depression, which becomes one of the major causes of global disease burden. It has attracted a lot of attention because of its high morbidity, high recurrence rate, and high suicide rate. The pathogenesis of depression is not clear, various factors participate in the pathogenesis of depression, and biological, psychological, social, environmental and genetic influences are all dangerous factors for depression. In clinical application, some chemically synthesized antidepressants have strong toxic and side effects such as lethargy, hypertension, hepatosis and the like, although they can relieve clinical symptoms of patients. In addition, the current effective antidepressants only alleviate the pain of 2/3 patients, and the therapeutic effects of these drugs are not clearly shown in the rest of patients, which is far from sufficient for the ideal treatment of depression.

The heart nourishing medicine is prepared from thirteen medicinal materials of astragalus, codonopsis pilosula, salvia miltiorrhiza, kudzuvine root, epimedium herb, hawthorn, rehmannia root, Chinese angelica, coptis, vinegar-processed corydalis tuber, lucid ganoderma, ginseng and honey-fried licorice root, wherein the ginseng, the astragalus, the codonopsis pilosula, the honey-fried licorice root and the like tonify qi of spleen and lung, the epimedium herb warms yang qi of kidney, and the salvia miltiorrhiza, the Chinese angelica, the hawthorn, the vinegar-processed corydalis tuber and the like activate blood circulation to dissipate blood stasis, promote; kudzu root, dried rehmannia root, etc. to nourish yin, promote the production of body fluid and nourish heart; ginseng, radix codonopsitis and the like are nourished at constant temperature to promote the secretion of saliva; rhizoma coptidis is added to clear away heart-fire and relieve restlessness; ganoderma lucidum, Codonopsis pilosula, Salvia miltiorrhiza, etc. have the effect of calming heart, nourishing heart and tranquilizing mind. The heart nourishing tablet uses qi tonifying drugs to tonify heart qi, helps to generate qi and blood, and highlights the characteristic of nourishing heart. The method is proposed in Danxi Xin Fa, Liu Yu (depression of six ingredients): "Qi and blood are harmonized, so all diseases are caused by stagnation of liver-heat. The visible harmonization of qi and blood can not only treat heart diseases, but also improve psychological diseases such as depression. Therefore, the 'double heart theory' of the heart nourishing tablet is proposed, namely the 'heart nourishing theory' of the heart nourishing tablet comprises heart and mind, and not only can treat diseases such as chronic heart failure and the like, but also can improve mental disorder diseases such as depression and the like. At present, the heart nourishing tablet is clinically used for coronary heart disease with qi deficiency and blood stasis, angina, myocardial infarction, heart failure, combined hyperlipidemia, hyperglycemia and the like. Moreover, clinical observation effects of the heart nourishing tablet on treating chronic heart failure such as angina pectoris and coronary heart disease are reported in many documents so far, and no report on the application of the heart nourishing tablet as an antidepressant is found.

Disclosure of Invention

The invention aims to provide application of the Yangxin tablet in preparing a medicament for treating depression according to the current situation that the Yangxin tablet has an anti-depression effect found in the research of a traditional Chinese medicine composition.

The heart nourishing tablet is prepared from QINGDAOSHANGFENGYAOYAO tablet (national Standard Z37021102) and is mainly prepared from radix astragali, radix Codonopsis, Saviae Miltiorrhizae radix, radix Puerariae, herba Epimedii, fructus crataegi, rehmanniae radix, radix Angelicae sinensis, Coptidis rhizoma, rhizoma corydalis, Ganoderma, Ginseng radix, and radix Glycyrrhizae Preparata.

The invention relates to an application of Yangxin tablet in preparing a medicine for treating depression, which belongs to the first disclosure.

Has the advantages that: the invention has definite and obvious curative effect through preclinical verification. Pharmacological experiments show that the medicine has obvious effect, safety, effectiveness and small side effect on treating the depression. Therefore, the heart nourishing tablet can be used for preparing the anti-depression drug and has good development and application prospects.

Detailed Description

The invention will now be further illustrated, but is not limited, by the following specific examples.

Yangxin tablet (manufacturing plant: Qingdao national Fengyao GmbH, batch No. 150310); fluoxetine (shanghai enzyme-linked biotechnology limited, lot 20150427). The sodium carboxymethylcellulose, the chloral hydrate and other reagents are all made in China and analyzed.

Example 1: test of Effect of Yangxin tablet on chronic mild unpredictable depressed rat

1 method of experiment

1.1 Experimental animals and groups

The experimental animals were provided by Shanghai Sphere-BiKai experimental animals Co., Ltd: 80 SD male rats, SPF grade, weight of 180-220 g, animal production license number: SCYK (Shanghai) 2013-0016. Before the experiment, the rats are placed in normal experiment environment adaptive feeding, food and water are normally provided, the 12-hour illumination period is ensured, and the 80 rats are randomly divided into a blank control group, a model group, a fluoxetine group, a high-dose heart-nourishing tablet group, a medium-dose heart-nourishing tablet group and a low-dose heart-nourishing tablet group.

1.2 animal modeling and drug delivery

During the model preparation process, rats in the model group, fluoxetine group, high-dose cardiotrophin group, medium-dose cardiotrophin group and low-dose cardiotrophin group receive 2 kinds of stress stimuli selected from the following according to the plan each day: turning off the lamp for 3 hours, crowding overnight, swimming with ice water at 4 ℃ for 5 minutes, turning on the lamp overnight, clamping the tail for 10 minutes, inclining at 45 degrees overnight, depriving drinking water overnight, shocking foot sole for 5 minutes, wetting the cage overnight, inclining at 45 degrees (8 hours in the day), depriving food overnight, wetting the cage (8 hours in the day), continuously carrying out the stressful stimulation for 35 days, and carrying out the detection of each detection index after the last stimulation every day. Blank control group, without any stimulation.

The positive medicines of fluoxetine and Yangxi tablet are dissolved or suspended to the required administration concentration by 0.5 percent of sodium carboxymethyl cellulose (CMC-Na). The administration is started every day from the first day of molding, the fluoxetine dose of the fluoxetine group is 10mg/kg/d, the cardiotrophin tablet dose of the high-dose cardiotrophin tablet group is 1000mg/kg/d, the cardiotrophin tablet dose of the medium-dose cardiotrophin tablet group is 500mg/kg/d, the cardiotrophin tablet dose of the low-dose cardiotrophin tablet group is 250mg/kg/d, the administration route is gastric lavage and is carried out once a day for 4 weeks, and the blank control group and the model group are normally fed without the administration of medicines.

1.3 detection index

1.3.1 sucrose Water preference test

Before the experiment, animals are trained to adapt to sugar-containing drinking water, 2 water bottles are placed in each cage at the same time, 1% of cane sugar water (the mass fraction of the cane sugar water is 1%) is contained in each 2 bottles in the first 24h, 1% of cane sugar water is contained in each bottle, pure water is contained in each bottle for the subsequent 24h, after fasting and water deprivation are carried out for 24h, each rat is given a pre-quantified 2 water bottle, 1% of cane sugar water and 1% of pure water are respectively added, after 1h, 2 water bottles are weighed, the mass difference between the front and the back of the 1% of cane sugar water experiment is sugar water consumption, the mass difference between the front and the back of the pure water experiment is pure water consumption, and the sum of the sugar water consumption and the pure water consumption is total liquid consumption, and the rat sugar water preference value is calculated according to the following formula, wherein the sugar preference value (%). sugar consumption/total liquid consumption × 100%.

1.3.2 Forced Swimming Test (FST)

During the test, the rats are individually placed in a plastic cylinder with the water depth of 25cm (the height is 45cm, the diameter is 30cm) and the water temperature is 25 ℃, the collection is carried out for 6 minutes, the first 2 minutes are taken as the adaptation stage of the rats, and the time for bringing the rats into the immobile state is counted after the last 4 minutes.

1.3.3 open field experiment (OFT)

And taking the number of the squares passing through the bottom surface of the animal as a horizontal activity (distance tracked) score, taking the number of times of standing as a vertical activity (standing up) score, and summing the horizontal and vertical activity scores to form a total score. The open box device is a box with length and width of l00cm (the bottom surface is equally divided into 25 equilateral squares) and height of 50cm and black finish. The rats are placed in the center grid, and the number of crossing grids (the number is counted by grids with four claws entering the center grid, the horizontal movement score) and the number of hind limb erections (two forepaws vacate or climb the wall, the vertical movement score) of the rats are observed within 3 min.

1.3.4 measurement of serum levels of 5-hydroxytryptamine (5-HT), Corticosterone (CORT) and adrenocorticotropic hormone (ACTH)

Each group was selected to have 8 cells, and the levels of 5-HT, CORT and ACTH in serum were measured by enzyme-linked immunosorbent assay (ELISA).

2 results of the experiment

2.1 sucrose Water preference test results

After molding, the sugar water consumption of the rats in the model group is obviously lower than that of the blank control group (P < 0.01); compared with the model group, the sugar water consumption of rats in each dose group and fluoxetine group of the Yangxi tablet is increased, and the difference has statistical significance (P <0.05), which is shown in table 1.

TABLE 1 results of sugar water consumption in groups of rats

Note: compared with the blank control group, the composition of the composition,^##P<0.01; in comparison with the set of models,^*P<0.05。

2.2 forced swimming test results

After modeling, the immobility time of forced swimming of the rat in the model group is obviously longer than that of a blank control group (P <0.01), which indicates that the modeling is successful and the rat has depression symptoms; compared with the model group, the rats in each dose group and fluoxetine group of the Yangxi tablet have reduced immobility time, and the difference has statistical significance (P <0.05), which is shown in table 2.

TABLE 2 comparison of swimming immobility time for rats in each group

2.3 open field test results

After modeling, the horizontal crossing grid number and the erecting times of the rats in the model group are obviously lower than those of a blank control group (P <0.01), which indicates that the rats have depression symptoms and the modeling is successful; compared with the model group, the rats of the cardiotrophin tablet dose group and the fluoxetine group have increased horizontal crossing grid number and erection times, and the difference has statistical significance (P <0.05 and P <0.01), which is shown in table 3.

TABLE 3 open field test results for each group of rats

Note: compared with the blank control group, the composition of the composition,^#P＜0.05，^##P<0.01; in comparison with the set of models,^*P<0.05，^**P<0.01

2.4 results of 5-HT, CORT and ACTH levels in rat serum

The serum levels of 5-HT, CORT and ACTH in the model rat are obviously lower than those in the blank control group (P < 0.001). The levels of 5-HT, CORT, ACTH were significantly elevated in the fluoxetine group compared to the model group (P <0.001, P <0.01, P < 0.001); 5-HT and ACTH levels of the low-dose group of the cardiotrophin tablet are obviously increased (P <0.001 and P < 0.01); dose groups in the cardiotrophin tablet had significantly elevated levels of CORT, ACTH (P <0.001, P < 0.01); the high dose group of cardiotrophin had significantly elevated levels of CORT and ACTH (P <0.001, P <0.01), as shown in table 4.

TABLE 4 comparison of 5-HT, CORT, ACTH content in serum of rats of each group

Note: compared with the blank control group, the composition of the composition,^#P<0.05，^##P<0.01，^###P<0.001; in comparison with the set of models,^**P<0.01，^***P<0.001

3 conclusion

The heart nourishing tablet can obviously improve the depression state of chronic mild unpredictable stress stimulation depressed rats and has the function of anti-depression.

Example 2: test of Effect of Heart nourishing tablets on cerebral ischemia reperfusion induced vascular depressed mice

1 method of experiment

1.1 Experimental animals and groups

The experimental animals were provided by Shanghai Sphere-BiKai experimental animals Co., Ltd: 90 ICR male mice, SPF grade, weight 18 ~ 22g, animal production license number: SCYK (Shanghai) 2013-0016. Before the experiment, the mice are placed in normal experiment environment for adaptive feeding, food and water are normally provided, the 12-hour illumination period is ensured, and the 90 mice are randomly divided into a pseudo-operation group, a model group, a fluoxetine group, a high-dose heart-nourishing tablet group, a medium-dose heart-nourishing tablet group and a low-dose heart-nourishing tablet group.

1.2 animal modeling and drug delivery

After the mice of the model group, the fluoxetine group, the high-dose cardiac muscle group, the medium-dose cardiac muscle group and the low-dose cardiac muscle group are bred adaptively, 3% chloral hydrate (0.1mL/10g of the weight of the mice) is injected into the abdominal cavity, after anesthesia succeeds, the supine position, incisors and limbs are fixed, the skin and fascia in front of the neck are cut off, the left and right carotid arteries are separated from two sides of the trachea respectively, the small-size artery clamp is used for blocking blood supply of the carotid arteries on two sides for 5min, the artery clamp is loosened to recover the blood supply for 10min, and the artery clamp is removed after the blood supply is blocked for 5min again. The operation of the mice in the sham group was the same as that in the other experimental groups, except that the blood supply to the carotid artery was not blocked. And (3) starting the ethological detection on the 8 th day after the operation, and determining that the animal model succeeds if the mice of the model group have obvious depressive behaviors compared with a fake operation group through the depressive behavior detection such as a tail suspension experiment and an open field experiment.

The positive medicines of fluoxetine and Yangxi tablet are dissolved or suspended to the required administration concentration by 0.5 percent of CMC-Na. The administration is started every day from the first day of molding, the dose of fluoxetine in the fluoxetine group is 15mg/kg/d, the dose of the Yangxin tablet in the high-dose Yangxin tablet group is 1500mg/kg/d, the dose of the Yangxin tablet in the medium-dose Yangxin tablet group is 750mg/kg/d, the dose of the Yangxin tablet in the low-dose Yangxin tablet group is 375mg/kg/d, the administration route is intragastric administration, and the administration interval is 1 time per day. The sham operation group and the model group do not give medicines, and the sham operation group normally drinks and eats water every day; the model group drinks and eats every day from the first day of model building; the fluoxetine group was administered daily from the first day of molding; the cardiotrophin tablet groups were dosed daily from the first day of molding.

1.3 detection index

1.3.1 Tail suspension experiment (TST)

A self-made mouse tail suspension device is adopted and arranged on the 8 th day after operation, the position which is about 1cm away from the tail tip is fixed on a tail hook of a tail suspension system test box by an adhesive tape, the head of a mouse is about 7.5cm away from the ground, the observation is carried out for 6min totally, the adaptation time is 2min, and the mouse immobility time after recording is set for 4 min.

1.3.2 open field experiment (OFT)

And (3) sequentially placing the mice into an open field test box on the 9 th day after operation, recording the mice after the mice are placed in the open field test box for 2min, wherein the test time is 15min, the number of the blocks of the mice passing through the bottom surface is recorded as the score of horizontal activity (vertical), and the number of times of standing is recorded as the score of vertical activity (standing up).

1.3.3 detection of related factors in Hippocampus cerebri tissue and serum

After the experiment is finished, blood is taken, serum is centrifuged, hippocampal tissues are taken and stored in a refrigerator at the temperature of-80 ℃, and the contents of Norepinephrine (NA), Dopamine (DA), 5-HT, tumor necrosis factor α (TNF- α), interleukin 1 β (IL-1 β), interleukin 6(IL-6) and the like are to be detected.

2 results of the experiment

2.1 Tail overhang test results

After modeling, the immobility time of the tail suspension of the mice in the model group is obviously longer than that of a sham operation group (P <0.01), and the mice can be judged to have depressive behavior; compared with the model group, the mice of the cardiotrophin tablet dose group and the fluoxetine group have reduced tail suspension immobility time, and the difference has statistical significance (P <0.05, P <0.01), which is shown in table 5.

TABLE 5 comparison of tail suspension immobility time of mice in each group

Note: compared with the blank control group, the composition of the composition,^##P<0.01; in comparison with the set of models,^*P<0.05，^**P<0.01

2.2 open field test results

After modeling, the number of horizontal crossing grids and the erecting times of the mice in the model group are obviously lower than those in a false operation group (P is less than 0.01), and the mice can be judged to have depressive behaviors; compared with the model group, the mice of each dose group and fluoxetine group of the Yangxi tablet have increased horizontal grid crossing and erection times, and the difference has statistical significance (P is less than 0.01 and P is less than 0.05), which is shown in table 6.

TABLE 6 open field test results for each group of mice

Note: compared with the blank control group, the composition of the composition,^#P<0.05，^##P<0.01; in comparison with the set of models,^*P<0.05，^**P<0.01

2.3 results of related factors in hippocampal tissue of brain and serum

Compared with a blank control group, the levels of NA, DA and 5-HT in the blood serum of mice in a model group are obviously reduced (P <0.001), the levels of TNF- α, IL-1 β and IL-6 are obviously increased (P <0.001), compared with the model group, the levels of DA and 5-HT in the blood serum of mice in a fluoxetine group and a cardiotrophy group are obviously increased (P <0.05, P <0.001), the levels of TNF- α, IL-1 β and IL-6 are obviously reduced (P <0.05, P <0.01 and P <0.001), and the specific table 7 shows.

TABLE 7 comparison of the NA, DA, 5-HT, TNF, IL-1 β, IL-6 content in the groups of mice

Note: compared with the blank control group, the composition of the composition,^#P<0.05，^##P<0.01，^###P<0.001; in comparison with the set of models,^*P<0.05，^**P<0.01，^***P<0.001. 3 conclusion

The success of model making of the mouse vascular depression model is found through tail suspension and open field experiments. The expression condition of related factors in mouse serum is detected, so that the cardiovascular disease accompanied with depression symptoms and inflammation phenomena are caused by bilateral carotid artery ligation of the mouse. The stomach-feeding heart-nourishing tablet can improve depression symptoms after gastric administration, and simultaneously has the function of relieving inflammation.

The tests clearly show that the invention discloses the application of the heart nourishing tablet in preparing the safe and efficient antidepressant, develops the medicinal value of the heart nourishing tablet and makes creative contribution to the development of the traditional Chinese medicine and pharmacy.

The above description is only an embodiment of the present invention, but the scope of the present invention is not limited thereto, and any changes or substitutions that can be made by those skilled in the art without inventive work within the technical scope of the present invention disclosed herein are intended to be covered by the scope of the present invention.

Claims

1. Use of YANGXIN tablet in preparing medicine for treating depression is provided.

2. The use of claim 1, wherein the YANGXINSHI tablet comprises radix astragali, radix Codonopsis, radix Salviae Miltiorrhizae, radix Puerariae, herba Epimedii, fructus crataegi, radix rehmanniae, radix Angelicae sinensis, rhizoma Coptidis, rhizoma corydalis preparata, Ganoderma, radix Ginseng, and radix Glycyrrhizae Preparata.