CN103142631A - Application of traditional Chinese medicine composition as antidepressant drug - Google Patents
Application of traditional Chinese medicine composition as antidepressant drug Download PDFInfo
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Abstract
The invention discloses application of a traditional Chinese medicine composition as antidepressant drug. Dosage forms of the drug comprise pharmaceutically acceptable dosage forms, such as tablets, capsules, solutions, suspensions, injections and infusion solutions. The composition consists of hesperidin and neohesperidin which may be in the ratio of (1: 1) to (9: 1) and comprises various drug dosage forms which are prepared in a manner that the composition is combined with pharmaceutical carriers. The drug has little toxicity and is free from the disadvantages of conventional antidepressant drugs, such as excited anxiety, constipation, anuresis, dizziness, sleepiness and tremor.
Description
Technical field:
The present invention relates to medical technical field, exactly it is that a kind of Chinese medicine composition is as the application of antidepressant drug.
Background technology:
Hesperidin and neohesperidin (Hesperidin/Neohesperidin) are the flavanone glycosides compound, for Rutaceae citrus plant secondary metabolite, are distributed widely in a lot of plants.Studies show that, Hesperidin is promoting to have stronger biological activity aspect gastric motility.Neohesperidin has stronger biological activity at aspects such as promoting gastric motility, blood fat reducing, atherosclerosis, blood sugar lowering, promotion skin microcirculation.China Patent No.: CN1704065A discloses the patent of invention that name is called " pharmaceutical applications of Hesperidin and/or naringin ", discloses the purposes of Hesperidin at preparation treatment flatulence, dyspepsia, infantile anorexia medicine.the patent No.: CN1836665B discloses the patent of invention that name is called " pharmaceutical applications of neohesperidin or its compositions ", the patent No.: CN1317938A discloses the patent of invention that name is called " be used for the treatment of or prevention and blood fat and blood sugar level raise the compositions that contains neohesperidin pair hydrogen chalcones of relevant disease ", the patent No.: CN102258528A discloses the patent of invention that name is called " the new purposes of neohesperidin ", neohesperidin is disclosed in treatment or prevention disease such as the hyperlipidemia relevant to blood fat or blood sugar level rising, arteriosclerosis, angina pectoris, apoplexy, flatulence, dyspepsia, infantile anorexia, improve and/or promote the application of skin microcirculation.Have no Hesperidin and the neohesperidin compositions purposes in preparation anti-depression aspect medicine.
Summary of the invention:
The invention provides a kind of Chinese medicine composition as the application of antidepressant drug.Hesperidin and neohesperidin compositions (1: 1～9: 1) can be used for prevention or treatment anxiety state or depressive state.
Hesperidin and neohesperidin compositions comprise and the pharmaceutical carrier combination, are used for prevention or treatment depressive state.Wherein said sick body is mammal, can be by oral, non-intestinal or topical routes, and form of administration can be the pharmaceutically acceptable dosage forms such as tablet, capsule, solution, suspension, injection, drip liquid, lyophilized powder.
Advantage of the present invention is: the present invention has disclosed Hesperidin and the neohesperidin compositions has antidepressant effect, for its application provides new approach.And toxicity is little, without the excited uneasiness of conventional antidepressants, constipation, urine retention, dizzy, drowsiness, the shortcoming such as tremble.
The specific embodiment:
Below zoopery be to further description of the present invention, but and do not mean that any limitation of the invention.
Example 1. autonomic activities irritability experiments
1. laboratory animal
The Wistar rat, male, body weight 200～220g, the SPF grade standard is weighed animal, and numbering is selected 40 of healthy rats.By the sequence of body weight size, be divided into 4 groups with randomized blocks, 10 every group.If blank group, positive controls, compositions (1: 1) administration group, compositions (5: 5) administration group.
2. sample source and processing
(1) blank group: normal saline, NaCl content 0.9%.
(2) positive controls: get fluoxetine Hydrochloride and use the normal saline standardize solution in volumetric flask, fluoxetine Hydrochloride concentration is 1.8mg/ml.Dosage is 7.2mg/kg.
(3) compositions (1: 1) administration group: get Hesperidin and neohesperidin (1: 1) appropriate, in volumetric flask, compositions (1: 1) concentration is 1.6mg/ml with the normal saline standardize solution.Hesperidin used and neohesperidin sample purity are more than 95%, and dosage is 8mg/kg.
(4) compositions (5: 5) administration group: get Hesperidin and neohesperidin (5: 5) appropriate, in volumetric flask, compositions (5: 5) concentration is 1.6mg/ml with the normal saline standardize solution.Hesperidin used and neohesperidin sample purity are more than 95%, and dosage is 8mg/kg.
3. experimental technique (open field test)
Adopting the bottom surface is foursquare spacious case, long 100cm, and wide 100cm, high 50cm, the bottom surface is divided into close fan-shaped of 100 areas with black line.During experiment, rat is placed on spacious case center, gets over lattice number (at least 3 pawls stride across the border) with horizontal movement in rat 5min and estimate its mobility; Estimate its inquiry with the upright number of times that moves both vertically (two fore paw built on stilts).Whether have autonomous excitation, the while is with the contrast of accompanying of the blank group that gives normal saline and the positive controls that gives the positive control drug fluoxetine Hydrochloride if investigating Hesperidin and neohesperidin compositions (1: 1) and (5: 5) by autonomic movement situation of change before and after each administration group administration relatively.
3. experimentation
By observing the activity of rat in spacious case, record the interior horizontal movement of 5min and get over the lattice number and the upright number of times that moves both vertically before administration; After 7 days, observe the activity of rat in spacious case in administration, record the interior horizontal movement of 5min and get over the lattice number and the upright number of times that moves both vertically.Each group experimental data is processed with the SPSS statistical software, and the horizontal movement rate of change is as follows with the rate of change computational methods that move both vertically:
Before horizontal movement rate of change=(administration after 7 days horizontal movement more horizontal movement lattice number more before lattice number-administration)/administration, lattice number * 100% is got in horizontal movement
More lattice number * 100% that moves both vertically before rate of change=(administration move both vertically after 7 days the more lattice number that moves both vertically before more lattice number-administration)/administration moves both vertically
Each group experimental data is carried out the t check, investigate it and whether have significant difference.
4. experimental result
By statistics, each administration group rat autonomic movement situation sees Table 1.
Before table 1. administration with administration each administration group rat open field test autonomic movement situation of change after 7 days
Use SPSS software, carry out the t check, more blank group respectively, compositions (1: 1) group, compositions (5: 5) group and fluoxetine Hydrochloride group administration front and back autonomic movement situation, the same with positive control drug fluoxetine Hydrochloride group with the blank group, compositions (1: 1) group, compositions (5: 5) group administration group rat horizontal movement and the difference (P＞0.05) that moves both vertically that there are no significant before and after administration, show give compositions (1: 1) and compositions (5: 5) afterwards to the central nervous system without autonomous excitation.
Example 2. chronic stress rat open field tests
1. laboratory animal
The Wistar rat, male, body weight 200～220g, the SPF grade standard is weighed animal, and numbering is selected totally 40 of healthy rats.By the sequence of body weight size, be divided into 4 groups with randomized blocks, 10 every group.If blank group, pathological model group, positive controls, compositions (1: 1) group, compositions (9: 1) group.
2. sample source and processing
(1) blank group: with embodiment 1.
(2) pathological model group: normal saline, NaCl content 0.9%.
(3) positive controls: with embodiment 1.
(4) compositions (1: 1) group: with embodiment 1.
3. experimental technique
(1) preparation of rat chronic Stress model: chronic stress stimulates as a kind of non-damage, with the process of mankind's psychosoma disease, similarity is arranged, the simulation that chronic stress model reality is tested " stress state " that run in people's daily life, for the specific clinical antidepressants of screening, the good suitability is arranged, this experiment is just take the chronic stress model as the basis, after giving positive control drug and Hesperidin and neohesperidin compositions (1: 1), investigate the antidepressant effect of Hesperidin and neohesperidin compositions (1: 1).
In the preparation of rat chronic Stress model, make stress stimulation meet the characteristics of unpredictability as far as possible, 28d is by the intensity of every day 1 or 2 kind of stimulation continuously, give alternately that rat is following to be stimulated: fasting 24h, prohibit water 24h, restriction and ingest that 2h, pairing raise 12h, the 45 ° of 2h of cage that incline, the 12h that throws light on all night, moist (200ml water is added to the 100g bedding and padding) 12h, stroboscopic (100min/s) 1h, white noise (110dB) 1h, forced swimming (4 ℃ of water temperatures) 5min, the braking 1h of raising, preparation chronic stress model.It is as follows that each administration group stress reach the administration situation:
A. blank group: do not stimulate, give normal saline.
B. pathological model group: stimulate to give simultaneously normal saline.
C. positive controls: stimulate to give simultaneously positive drug, dosage is with embodiment 1.
D. Hesperidin and neohesperidin compositions (1: 1) are organized: stimulate to give simultaneously compositions (1: 1), dosage is with embodiment 1.
(2) open field test: adopting the bottom surface is foursquare spacious case, long 100cm, and wide 100cm, high 50cm, the bottom surface is divided into close fan-shaped of 100 areas with black line.During experiment, rat is placed on spacious case center, gets over lattice number (at least 3 pawls stride across the border) with horizontal movement in rat 5min and estimate its mobility; Estimate its inquiry with the upright number of times that moves both vertically (two fore paw built on stilts).By Hesperidin before and after administration relatively with neohesperidin compositions (1: 1) administration group investigates Hesperidin with pathological model group autonomic movement rate of change (comprising the horizontal movement rate of change and the rate of change that moves both vertically) and whether the neohesperidin compositions has antidepressant effect, the while is with the contrast of accompanying of the blank group that gives normal saline and the positive controls that gives the positive control drug fluoxetine Hydrochloride.
4. experimentation
By observing the activity of rat in spacious case, record the interior horizontal movement of 5min and get over the lattice number and the upright number of times that moves both vertically before administration; After 28 days, observe the activity of rat in spacious case at chronic stress, record the interior horizontal movement of 5min and get over the lattice number and the upright number of times that moves both vertically.Horizontal movement rate of change and the rate of change computational methods that move both vertically are as follows:
The horizontal movement rate of change=(stress be after 28 days horizontal movement more the lattice number-stress before horizontal movement lattice number more)/stress before horizontal movement get over lattice number * 100%
Move both vertically rate of change=(the lattice number that stress move both vertically after 28 days more-stress before the more lattice number that moves both vertically)/stress before more lattice number * 100% that moves both vertically
Result obtains positive number for increasing, and negative is for descending, and each group experimental data is processed with the SPSS statistical software, carries out the t check, investigates Hesperidin and neohesperidin compositions administration group and pathological model group autonomic movement situation and whether has significant difference.
5. experimental result
By statistics, each administration group autonomic movement situation sees Table 2.
Each administration group open field test autonomic movement situation of change of table 2 chronic stress rat model
Use SPSS software, carry out the t check, relatively there is extremely significant difference (P＜0.01) in the pathological model group with blank group autonomic movement situation (horizontal movement rate of change and the rate of change that moves both vertically) before and after administration, show under the state of chronic stress, rat do not have under pharmaceutical intervention its autonomic movement emotionally condition be subject to impact, horizontal movement rate of change and the rate of change that moves both vertically all obviously descend, and prompting chronic stress model is successfully prepared; Each administration group and pathological model group autonomic movement situation before and after administration compares (horizontal movement rate of change and the rate of change that moves both vertically) and all has extremely significant difference (P＜0.01), show that Hesperidin and neohesperidin compositions and positive control drug fluoxetine Hydrochloride all can have significant resistant function to the rat horizontal movement rate of change that causes due to chronic stress and the rate of change decline that moves both vertically, prompting Hesperidin and neohesperidin compositions (1: 1) have the pharmacologically active of resisting the autonomic activities minimizing that causes due to depression.
Example 3. monoamine oxidase A suppress active testing
1. sample and reagent
Hesperidin: be purchased from Products in China and examine and determine institute, content 98%
Neohesperidin: be purchased from Products in China and examine and determine institute, content 98%
Pargyline: sigma company product, specification 1g/ bottle
Sodium phosphate, sucrose all are purchased from Beijing chemical reagents corporation
MAO active testing test kit: be purchased from Nanjing and build up bio-engineering research institute, test kit forms:
Reagent one: aniline solution (0.016mol/L)
Reagent two: pH7.6Tris buffer
Reagent is crossed solution chlorate's (reaction terminating liquid) at three: 10%
Reagent four: cyclohexane extraction reagent
2. experimental technique
monoamine neurotransmitter is the medium of nervous system conducted signal, its normal presence is the prerequisite that nervous system normally plays a role, in the study of incident mechanism of depression, researcher finds that the minimizing of monoamine neurotransmitter and the morbidity of depression have dependency, and the activity of monoamine oxidase A (MAO-A) increases the monoamine neurotransmitter minimizing that directly causes synaptic space extremely, some antidepressants of clinical practice just are based on monoamine hypothesis design (as imipramine, phenelzine etc.), therefore, seeking oxidase inhibitor is to find to have one of approach of antidepressant activity medicine.
The oxidation under the MAO effect of this experimental basis benzylamine generates the principle of benzyl aldehyde, measures the amount of oxidation product, the activity of indication MAO-A in 242nm wavelength place trap with the cyclohexane extraction extract product.
3. experimentation
(1) preparation of the thick enzyme of rat liver mitochondria monoamine oxidase, MAO (MAO): with Sprague-Dawley rat sacrificed by decapitation, get liver, with 4 ℃ of buffer (pH=7.6, 0.2M sodium phosphate buffer) repeatedly rinse well, take 10g, shred rear grinding, break into homogenate with high speed disperser, the centrifugal 10min of 0.3M sucrose solution 3000rpm that adds pre-cooling with 1: 20 (w/v), get supernatant, the centrifugal 30min of 10000rpm, getting precipitation is dissolved in the 40ml buffer, high speed disperser is beaten even, divide and be filled to 40 pipes (1ml/ pipe), and mensuration protein content (biuret method),-80 ℃ of storages are standby.
(2) preparation of specimen solution: precision takes Hesperidin and neohesperidin reference substance, ultrasonic dissolution in the 10ml volumetric flask, standardize solution, draw respectively the solution of different volumes from this titer, be mixed with the test solution of a series of variable concentrations, make it add the concentration after enzyme liquid and reagent one and reagent two to be respectively 400,200,100,50,25,6.25,3.125 μ g/ml.
(3) MAO-A suppresses active assay method: add MAO-B type inhibitor 300 μ l pargyline pargyline (500nmol/L) to 30ml rat liver mitochondria enzyme, 37 ℃ of temperature are bathed half an hour, to suppress the activity of MAO-B.Add successively each 0.3ml of a series of testing sample solutions in measuring pipe, reagent one (benzylamine substrate liquid) 0.3ml, reagent two (pH7.6Tris buffer) 3ml, and 0.6ml enzyme liquid, blank tube is with physiologic saline for substitute enzyme liquid, and all the other are identical.Place 3h in 37 ℃ of water-baths, respectively add 10% after taking-up and cross chloric acid 0.3ml, respectively add cyclohexane extraction 3.0ml, rotation mixing 2min on vortex mixer, centrifugation (2000r/min) 10min gets supernatant in quartz colorimetric utensil, returns to zero with blank, measure absorbance in the 242nm wavelength, measure MAO-A active.Take the enzymatic activity of the matched group that only adds the substrate without inhibitor as 100%, calculate determinand to the suppression ratio of MAO-A activity.
MAO-A maximum inhibition=(matched group absorbance-test group absorbance)/matched group absorbance * 100%
4. experimental result
The compositions of different proportion Hesperidin and neohesperidin sees Table 3 to the inhibitory action of MAO-A activity.
The inhibitory action of table 3 different pharmaceutical to the MAO-A activity
Result shows, the compositions of Hesperidin and neohesperidin (1: 1) has shown that it has the effect of significant inhibition MAO-A activity, and it is active that prompting Hesperidin and neohesperidin compositions have the antidepressant pharmacology.
Example 4. chronic stress rat sucrose are degree of having a liking for determination experiment partially
1. laboratory animal
With embodiment 2.
2. sample source and processing
(1) blank group: with embodiment 1.
(2) pathological model group: with embodiment 2.
(3) positive controls: with embodiment 1.
(4) Hesperidin and neohesperidin compositions (5: 5) group: with embodiment 1.
3. experimental technique
(1) preparation of rat chronic Stress model: the preparation of rat chronic Stress model and each administration group stress reach the administration situation all with example 2.
(2) sucrose water degree of having a liking for experiment partially: rat is after being stimulated by chronic stress, with the performance that interest occurs and go down, at first this experiment is carried out sucrose water to rat and is partially had a liking for training before carrying out chronic stress, set up it to the preference of sucrose solution, after carrying out the chronic stress stimulation, can cause because of the disappearance of interest the decline of degree of having a liking for partially of sucrose water for the rat of antidepressant drug, therefore, by relatively each administration group and pathological model group sucrose water degree of having a liking for situation of change partially before and after administration, can investigate the anhedonia that the antagonism of Hesperidin and neohesperidin compositions causes due to the rat chronic stress stimulation, investigate and respectively to organize rat sucrose water before and after neohesperidin and neohesperidin compositions group and the administration of pathological model group and partially whether have significance between degree of having a liking for rate of change, the while is with the contrast of accompanying of the blank group that gives normal saline and the positive controls that gives the positive control drug fluoxetine Hydrochloride.
4. experimentation
First rat is carried out learning training before administration: water is prohibited in fasting, only gives 1% sucrose water 48h; Sucrose degree of having a liking for is partially measured: after training end, normal drinking water is raised 3d, then fasting taboo water 23h, then allows rat freely drink 2 bottles of different water, and wherein one bottle is 1% sucrose water, and one bottle is tap water.Carry out the amount of drinking water (g) of 1h and measure, by formula calculate sucrose degree of having a liking for partially.Rat conform after 1 week by sucrose partially degree of having a liking for 40 rat equilibriums are divided into 4 groups: chronic stress is measured rat sucrose water degree of having a liking for partially after stimulating 28 days again.Calculate simultaneously sucrose degree of having a liking for rate of change partially
Sucrose is degree of having a liking for=sucrose diseases caused by retention of fluid consumption/(sucrose diseases caused by retention of fluid consumption+drinking purpose of tap water amount) * 100% partially
Sucrose partially degree of having a liking for rate of change=(stress be after 28 days sucrose partially degree of having a liking for-stress before sucrose degree of having a liking for partially)/stress before sucrose degree of having a liking for * 100% partially
Each group experimental data is processed with the SPSS statistical software, is carried out the t check, investigate Hesperidin and neohesperidin compositions (5: 5) group and pathological model group rat sucrose partially degree of having a liking for rate of change whether have significant difference.
5. experimental result
By statistics, each sample sets rat sucrose partially degree of having a liking for rate of change situation see Table 4.
Use SPSS software, carry out the t check, pathological model group and blank group before and after administration sucrose partially degree of having a liking for rate of change relatively have extremely significant difference (P＜0.01), show under the state of chronic stress, rat is not having to have caused its disappearance to the interest of original foundation under pharmaceutical intervention, sucrose degree of having a liking for rate of change partially is starkly lower than blank group, points out simultaneously the chronic stress model to be successfully prepared; Hesperidin and neohesperidin compositions (5: 5) group, positive control drug group and pathological model group before and after administration sucrose partially degree of having a liking for rate of change more all have difference (P＜0.01) extremely significantly, show that Hesperidin and neohesperidin compositions (5: 5) group and positive control drug fluoxetine Hydrochloride all can have significant resistant function to the rat body weight anhedonia symptom that causes due to chronic stress, the prompting Hesperidin has opposing with neohesperidin compositions (5: 5) and causes the pharmacologically active of the brain malfunction relevant to anhedonia due to depression.
Each sample sets rat sucrose of table 4. chronic stress rat model is degree of having a liking for rate of change partially
Example 5. mice forced swimming dead time determination experiments
1. laboratory animal
The ICR mice, male, body weight 18-20g, totally 20,10 every group.
2. sample source and processing
(1) blank group: with embodiment 1.
(2) Hesperidin and neohesperidin compositions (5: 5) group: with embodiment 1.
3. experimental technique
Mice is put into the cylindrical glass cylinder of high 20cm, diameter 14cm, 1, every cylinder, in cylinder the depth of water according to requirement of experiment 15cm, water temperature (25 ± 1) ℃, before training group mouse experiment, training swimming 15min, take out subsequently and put back in cage, tests after 24h.During experiment, mice is recorded the accumulative total dead time of mice in rear 4min at cylinder went swimming 6min.Dead time (immobility time) refers to that mice stops struggling, being floating state in water, or tiny limb motion is only arranged to keep head to keep afloat.With investigate the antagonism of Hesperidin and neohesperidin compositions (5: 5) due to chmice acute stress cause demoralized.Simultaneously with the blank group that the gives normal saline contrast of accompanying.
4. experimental result
By statistics, each is organized the mice forced swimming dead time and sees Table 5.
Table 5. is respectively organized the mice forced swimming dead time
Above-mentioned experimental result demonstration, the Pharmaceutical composition (1: 1～9: 1) that Hesperidin and neohesperidin form has antidepressant activity, can be applicable to the preparation of antidepressant drug.
With the Pharmaceutical composition of Hesperidin and neohesperidin composition, can also comprise with pharmaceutical carrier combination pharmaceutically commonly used being prepared into preparation commonly used, as pharmaceutically acceptable dosage forms such as tablet, capsule, solution, suspension, injection, drip liquid.Can adopt oral, non-intestinal or topical routes.
Claims (3)
1. a Chinese medicine composition as the application of antidepressant drug, is characterized in that: the application in the preparation antidepressant drug of Hesperidin and neohesperidin compositions.
2. the compositions according to claim 1, the ratio of its contained Hesperidin and neohesperidin can be 1: 1 to 9: 1.
3. according to claim 1-2 described purposes, it is characterized in that: pharmaceutical dosage form is tablet, capsule, solution, suspension, injection, drip liquid or freeze-dried powder etc.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1416881A (en) * | 2002-11-27 | 2003-05-14 | 北京中医药大学 | Medicine composition for treating depression and its prepn |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1416881A (en) * | 2002-11-27 | 2003-05-14 | 北京中医药大学 | Medicine composition for treating depression and its prepn |
Non-Patent Citations (2)
| Title |
|---|
| 李军，等: "反向高效液相色谱法测定四逆散抗抑郁有效部位中新橙皮苷的含量", 《北京中医药大学学报》, vol. 27, no. 1, 31 January 2004 (2004-01-31), pages 54 - 56 * |
| 蔡莉，等: "橙皮苷对慢性应激抑郁模型大鼠行为学及HPA轴的影响", 《中国中药杂志》, vol. 38, no. 2, 31 January 2013 (2013-01-31), pages 229 - 233 * |
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Application publication date: 20130612 |