CN110464730A - Application and relative medicine of the Physcion -8-O- β-D- glucopyranoside in prevention and treatment depression - Google Patents
Application and relative medicine of the Physcion -8-O- β-D- glucopyranoside in prevention and treatment depression Download PDFInfo
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- CN110464730A CN110464730A CN201910864056.4A CN201910864056A CN110464730A CN 110464730 A CN110464730 A CN 110464730A CN 201910864056 A CN201910864056 A CN 201910864056A CN 110464730 A CN110464730 A CN 110464730A
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Biomedical Technology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Psychiatry (AREA)
- Pain & Pain Management (AREA)
- Molecular Biology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses purposes of the Physcion -8-O- β-D- glucopyranoside in prevention and treatment depression.The present invention also provides a kind of drugs for preventing and treating depression, and drug is using Physcion -8-O- β-D- glucopyranoside as active constituent, in addition pharmaceutically acceptable auxiliary material or adjuvanticity ingredient are prepared.Depression, depressive neurosis that drug of the present invention induces endogenous depression, reactive depression, masked depression, drug-induced secondary depression, climacteric or post-natal depression, brain trauma or cerebral apoplexy etc. has good control efficiency, it is curative for effect, without additive and dependence, without apparent toxic side effect.The present invention provides a kind of new applications of Physcion -8-O- β-D- glucopyranoside, have widened the application scenarios of Physcione-monoglucoside, have found new scheme for the prevention and treatment of depression.
Description
Technical field
The present invention relates to a kind of technical field of pharmaceuticals, and in particular to a kind of Physcion -8-O- β-D- glucopyranose
Application and corresponding drug of the glycosides in prevention and treatment depression.
Background technique
Depression is the higher major disease of disease incidence.Depression is a kind of disease that psychiatric department is common, according to world health
Tissue statistics, depression have become the big illness in the world the 4th, Chinese 2nd big Disease Spectrum, it is predicted that the year two thousand twenty is likely to become only
Inferior to the second largest disease of coronary heart disease, the 15% of global disease burden is accounted for.The disease incidence of lifelong depression between 6%~8%,
As gradually aging, disease incidence of the depression in 60 years old or more crowd of population will be up to 20%~50%.Depression disease
People is the people at highest risk of suicide, falls ill in patient to convalescence, there is the danger of suicide always.The identifying and diagnosing rate of depression is very
Low, effective cure rate is also very low.Existing antidepression Western medicine is mainly: tricyclic antidepressants (TCAs), and selective 5-HT reuptake inhibits
Agent (SSRIs), monoamine oxidase inhibitors (MAOIs), the toxic side effect of their equal various degrees, and it is expensive,
New antidepressants are thus researched and developed from traditional Chinese medicine with important theoretical and practical significance.
The fleece-flower root is the dried root of polygonum multiflorum thunb Polygonum multiflorum Thunb., is famous
The raw ripe different Chinese medicine controlled, there is Radix Polygoni Multiflori and RADIX POLYGONI MULTIFLORI PREPARATA.Health product is mild-natured, sweet in flavor, bitter；Return heart, liver, large intestine channel；Product becomes
Temperature, taste turn sweet, return liver and kidney channel.Li Shizhen (1518-1593 A.D.) is recorded in Compendium of Material Medica: " all Zhu Mingshan, remote mountains production person are that is, big and good ".
Modern studies have found that mainly containing Stibene-glucoside, rheum emodin, Physcion, emodin monoglucoside, rheum officinale in the fleece-flower root
The ingredients such as plain methyl ether glucoside.Wherein, rheum emodin, Physcion neuroprotection be research hotspot in recent years.
The activity research of Physcion -8-O- β-D- glucopyranoside still belongs to blank.
Summary of the invention
The purpose of the present invention is open Physcion -8-O- β-D- glucopyranoside and contain Physcion -
The drug of 8-O- β-D- glucopyranoside can be used for the prevention and treatment of depression, have the characteristics that small toxicity, will not be to human body
Cause side effect.
By experimental verification, Physcion -8-O- β-D- glucopyranoside or formed using it as active component
Pharmaceutical composition etc. to endogenous depression, reactive depression, masked depression, drug-induced secondary depression,
Various depression including depression and depressive neurosis that climacteric or post-natal depression, brain trauma or cerebral apoplexy induce
Shape has good control efficiency, while the learning memory decline etc. secondary to depression has apparent relaxation effect.
Crowd is used for different, it can be by Physcion -8-O- β-D- glucopyranoside and different pharmacy
Upper acceptable auxiliary material mixing, is made the drugs such as tablet, capsule, granule or oral solution.Pharmaceutically acceptable auxiliary material root
It can be with according to the difference of drug character are as follows:
(1) tablet: one or more in starch, Icing Sugar, dextrin, microcrystalline cellulose, magnesium stearate, ethyl alcohol etc..
(2) capsule: mannitol, microcrystalline cellulose, lactose, starch, magnesium stearate, talcum powder and dodecyl sodium sulfate
Deng one of or it is a variety of.
(3) granule: starch, Icing Sugar, glucose sugar, dextrin, ethyl cellulose, ethyl alcohol, microcrystalline cellulose, talcum powder, sweet
One of oil etc. are a variety of.
(4) oral agents: one or more in sucrose, syrup, essence, Arabic gum, gelatin, tartaric acid etc..
The beneficial effects of the present invention are:
Drug of the present invention is for endogenous depression, reactive depression, masked depression, drug-induced secondary
Depression, depressive neurosis that depression, climacteric or post-natal depression, brain trauma or cerebral apoplexy induce etc. has good
Control efficiency, it is curative for effect, without additive and dependence, without apparent toxic side effect.The present invention provides Physcion -8-
A kind of new application of O- β-D- glucopyranoside, has widened the application scenarios of Physcione-monoglucoside, is depression
Prevention and treatment has found new scheme.
Specific embodiment
The present invention is that research sample constructs corresponding depression model, then investigates using rheum emodin first with mouse and rat
The situation of change of experiment sample before and after ether -8-O- β-D- glucopyranoside, to verify Physcion -8-O- β-D- pyrans Portugal
Polyglycoside has control efficiency to depression really.
The specific technical solution of the present invention is described in detail below with reference to embodiment.
Experimental material:
1. experimental animal: male Kunming system SPF grades of mouse, 30 ± 2g of weight；Male SPF grades of SD rat, male, weight
215 ± 5g is purchased from Sichuan Province's experimental medicine animal center, SCXK [Chongqing] 2018-0003.It is dark to receive 12h illumination/12h daily,
Periodicity of illumination is 8:00-20:00, and 20 ± 2 DEG C of laboratory temperature, humidity 60%, animal can voluntarily absorb standard feed and clear
Clean to use water, zoopery is in accordance with International Laboratory Animal ethics requirement.
2. drug: Physcion -8-O- β-D- glucopyranoside (Natural Medicine Chemistry research department, Southwest Jiaotong University
There is provided), suspension is made with 0.5% shuttle methylated cellulose aqueous solution, it is spare；Reserpine；Prozac.
Embodiment one: mouse experiment
Behavioral despair 1. (behavioural despair, BD) depression model
BD model includes forced swim test (Forced Swimming Test, FST) and tail-suspention test (Tail
Suspension Test, TST), theoretical basis is: under the stressed condition of forced swimming or outstanding tail, animal goes out after struggling
Existing desperate performance, i.e., motionless state, and antidepressant can be shortened the dead time of animal.When the former is with animal in water motionless
Between, the latter hung using animal after dead time as evaluation Degree of Depression index.Due to the behavior of such animal pattern
The change almost majority antidepressants reverse applied by present clinic is learned, has the characteristics that sensitive, simplicity, therefore is usually used in
The quick screening of antidepressants is that current antidepressant screens the animal model being most widely used.But influence BD model
Factor is more, such as judgement, the quiet degree of environment and the time of experiment of the motionless state of animal may all influence experiment
As a result accuracy.
Experimental method:
KM mouse 100 is grouped into Normal group, Physcion -8-O- β-D- glucopyranoside suspension at random
High, medium and low dosage group, positive drug group is 5 groups total, every group of 20 animals, and groups of animals dosage regimen is as follows:
(1) it Normal group: takes orally to distilled water；
(2) Physcion -8-O- β-D- glucopyranoside suspension high dose group: 120mg/kg.d；
(3) Physcion -8-O- β-D- glucopyranoside suspension middle dose group: 60mg/kg.d；
(4) Physcion -8-O- β-D- glucopyranoside suspension low dose group: 30mg/kg.d
(5) prozac group: 5mg/kg.d.
Tail-suspention test (Tail Suspension Test, TST)
The daily gastric infusion of groups of animals 1 time, successive administration 7 days, last day positive controls gave prozac aqueous solution,
After 30min is administered, by mouse tail away from being fixed at end about 2cm with clip, hang upside down mouse in outstanding boot, head is from case
Bottom about 5cm.After mouse hangs 2min, observation is got started, observes and continues 6min, add up the dead time of mouse in this 6min
(mouse stops struggling in the sky, or only tiny limb motion).
Forced swim test (Forced Swimming Test, FST)
After each group mouse last gives relative medicine or distilled water 30min, mouse head is put into diameter 16cm, water downward
In the swimming cup of deep 18cm, 25 ± 2 DEG C of water temperature, immediately with the dead time in stopwatch record mouse 6min.Listed in table 1 through
Cross different pharmaceutical treated that outstanding tail is motionless and non-swimming time.
Influence of 1 each group of table to the dead time in Tail suspension test and in forced swim test
Note: compared with Normal group﹡P < 0.05,﹡ ﹡P<0.01；#P < 0.05 compared with Prozac group, ##P < 0.01 (under
Together).
From table 1 it follows that excessively high, middle dosage the Physcion -8-O- β-D- glucopyranoside of injection and hundred
The mouse tail suspension dead time of excellent solution is greatly shortened with non-swimming time, shows Physcion -8-O- β-D- pyrans
Glucoside is high, middle dose group has apparent antidepressant effect to behavioral despair depression model.
2. the influence pair drug-induced depressive state
The compounds such as reserpine are by exhausting that the symptom complex of intracerebral monoamine transmitters induction animal specifically includes that under body temperature
Drop, ptosis and activity inhibit.These symptoms may be that reserpine reduces intracerebral monoamine transmitters, especially 5- hydroxyl
Tryptamines (5-HT), and the result that supervention 5-HT receptor sensitivity changes.Monoamine transmitters system mainly includes 5-HT system, NE system
System and dopamine (DA) system, play an important role in the pathogenesis of depression.5- in Brain of Patients with Depression and cerebrospinal fluid
HT, 5-HI-AA, NE equal size are lower than normal person.5-HT is related to the adjusting of emotion, sleep, vigilance, memory and appetite etc., NE
It is insufficient then can lead to mental retardation.Monoamine oxidase (MAO) is the important inactivator of monoamine transmitters (5-HT, NE, DA), if this
Enzyme is suppressed, and increases intracerebral monoamine transmitter contents, this has positive effect to depression is improved.In 1950's,
People when observing the curative effect of antihypertensive reserpine, take this medicine for a long time there are about 10~15% patient and can produce suppression by discovery
Strongly fragrant symptom.Later pharmaceutical research shows that the basic pharmacological action of reserpine is to exhaust that the monoamine in nerve endings vesica is passed
Matter thus proposes the monoamine hypothesis of depression, it is believed that it is the depressed mechanism occurred that synaptic cleft monoamine neurotransmitter, which is reduced, and anti-suppression
Strongly fragrant medicine makes mediator metabolism reduce and play antidepressant effect by blocking monoamine-reuptake or inhibiting monoamine oxidase (MAO).
Experimental method:
KM mouse 120 is grouped into Normal group, model group, Prozac group, Physcion -8-O- β-D- pyrrole at random
The high, medium and low dosage group of glucopyranoside glycosides, 6 groups total, every group of 20 animals, groups of animals dosage regimen are as follows:
(1) it Normal group: takes orally to distilled water；
(2) Physcion -8-O- β-D- glucopyranoside suspension high dose group: 120mg/kg.d；
(3) Physcion -8-O- β-D- glucopyranoside suspension middle dose group: 60mg/kg.d；
(4) Physcion -8-O- β-D- glucopyranoside suspension low dose group: 30mgg/kg.d；
(5) prozac group: 5mg/kg.d；
(6) model group: reserpine 1mg/kg.d.
Each group mouse continuous gavage distilled water or relative medicine 6 days, each group gives reserpine 1mg/kg except for the normal group,
Ptosis after 60min, temperature decline, activity inhibit after 180min.30min is put into mouse prologue to next day mouse after the last administration
In experimental box, adapts to 2min, observe the level of mouse in subsequent 4min, Vertical movements number, that is, creep grid number and standing time
Number.The activity condition of each group mouse is listed in table 2.
2 each group of table creeps the influence of grid number and standing number to mouse open field test
Note: compared with model group△P < 0.05,△△P<0.01
From table 2 it can be seen that the antidepressant effect and monoamine mechanism phase of Physcion -8-O- β-D- glucopyranoside
It closes.
Embodiment two: rat experiment
1. chronic unpredictable sexual stimulus (CUMS) model
After the weight for weighing experimental rat, 60 rats are randomly divided into 6 groups, every group 10；It is respectively as follows: control group, model
Group, extract with fluoxetine group (10mgkg-1), Physcion -8-O- β-D- glucopyranoside (PSG) it is basic, normal, high
(20mg·kg-1, 40mgkg-1, 80mgkg-1) dosage group.Each group rat experiment before adapt to environment 1 week, after carry out for
The building of phase 4 weeks chronic unpredictable mild stimulation depression models.Control rats are normally ingested drinking-water, do not give any thorn
Swash；Remaining each group selects a kind of Coping style daily, avoids repeating.Coping style include round the clock overturn for 24 hours, mouse cage tilt 45 °
For 24 hours, 4 DEG C of ice water swimming 5min, constraint 3h, moist paddings for 24 hours, folder tail 1min, prohibit water for 24 hours, for 24 hours, solely cage stress wait for fasting.Slowly
Property stress start to be administered after 3 weeks, 1 time a day, successive administration 1 week (continuing modeling during administration), control group and model group rats
Isometric physiological saline is gavaged daily.
2. open field test (OPEN FIELD TEST)
More dim in light and relatively quiet place (at night 20 points or so), is put into open field test dress for single rat
In the center grid set, start timing, the level in rat 5min of observing passes through grid lattice number, and (3 claws of rat enter
Get a point in same grid) it is calculated as horizontal score and rat standing number (two rear solid end standing numbers of rat, primary obtain of standing
One point) it is calculated as vertical score, after every experiment movement for having observed a rat, with 70% ethanol solution cleaning device, keep away
The test result for exempting from the lower rat of odor impact of a upper rat, by the horizontal score of each rat and vertical call
It is to be analyzed on minute book.The results are shown in Table 3.
The horizontal score of 3 rat open field test of table and vertical score
Note: compared with blank group#P < 0.05,##P<0.01；Compared with model group﹡P < 0.05,﹡ ﹡P < 0.01 (similarly hereinafter)
3. syrup preference tests (SUCROSE PREFEREENCE TEST；SPT)
The only cage of rat is raised, and bilateral symmetry puts two water bottles at random in rearging cage, and the 1% of equivalent is contained inside water bottle
Sucrose solution gives rat 48 hours 1% aqueous sucrose solutions, then prohibits water 16 hours to each rat again；Prohibit water 16 hours
Afterwards, one of water bottle in big mouse cage is changed to distilled water, i.e., one distilled water of water bottle in big mouse cage, one is to fill
1% sucrose solution of the distilled water configuration of amount, the gross mass of weigh with scale the two water bottles and solution are simultaneously recorded in minute book
On；After 1 hour, removes the two water bottles and the quality of weigh with scale water bottle and solution and be recorded in experiment on this, with rat
Consumption 1% aqueous sucrose solution relative to the total intake liquid of rat amount percentage as rat to the preference of sucrose.In
It is normal right in order to avoid as far as possible during the experiment because jejunitas process of cutting off the water supply influences the metabolism of control group in this experimentation
Only baseline level is tested according to group.
After modeling 4 weeks, model group rats are substantially reduced (P < 0.01) the preference degree of syrup compared with blank control group rat, and
After giving middle and high dosage Physcion glycosides and Prozac, the syrup preference degree of rat obviously rises (P < 0.05, P < 0.01),
Show Physcion glycosides can improve stress caused by anhedonia, alleviate depressive symptom, the results are shown in Table 4.
The syrup preference of 4 rat syrup preference of table test
4. rat forced swimming test
Single rat is put into homemade sink, the depth of the water in experimental trough is 30cm, and the temperature of water is 25 ± 2
DEG C, make rat hindlimb that plastic barrel bottom can not be leaned on to support body, allows its free swimming 6min to adapt to environment.2nd day formal real
It tests, rat is put into the time in sink for 6min, by not knowing that the personnel of experimental program record rat in rear 4min with stopwatch in total
Non-swimming time in inherent pond (with rat in water only with small limb motion, only keeps the head to be on the water surface
Index), record the non-swimming time of each rat.
After modeling 4 weeks, the dead time of model group rats is apparently higher than blank control group, and difference has statistical significance (P
< 0.01), it is administered after middle and high dosage Physcion glycosides and Prozac that can be obviously shortened rat motionless in forced swimming
Time (P < 0.05 or P < 0.01), show that the depressive state of animal is improved, the results are shown in Table 5.
5 rat forced swimming test of table
5. the influence pair rat hippocampus monoamine neurotransmitters
After 30min is administered in forced swim test next day, broken end takes brain, on ice the removing full hippocampal tissue of bilateral rapidly, with pre-
Cold PBS rinses hippocampal tissue, detects NA, 5-HT, MAO content, operates by kit specification.
After the chronic unpredictability mildness stress stimulation of 28d, compared to the blank group compared with model group rats hippocampus
Monoamine neurotransmitter has reduction (P < 0.01)；Compared with model group, middle and high dosage Physcion glycosides and Prozac is administered
Group rat hippocampus area monoamine neurotransmitters are significantly raised (P < 0.05 or P < 0.01).The results are shown in Table 6.
6 rat hippocampus monoamine neurotransmitters of table
6. the influence pair rat hippocampus monoamine oxidase content
After 28 days chronic unpredictability mildness stress stimulations, compared to the blank group compared with model group rats hippocampus
Area MAO is increased；Compared with model group, middle and high dosage Physcion glycosides is administered and Prozac group rat hippocampus area MAO contains
Amount decreases.The results are shown in Table 7.
7 rats hippocampus monoamine oxidase content of table
Above the results showed that Physcion -8-O- β-D- glucopyranoside has on rat CUMS model
Apparent antidepressant effect.
Although be described in detail to a specific embodiment of the invention in conjunction with the embodiments, should not be construed as to this
The restriction of the protection scope of patent.In range described by claims, those skilled in the art are without creative work
The various modifications and deformation that can make still belong to the protection scope of this patent.
Claims (4)
1. application of the Physcion -8-O- β-D- glucopyranoside in prevention and treatment depression.
2. application according to claim 1, it is characterised in that: the depression is endogenous depression, reactive depression
The depression that disease, masked depression, drug-induced secondary depression, involutional depression, post-natal depression, brain trauma induce
The depression or depressive neurosis that disease, cerebral apoplexy induce.
3. a kind of drug for preventing and treating depression, it is characterised in that: the drug includes Physcion -8-O- β-D- glucopyra
Glucosides and pharmaceutically acceptable auxiliary material.
4. it is according to claim 3 prevention and treatment depression drug, it is characterised in that: the drug be tablet, capsule,
Granula or oral solution.
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| CN112023027A (en) * | 2020-07-21 | 2020-12-04 | 广东海洋大学 | Application of thymosin or derivative thereof and medicine for treating anhedonia type depression |
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