CN1552331A - Improvement of chronic mild stress BALB/C mouse depression by compound 7-carbonyl epiandrosterone - Google Patents
Improvement of chronic mild stress BALB/C mouse depression by compound 7-carbonyl epiandrosterone Download PDFInfo
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- CN1552331A CN1552331A CNA031238564A CN03123856A CN1552331A CN 1552331 A CN1552331 A CN 1552331A CN A031238564 A CNA031238564 A CN A031238564A CN 03123856 A CN03123856 A CN 03123856A CN 1552331 A CN1552331 A CN 1552331A
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- dehydroepiandrosterone
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Abstract
A synthetic compound 7-carboxyl dehydroepiandrosterone is disclosed, which can be used to relax the chronic minimal irritable BALB/C depression of mouse by increasing the quantity of cane sugar solution drunk by said mouse and its autogenic activity and improving its immunity and memory.
Description
Technical field:
The present invention is by setting up chronic mild stress depression disease model, and research 7-carbonyl dehydroepiandrosterone relates to the exploitation and the application of novel drugs in the biomedical high-tech to the improvement effect of depressed depression.
Background of invention:
World Health Organization (WHO) once delivered an investigation about " disease burden ", due to illness to cause " permanent disability "---the functional impairment statistics, depression occupies the second, is only second to the chronic obstructive lung illness, accounts for 6.2% of the total burden of whole diseases; If add the bipolar affective disorder that occupies the 13rd (manic---depressive state is outbreak alternately), then reach 8.0%.Along with modernization process, the importance of depression also will continue to increase, and estimate after 25 years, will account for the total burden about 10% of disease.In a sense, depression will be cross-centennial challenge.On the pathogeny of anxiety-depression, think that central nervous system's biochemical function is closely related unusually with it, and relate generally to neurotransmitteies such as NE, 5-HT.As far back as the 1950's, just there is oxidase inhibitor (MAOIS) to be applied to the treatment of depression, because of being replaced by tricyclic antidepressants (TCAS) behind its serious toxicity, the TCAS curative effect is better, is leveraged to the present., clinical discovery, TCAS cut off the untoward reaction of use but still having many patients of making to be difficult to stand.Their immunologic hypofunction and not effect of damage in learning and memory simultaneously to occurring together with depression.Therefore select toxic and side effects little, therapeutic effect chemical compound good and that can improve depressed associated disease becomes the target of psychopharmacologist pursuit.
Goal of the invention:
By BALB/C mice is used the multiple multiple stressor of arranging in unpredictable mode, set up to the similar animal model of people's depression basis on, research 7-carbonyl dehydroepiandrosterone is to the improvement effect of depressed mice depressive symptom, and estimate 7-carbonyl dehydroepiandrosterone to the concurrent immunologic hypofunction of depression and the improvement effect of learning memory disorder, for 7-carbonyl dehydroepiandrosterone is established the theory and technology basis in clinical practice.
Content and requirement:
Set up chronic mild stress depression animal model, replenish 7-carbonyl dehydroepiandrosterone for depressed mice, measure mice 2% sucrose solution and drink quantitative changeization, observe sense of euphoria's situation that 7-carbonyl dehydroepiandrosterone causes reversing depression.Observe the influence of the depressed spontaneous activity in mice of 7-carbonyl dehydroepiandrosterone simultaneously.7-carbonyl dehydroepiandrosterone causes the immunocompromised function to depression influence is estimated in the analysis of bind lymphocytes proliferation experiment and nature cell (NK) killing experiments.Use Morris water maze method, after evaluation 7-carbonyl dehydroepiandrosterone replenishes, to the influence of depressed ability of learning and memory in mice.
The technical specification that this chemical compound reaches is:
1. can recover the 2% sucrose solution amount of drinking that the depression mice reduces after 7-carbonyl dehydroepiandrosterone replenishes, improve depressed mice sense of euphoria and lack symptom.
2. can reverse depressed spontaneous activity in mice after 7-carbonyl dehydroepiandrosterone replenishes and reduce, recover spontaneous activity in mice.
3. it is low that 7-carbonyl dehydroepiandrosterone replenishes the depressed immune function of mice that causes of back reverse, strengthens depressed immune function of mice.
4. 7-carbonyl dehydroepiandrosterone replenishes the depressed mice space learning memory ability of back improvement, strengthens depressed learning ability of mice.
Description of drawings:
Fig. 1. 7-carbonyl dehydroepiandrosterone structural formula
Molecular formula C
19H
27O
3, molecular weight: 302.4
Fig. 2. 7-carbonyl dehydroepiandrosterone is to the depressed mice 2% sucrose solution amount of drinking
Control is a matched group, and Stress is a model group, and Stress+7OD-L is a 5mg/kg dosage group, and Stress+7OD-H is a 15mg/kg dosage group.
Fig. 3. 7-carbonyl dehydroepiandrosterone is to the influence of depressed spontaneous activity in mice
Control is a matched group, and Stress is a model group, and Stress+7OD-L is a 5mg/kg dosage group, and Stress+7OD-H is a 15mg/kg dosage group.
Fig. 4. 7-carbonyl dehydroepiandrosterone is to the influence of depressed mice space learning memory
Control is a matched group, and Stress is a model group, and Stress+7OD-L is a 5mg/kg dosage group, and Stress+7OD-H is a 15mg/kg dosage group.
Fig. 5. the influence that 7-carbonyl dehydroepiandrosterone stimulates proliferation and reacts depressed mouse T lymphocyte Con A
Control is a matched group, and Stress is a model group, and Stress+7OD-L is a 5mg/kg dosage group, and Stress+7OD-H is a 15mg/kg dosage group.
Fig. 6. 7-carbonyl dehydroepiandrosterone is to the influence of depressed NK cells in mice killing activity
Control is a matched group, and Stress is a model group, and Stress+7OD-L is a 5mg/kg dosage group, and Stress+7OD-H is a 15mg/kg dosage group.
Embodiment:
1. synthetic preparation 7-carbonyl dehydroepiandrosterone
(10g 0.0255mol) is dissolved in the mixed solution of 12ml pyridine and 8ml acetic anhydride, stirs under the room temperature and spends the night with DHEA.TLC method monitoring reaction carries out degree, and (developing solvent is an ethyl acetate: petroleum ether=1: 3), behind the 254nm ultraviolet detection, develop the color after soaking into post-heating with 5% sulphuric acid/alcoholic solution.(DHEA and 3 β-Acetoxyandrost-5-ene-17-one does not all have fluorescence, but can develop the color.) reactant mixture is poured in the 100ml frozen water, regulating pH with 2M HCl solution is 6-7, sucking filtration is collected precipitate, and solids is washed repeatedly to filtrate neutrality with frozen water.In the dry 10hr of infrared lamp box.Obtain white solid 10.5g, m.p.171-173 ℃, yield is 92%.Recrystallization (acetone/petroleum ether) obtains white crystals, m.p.172-173 ℃.
At there-necked flask device return duct, condensing tube and breather, 2.5g N-hydroxyphthalimide is dissolved in the mixed solution of 55ml of acetone/ethyl acetate (1: 1), add 3 β-acetic acid oxygen DHEA 5g and the fine 0.5g of azo hexamethylene.To react reflux, and lasting bubbling air, and in reaction, add azo hexamethylene fine (each approximately 50mg * 15 times) in batches.React after 50 hours, with the solvent evaporate to dryness.Add toluene 40ml, after 50 ℃ of constant temperature stir 1h, be placed to room temperature.Solids removed by filtration (N-hydroxyl phthalic imines), reusable, and wash with small amount of toluene.Filtrate is colourless to water layer with the solution washing of saturated sodium bicarbonate.Toluene is removed in decompression.With silica gel chromatography purification (post: 5 * 15cm, developing solvent: ethyl acetate: petroleum ether=1: 4) collect the filtrate section that contains product, obtain crude product 1.5g.Column chromatography purification (post: 20 * 3cm, eluant petroleum ether: ethyl acetate=4: 1), collect eluent, concentrate, obtain the 220mg faint yellow solid.M.p.185-187 ℃, yield is 31%.Use the acetone/methanol recrystallization, obtain white crystal, fusing point 186-187 ℃.
About 2g steroidal is dissolved in the 90ml methanol, is dissolved in the aqueous solution of 2.5ml, 1 hour (TLC developing solvent petroleum ether: ethyl acetate=3: 2) of reactant liquor stirring at room to wherein adding potassium hydroxide 500mg.Decompression is removed methanol to half volume, pours in the 100ml water, place 0 ℃ about 1 hour, solid collected by filtration, and washing with water repeatedly obtains drying solid 1.7g.Fusing point detects to 212-217 ℃.
Recrystallization is dissolved in solid in the chloroform earlier, and filters once with Cotton Gossypii.Filtrate collection is concentrated, behind the adding petroleum ether crystal is separated out, collect solid, and use a spot of chloroform: petroleum ether is about 1: 5 liquid scrubbing, and drying solid obtains acicular crystal 1.55g.m.p.219-222℃。Structure is seen Fig. 1.
2. 7-carbonyl dehydroepiandrosterone suspension preparation
Take by weighing 7-carbonyl dehydroepiandrosterone, be mixed with 2mg/ml and two kinds of suspensions of 6mg/ml with Oleum sesami (Sigma company product).
3. set up chronic mild stress depression disease animal model
The present invention adopts the mice of foundation such as Monleon program also to change a little, stress program comprise following stressor content weekly: twice food deprivation, each 12h; Twice drinking-water is deprived, each 14h; Twice illumination all night; Twice wet cage raised, each 14h; Twice frozen water swimming, each 5min; Hang each 30min for twice by the feet; Twice pairing raised, each 17h.Above-mentioned stressor makes up enforcement at random, and every day, two kinds of stressors were handled, and carried out for 4 weeks continuously.Control mice is also raised in same environment, does not handle treated animal and stressor but do not contact.
4. animal is replenished 7-carbonyl dehydroepiandrosterone suspension
Stressed animal is divided into three groups of model group, 7-carbonyl dehydroepiandrosterone low dosage (5mg/kg), 7-carbonyl dehydroepiandrosterone high dose (15mg/kg).7-carbonyl dehydroepiandrosterone low dosage, three groups of mices of 7-carbonyl dehydroepiandrosterone high dose 8:00 every morning are by every kg body weight 5ml lumbar injection 2mg/ml or 6mg/ml 7-carbonyl dehydroepiandrosterone suspension; Matched group and model group animal lumbar injection Oleum sesami replace 7-carbonyl dehydroepiandrosterone suspension.
5. 7-carbonyl dehydroepiandrosterone is to the influence of the depressed mice 2% sucrose solution amount of drinking
After stress handling for 4 weeks, earlier water 3h is prohibited in the mice fasting, then drinking water is changed into 2% sucrose solution, measure the 2% sucrose solution amount of drinking in the 1h, and proofread and correct through body weight.7-carbonyl dehydroepiandrosterone can increase the depressed mice sucrose solution amount of drinking, and reverses the depressed sense of euphoria's disappearance (Fig. 2) that causes.
6. 7-carbonyl dehydroepiandrosterone is to the influence of depressed spontaneous activity in mice
After 4 all chronic stress processing finish, in quiet environment, each group BALB/C mice is put into spontaneous activity in mice case (institute of Materia Medica,Chinese Academy of Medical Sciences development) respectively, observe of the influence of 7-carbonyl dehydroepiandrosterone depressed spontaneous activity in mice.7-carbonyl dehydroepiandrosterone can increase depressed spontaneous activity in mice (Fig. 3).
7. 7-carbonyl dehydroepiandrosterone is to the influence of depressed mice space learning memory
Water maze laboratory carries out after spontaneous activity is measured.The water maze device comprises drum and the sport video capture system composition (Beijing Jie Riou scientific ﹠ technical corporation product) of a diameter 90cm.Experiment is injected clear water before beginning in bucket, depth of water 15cm regulates 20 ℃ of water temperatures, places the circular real platform of a diameter 7cm then in bucket, and table top does not have about water 1cm, with burnt black ink water is transferred and is deceived, in order to avoid animal is seen real platform.Open the water maze test program, demarcate parameters such as catching the visual field, real platform, empty platform and place of entry, the animal head is put into water towards the bucket wall.Mice freely moves about in bucket and seeks real platform, and the video system of bucket top is caught its swimming track.When testing for the first time,, mice is taken out rapidly, towel off the dried rearging cage of putting back to if mice is found real platform and stop 2s on platform in 120s; If mice fails to find real platform at 120s,, take out to dry then and put back in the cage 15s on the mice mounting table.Water maze laboratory carried out 3 days altogether, and respectively carry out once afternoon every morning.7-carbonyl dehydroepiandrosterone can strengthen depressed mice space learning memory ability (Fig. 4).
8. 7-carbonyl dehydroepiandrosterone is to the stimulate proliferation influence of ability of depressed mouse T lymphocyte Con A
After spontaneous activity is measured and is finished, with the mice sacrificed by decapitation.Prepare the mouse spleen single cell suspension routinely and add cell suspension (2 * 10 in the every hole of 96 well culture plates
6Individual/ml) 100 μ l and Con A 2 μ g/ml, control wells is with complete medium replaced C on A.4 multiple pipes are all established in experiment and contrast.Culture plate is put 37 ℃, 5%CO
2Cultivate 72h under the condition, cultivate and stop preceding 8h, every hole adds 37kBq
3H-TdR (emission ratio activity 0.93TBqmmol
-1), harvesting on cell harvestor subsequently, the filter membrane oven dry adds 5ml liquid and dodges liquid and place on the liquid scintillation counter and measures.7-carbonyl dehydroepiandrosterone can strengthen the multiplication capacity (Fig. 5) that depressed mouse T lymphocyte stimulates Con A.
9. 7-carbonyl dehydroepiandrosterone is to the influence of depressed NK cells in mice killing activity
Adjust cell density 4 * 10 with culture fluid
6Individual ml
-1, be target cell with mouse lymph lymphoma YAC-1 cell, every hole adds 75 μ l splenocyte suspensions on 96 well culture plates, presses the effector lymphocyte: target cell=add 75 μ l YAC-1 target cell suspensions at 50: 1, laying effect cell and target cell contrast in addition.Every hole 150 μ l establish 4 parallel pipes, 37 ℃, 5%CO
2Cultivate 10h under the condition, adopt mtt assay to measure the A value.7-carbonyl dehydroepiandrosterone can strengthen depressed NK cells in mice killing activity (Fig. 6).
Claims (3)
1. the present invention relates to the synthetic chemical compound 7-carbonyl epiandrosterone that can improve chronic mild stress the mice depressive symptom, it is characterized in that: molecular weight 302.4, molecular formula are C
19H
27O
3
2. the 7-carbonyl epiandrosterone according to claim 1 is characterized in that: can significantly increase depressed mice sucrose solution drink amount, reverse sense of euphoria's disappearance; Can significantly increase depressed spontaneous activity in mice, thereby improve the mice depressive symptom.Improve immunologic function disorder and learning and memory decline that the depression mice is occurred together.
3. according to claim 1,2 described 7-carbonyl epiandrosterones, it is characterized in that: can be used as new antidepressants drug candidate, and can be used as the immunostimulant of the immunologic hypofunction that depression occurs together and the promoter of learning memory disorder.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20080070879A1 (en) * | 2006-09-14 | 2008-03-20 | Sharon Sageman | 7-keto dhea for psychiatric use |
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- 2003-06-04 CN CNA031238564A patent/CN1552331A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20080070879A1 (en) * | 2006-09-14 | 2008-03-20 | Sharon Sageman | 7-keto dhea for psychiatric use |
| US8124598B2 (en) * | 2006-09-14 | 2012-02-28 | Sharon Sageman | 7-keto DHEA for psychiatric use |
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