CN102973563A - Application of ombination of esveratrol and piperine used for preparation of medicament for treatment of depression - Google Patents
Application of ombination of esveratrol and piperine used for preparation of medicament for treatment of depression Download PDFInfo
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- CN102973563A CN102973563A CN2011102697350A CN201110269735A CN102973563A CN 102973563 A CN102973563 A CN 102973563A CN 2011102697350 A CN2011102697350 A CN 2011102697350A CN 201110269735 A CN201110269735 A CN 201110269735A CN 102973563 A CN102973563 A CN 102973563A
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- piperine
- resveratrol
- depression
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- esveratrol
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- MXXWOMGUGJBKIW-YPCIICBESA-N piperine Chemical compound C=1C=C2OCOC2=CC=1/C=C/C=C/C(=O)N1CCCCC1 MXXWOMGUGJBKIW-YPCIICBESA-N 0.000 title claims abstract description 25
- 229940075559 piperine Drugs 0.000 title claims abstract description 25
- WVWHRXVVAYXKDE-UHFFFAOYSA-N piperine Natural products O=C(C=CC=Cc1ccc2OCOc2c1)C3CCCCN3 WVWHRXVVAYXKDE-UHFFFAOYSA-N 0.000 title claims abstract description 25
- 235000019100 piperine Nutrition 0.000 title claims abstract description 25
- 239000003814 drug Substances 0.000 title claims abstract description 15
- 238000002360 preparation method Methods 0.000 title claims abstract description 6
- 208000020401 Depressive disease Diseases 0.000 title abstract description 3
- LUKBXSAWLPMMSZ-OWOJBTEDSA-N Trans-resveratrol Chemical compound C1=CC(O)=CC=C1\C=C\C1=CC(O)=CC(O)=C1 LUKBXSAWLPMMSZ-OWOJBTEDSA-N 0.000 claims description 23
- QNVSXXGDAPORNA-UHFFFAOYSA-N Resveratrol Natural products OC1=CC=CC(C=CC=2C=C(O)C(O)=CC=2)=C1 QNVSXXGDAPORNA-UHFFFAOYSA-N 0.000 claims description 19
- 229940016667 resveratrol Drugs 0.000 claims description 19
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- XZZXIYZZBJDEEP-UHFFFAOYSA-N imipramine hydrochloride Chemical compound [Cl-].C1CC2=CC=CC=C2N(CCC[NH+](C)C)C2=CC=CC=C21 XZZXIYZZBJDEEP-UHFFFAOYSA-N 0.000 description 2
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- YHXISWVBGDMDLQ-UHFFFAOYSA-N moclobemide Chemical compound C1=CC(Cl)=CC=C1C(=O)NCCN1CCOCC1 YHXISWVBGDMDLQ-UHFFFAOYSA-N 0.000 description 2
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- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
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- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
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- PIOVAOYWMIMBNZ-UHFFFAOYSA-N OC(C(C(=O)O)C1=CC=CC=C1)(C)O Chemical compound OC(C(C(=O)O)C1=CC=CC=C1)(C)O PIOVAOYWMIMBNZ-UHFFFAOYSA-N 0.000 description 1
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- AHOUBRCZNHFOSL-UHFFFAOYSA-N Paroxetine hydrochloride Natural products C1=CC(F)=CC=C1C1C(COC=2C=C3OCOC3=CC=2)CNCC1 AHOUBRCZNHFOSL-UHFFFAOYSA-N 0.000 description 1
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- BTFHLQRNAMSNLC-UHFFFAOYSA-N clorgyline Chemical compound C#CCN(C)CCCOC1=CC=C(Cl)C=C1Cl BTFHLQRNAMSNLC-UHFFFAOYSA-N 0.000 description 1
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- LUKBXSAWLPMMSZ-UHFFFAOYSA-N resveratrol Chemical compound C1=CC(O)=CC=C1C=CC1=CC(O)=CC(O)=C1 LUKBXSAWLPMMSZ-UHFFFAOYSA-N 0.000 description 1
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- MEZLKOACVSPNER-GFCCVEGCSA-N selegiline Chemical compound C#CCN(C)[C@H](C)CC1=CC=CC=C1 MEZLKOACVSPNER-GFCCVEGCSA-N 0.000 description 1
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- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The present invention relates to a drug combination therapy. The combination of esveratrol and piperine are used for treating depression. Animal experiments show that the combination of esveratrol and piperine has a good anti-depressant effect, and is a relatively promising natural anti-depressant medicament, and can be used for the preparation of a medicament for the treatment of depression.
Description
Technical field
The present invention relates to a kind of new purposes of resveratrol and piperine coupling, particularly relate to the purposes for the preparation of the Cure of depression medicine.
Background technology
Depression is a kind of able-bodied affective disorder mental sickness that has a strong impact on.Along with people's survival and development pressure increases day by day, depression has become the commonly encountered diseases of modern society.The major depressive disorder patient shows as particularly norepinephrine (NE) and the change of 5-hydroxy tryptamine (5-HT) reflexive ground of monoamine neurotransmitter in the brain.At present, Drug therapy is that the first-selection for the treatment of depression is selected.It all is by improving Monoamines level such as 5-HT, NE performance antidepressant effect that several typical antidepressants are arranged clinically.But most drug all has untoward reaction, and therapeutic effect is not fine.So, the effectiveness of medicine and the research of safe treatment factor are seemed significant.Because Chinese traditional medicinal plants has good compliance and gentle side effect, is widely used in the treatment of mental sickness.In the history of China, Rhizoma Polygoni Cuspidati is a kind of plant that mental sickness is had good therapeutical effect.Its main effective ingredient trans-resveratrol has multiple pharmacologically active, as improves learning and memory, antiinflammatory, antioxidation and neuroprotective etc.Studies show that trans-resveratrol has the active ability of monoamine oxidase, MAO (MAO) that suppresses neurogliocyte.MAO is Mitochondria Isoenzyme, but specificity catalysis metabolism monoamine neurotransmitter, such as 5-HT, NE, DA and other micro-amine substances.The MAO inhibitor has good therapeutical effect to some neuropsychiatric diseases, such as dysthymic disorder, parkinsonism etc.In the recent period to studies show that of rat, trans-resveratrol can suppress the reuptake of NE and 5-HT in the rat brain.But whether trans-resveratrol is by the inhibition to the MAO activity, and then the level of amine neurotransmitter there is no final conclusion in the increase brain.
Piperine is the main active chemistry in " king of spice " Fructus Piperis, belong to the cinnamamide alkaloid, the pharmacological action of piperine is comparatively extensive, have the effects such as antioxidation, immunomodulating, be a kind of biological activity reinforcing agent, simultaneously the hypothalmus-pituitary-adrenal axis functional disorder that chronic stress is induced had certain regulating action.Piperine and some polyphenol compounds share, and can obviously improve the bioavailability of polyphenol compound, make the polyphenol compound of low dosage show very strong pharmacologically active.Most polyphenol compounds have the effect that suppresses monoamine oxidase, MAO, with polyphenol compound and piperine use in conjunction, can act on the different pathological process that depression occurs, to reach the reduction dosage, improve the purpose of curative effect of medication, for the natural antidepressants of Development of New Generation high-efficiency low-toxicity provide new thinking.
Summary of the invention
Purpose of the present invention provides a kind of new purposes of resveratrol and piperine coupling.
Finding that through zoopery resveratrol and piperine coupling have preferably antidepressant effect, is a kind of more rising natural antidepressant, can be used for preparing the medicine of Cure of depression.
The specific embodiment
The present invention is described by the following examples
Embodiment 1: Tail suspension test, forced swimming experiment, autonomic activities experiment, PCPA experiment, reserpine experiment
1, tested medicine
Title: resveratrol (Resveratrol), piperine (Piperine)
Character: resveratrol, the off-white color fine powder, gas is special, and is lightly seasoned, extracts piperine, white crystalline powder from Rhizoma Polygoni Cuspidati
The source: available from Shaanxi Sen Fu Bioisystech Co., Ltd, purity is 98%
The medicine preparation: piperine dissolves with 0.5% sodium carboxymethyl cellulose, is made into 2.5mg/kg, carries out the mouse peritoneal injection by 0.1ml/10g dosage.Resveratrol dissolves with 0.5% sodium carboxymethyl cellulose, is made into respectively 1.25mg/kg, 2.5mg/kg, and 5mg/kg, 10mg/kg, five dosage of 20mg/kg, it is oral to carry out mouse stomach by 0.1ml/10g dosage.
2, control drug
Imipramine hydrochloride (imipramine hydrochloride), fluoxetine (fluoxetine hydrochloride), PCPA (p-chlorophenylalanine HCl): available from U.S. Sigma company.Before using imipramine and fluoxetine are mixed with 10mg/kg concentration with distilled water, PCPA is mixed with 300mg/kg concentration with distilled water, gives the mouse peritoneal injection by above-mentioned specification.Reserpine (Reserpine): available from Nat'l Pharmaceutical ﹠ Biological Products Control Institute.Be mixed with 2.5mg/kg concentration with 1% glacial acetic acid before using, give mouse subcutaneous injection by above-mentioned dosage
3, animal and grouping
The ICR male mice, body weight 20-24g.Wenzhou Medical College's Experimental Animal Center provides.
Animal is divided into 7 groups at random, matched group piperine 2.5mg/kg, five dosage group piperine 2.5mg/kg+ resveratrol 1.25mg/kg, 2.5mg/kg, 5mg/kg, 10mg/kg, 20mg/kg and positive control drug group imipramine group, 12 every group.
4, experimental technique
1. Tail suspension test: according to document (Steru, L., Chermat, R., Thierry, B., and Simon, P. (1985) The Tail Suspension Test:A New Method for Screening Antidepressants in Mice.Psychopharmacology (Berl) 85:367-370.) carry out.Fixing at distance mice tail end 1cm place with adhesive plaster, and hang on liftoff 50cm place.During beginning, mice struggle activity because of the despair transfixion, is observed laboratory animal behavior in the 6min after a period of time, and the dead time of the interior accumulative total of the rear 4min of record.
2. mice forced swimming experiment: according to document (Porsolt, R.D., Bertin, A., and Jalfre, M. (1977) Behavioral Despair in Mice:APrimary Screening Test for Antidepressants.Arch Int Pharmacodyn Ther 229:327-336.) carry out.24h before test places (high 25cm in the glass container with mice; Diameter 10cm; Depth of water 10cm; 24 ± 1 ℃ of water temperatures) training 15min.Mice is put into water and namely begins swimming, because of desperate floating motionless, when mice stops to struggle, floats in the water after a period of time, only does some necessary operations and keeps namely being considered as the dead time on heads bubble through the water column.Observe laboratory animal behavior in the 6min, the 4min dead time behind the meter.
3. spontaneous activity in mice: according to document (Xu, Y., Ku, B.S., Yao, H.Y., Lin, Y.H., Ma, X., Zhang, Y.H.et a1. (2005) Antidepressant Effects of Curcumin in the Forced Swim Test and Olfactory Bulbectomy Models of Depression in Rats.Pharmacol Biochem Behav 82:200-206.) carry out.Mice is placed in the spontaneous activity tester, and built-in camera record mice is movable.After putting into first adaptation 5min, the movable number of times of mice in the record 10min.
4. PCPA experiment: according to document (Redrobe, J.P., Bourin, M., Colombel, M.C., and Baker, G.B. (1998) Psychopharmacological Profile of the Selective Serotonin Reuptake Inhibitor, Paroxetine:Implication of Noradrenergic and Serotonergic Mechanisms.J Psychopharmacol 12:348-355.) carry out.For three days on end, inject a PCPA (300mg/kg) every day.To the 4th day, give piperine, resveratrol or fluoxetine 60min and 30min after, carry out respectively forced swimming and outstanding tail the test.
5. reserpine experiment: according to document (Bourin, M., Poncelet, M., Chermat, R., and Simon, P. (1983) The Value of the Reserpine Test in Psychopharmacology.Arzneimittelforschung 33:1173-1176.) carry out.With mouse subcutaneous injection 2.5mg/kg reserpine.Measure the anus temperature before the administration as basal body temperature, 4h measures the temperature decline situation after the administration.Blepharoptosis is 0.5h after administration, and 1h measures, and marks according to following requirement: 0, and eyes are opened fully; 1,1/4 closes one's eyes; 2,1/2 close one's eyes; 3,3/4 close one's eyes; 4, close one's eyes fully.
5, data statistics processing
Result data represents with mean ± standard error, uses the SPSS13.0 statistical software, selects one factor analysis of variance (one-wayANOVA), and group difference is relatively used Dunnett ' s test check.
6, result's statistics
1. Tail suspension test result:
Annotate: compare with normal group,
*P＜0.05,
*P＜0.01
2. mice forced swimming experimental result:
Annotate: compare with normal group,
*P＜0.05,
*P＜0.01
3. spontaneous activity in mice experimental result:
4. PCPA experimental result:
Annotate: compare with normal group,
*P＜0.05,
*P＜0.01
Annotate: compare with normal group,
*P＜0.05,
*P＜0.01
5. reserpine experiment
Annotate: compare with the reserpine group,
*P＜0.05,
*P＜0.01
Embodiment 2; The mice monoamine oxidase, MAO, monoamine neurotransmitter and metabolite content thereof are measured
1, is subjected to reagent: with embodiment 1
2, positive control drug: dihydro bromine dog urea amine, 4-hydrogen quinoline, Selegiline, clorgiline, 5-hydroxy tryptamine (5-HT), norepinephrine (NA), dopamine (DA), 5-hydroxy-iso-butyric acid (5-HIAA), dihydroxyphenyl butanoic acid (DOPAC) are all available from U.S. Sigma company.Moclobemide is available from Nat'l Pharmaceutical ﹠ Biological Products Control Institute.
3, experimental technique
1. monoamine neurotransmitter and metabolite content thereof are measured:
(the piperine i.p. of 60min after the administration; Resveratrol, p.o.; Imipramine i.p.), with the quick sacrificed by decapitation of mice, is isolated rapidly frontal cortex, Hippocampus, striatum and hypothalamus on ice, put into the Eppendorf pipe after weighing, and places-80 ℃ of refrigerators to preserve.Add 200 μ l ice 0.4mol/L HCLO4 in every 100mg cerebral tissue, ultrasonic homogenate in the ice bath, 4 ℃ of lucifuges leave standstill 60min, centrifugal 20min (12,000rpm, 4 ℃), get supernatant, recentrifuge 20min (12,000rpm, 4 ℃), get supernatant and carry out monoamine mensuration.
The content of 5-HT, NE, DA, 5-HIAA and DOPAC adopts the high performance liquid chromatogram electrochemical process to measure in the cerebral tissue.Sample supernatant liquid filtering (aperture 0.22 μ m) is got 20 μ l auto injections after processing.Chromatographic column is Diamonsilim C18 (150 * 4.6mm I.D., 5 μ m), mobile phase composition: 125mmol/L citric acid one sodium citrate buffer solution (p H=4.3), 0.1mmol/L EDTA, 1.2mmol/L octyl sodium sulfonate, 16% methanol.Flow velocity: 1.0ml/min.Sensors work voltage is respectively: 50,100,200,300,400 and 500mV.The content of monoamine and metabolite thereof heavily represents with ng/g wet tissue in the cerebral tissue.
2. the mensuration of monoamine oxidase, MAO:
(the piperine i.p. of 60min after the administration; Resveratrol, p.o.; Imipramine, i.p.) or 60min (moclobemide, p.o.), with the quick sacrificed by decapitation of mice, isolate rapidly cerebral tissue on ice, rear adding 4ml glacial phosphoric acid buffer (pH=7.8 weighs, 0.05mol/L) make homogenate, in the 2.5ml phosphate buffer, add 20% triton 0.4ml and tissue homogenate 0.2mL, solution mixes rear 37 ℃ of preincubate 10min, in reactant liquor, add 30 μ L 2.19mmol/L substrates (final concentration is 22 μ mol/L), 37 ℃ of preincubate 30min add 0.2m 5mol/L perchloric acid solution, cooling and centrifugal (1500 * g in reactant liquor, 10min), in the 0.5mL supernatant, add 1mol/L sodium hydroxide solution 2.5mL.At exciting light 318nm, utilizing emitted light 380nm place measures the fluorescence intensity of product 4-hydrogen quinoline by spectrofluorophotometer.Activity of monoamine oxidase represents with nmol/30min/mg protein.Adopt the Bradford method to measure protein content.
4, experimental result:
1. the mensuration of mice Different brain region monoamine neurotransmitter and metabolite content thereof
Table one: resveratrol and piperine coupling are on the impact (n=8, mean ± standard error) of frontal cortex cortex brain district's monoamine neurotransmitter and metabolite content thereof
Compare with normal group,
*P＜0.05,
*P＜0.01
Table two: resveratrol and piperine coupling are on the impact (n=8, mean ± standard error) of hippocampus of mice brain district's monoamine neurotransmitter and metabolite content thereof
Compare with normal group,
*P＜0.05,
*P＜0.01
Table three: resveratrol and piperine coupling are on the impact (n=8, mean ± standard error) of mouse hypothalamus brain district's monoamine neurotransmitter and metabolite content thereof
Compare with normal group,
*P＜0.05,
*P＜0.01
2. the mensuration (n=8, mean ± standard error) of activity of monoamine oxidase in the mouse brain
Compare with normal group,
*P＜0.05,
*P＜0.01,
* *P＜0.001
Mouse tail suspension, forced swimming, PCPA, reserpine model are adopted in above-mentioned experiment, measure the Different brain region activity of monoamine oxidase, inquired into the antidepressant effect of resveratrol and piperine coupling from the angle of pharmacology and neuro chemistry, the result shows, the antidepressant effect of resveratrol is similar to the effect of classical antidepressants imipramine after the administration, can significantly reduce the dead time of mice in outstanding tail and forced swimming experiment, and on not obviously impact of autonomic activities.Resveratrol can suppress the activity of monoamine oxidase A, and impact synthetic on monoamine neurotransmitter and metabolism is one of mechanism of resveratrol antidepressant effect.
Claims (1)
1. resveratrol and piperine coupling are for the preparation of the purposes of Cure of depression medicine.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105687168A (en) * | 2016-01-22 | 2016-06-22 | 江苏大学 | Application of resveratrol in preparation of antidepressant |
| CN114304633A (en) * | 2022-01-04 | 2022-04-12 | 中南大学 | A kind of resveratrol-piperine compound microcapsule and its preparation method and application |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101801361A (en) * | 2007-06-22 | 2010-08-11 | e-生物有限公司 | Treatment of depression |
| CN101985440A (en) * | 2010-10-30 | 2011-03-16 | 暨南大学 | Method for producing piperine |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101801361A (en) * | 2007-06-22 | 2010-08-11 | e-生物有限公司 | Treatment of depression |
| CN101985440A (en) * | 2010-10-30 | 2011-03-16 | 暨南大学 | Method for producing piperine |
Non-Patent Citations (1)
| Title |
|---|
| JEREMY J ET AL.: "Enhancing the bioavailability of resveratrol by combining it with piperine", 《MOLECULAR NUTRITION & FOOD RESEARCH》, vol. 55, no. 8, 31 August 2011 (2011-08-31), pages 1169 - 1176 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105687168A (en) * | 2016-01-22 | 2016-06-22 | 江苏大学 | Application of resveratrol in preparation of antidepressant |
| CN114304633A (en) * | 2022-01-04 | 2022-04-12 | 中南大学 | A kind of resveratrol-piperine compound microcapsule and its preparation method and application |
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