CN103585169A - Pharmaceutical composition capable of increasing the content and the utilization degree of cyclic adenosine monophosphate in vivo and manufacturing method of the pharmaceutical composition - Google Patents
Pharmaceutical composition capable of increasing the content and the utilization degree of cyclic adenosine monophosphate in vivo and manufacturing method of the pharmaceutical composition Download PDFInfo
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- CN103585169A CN103585169A CN201210290270.1A CN201210290270A CN103585169A CN 103585169 A CN103585169 A CN 103585169A CN 201210290270 A CN201210290270 A CN 201210290270A CN 103585169 A CN103585169 A CN 103585169A
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- pharmaceutical composition
- adenosine monophosphate
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- ginsenoside
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- 239000008194 pharmaceutical composition Substances 0.000 title claims description 71
- 238000004519 manufacturing process Methods 0.000 title claims description 7
- IVOMOUWHDPKRLL-KQYNXXCUSA-N Cyclic adenosine monophosphate Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=CN=C2N)=C2N=C1 IVOMOUWHDPKRLL-KQYNXXCUSA-N 0.000 title abstract description 40
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- LPLVUJXQOOQHMX-UHFFFAOYSA-N glycyrrhetinic acid glycoside Natural products C1CC(C2C(C3(CCC4(C)CCC(C)(CC4C3=CC2=O)C(O)=O)C)(C)CC2)(C)C2C(C)(C)C1OC1OC(C(O)=O)C(O)C(O)C1OC1OC(C(O)=O)C(O)C(O)C1O LPLVUJXQOOQHMX-UHFFFAOYSA-N 0.000 claims abstract description 22
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- YURJSTAIMNSZAE-HHNZYBFYSA-N ginsenoside Rg1 Chemical compound O([C@@](C)(CCC=C(C)C)[C@@H]1[C@@H]2[C@@]([C@@]3(C[C@@H]([C@H]4C(C)(C)[C@@H](O)CC[C@]4(C)[C@H]3C[C@H]2O)O[C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)C)(C)CC1)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O YURJSTAIMNSZAE-HHNZYBFYSA-N 0.000 claims description 33
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- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
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- A—HUMAN NECESSITIES
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Abstract
The invention discloses an oral medicine or a health-care food, wherein the oral medicine or the health-care food which is capable of increasing the content and the utilization degree of cyclic adenosine monophosphate (cAMP) in vivo is manufactured by using panaxosides (Rg1+Rb1+Re), glycyrrhizic acid and jujube cAMP as the main components.
Description
Technical field
The invention relates to a kind of pharmaceutical composition, espespecially a kind of oral drugs and health food.
Background technology
Win the scientist Earl Wilbur Sutherland Jr. of Nobel Prize in Physiology or Medicine in 1971, found the mechanism of action of cAMP in cell; And win scientist Edmond H.Fischer and the Edwin G.Krebs of Nobel Prize in Physiology or Medicine in 1992, further found the mechanism of action of cAMP → PKA (being cAMPdependent protein kinase) in cell; Win the scientist Eric Kandel of Nobel Prize in Physiology or Medicine in 2000, more further found the mechanism of action of cAMP → PKA → CREB in cell.Dependent interaction that it serves to show cAMP in cell, physiology and medical science with the mankind, have absolute and very great association; For example, when Eric Kandel probes into out the mechanism of action that impermanent memory and longterm memory form, be in dependent cells cAMP → PKA → CREB signal transduction pathway (second message,second messenger's Signal Transduction Pathways) and win Nobel Prize after, scientists thinks, these achievements are keys that medicine is strengthened in invention memory.Although, the continuous effort of scientists, attempt research and development are the medicine of the interior cAMP → PKA → CREB signal transduction pathway of activating brain cell rapidly, make the mankind be strengthened memory, to improve learning capacity, and prevention and treat the cranial nerve degenerative disease such as forgetful, old man is dull-witted, A Zihaimo, parkinson, more can prevent and treat cAMP content and the low relevant disease of availability, for example melancholia in other body; But Earl Wilbur Sutherland Jr. in 1971 obtains Nobel Prize in Physiology or Medicine so far, has surpassed 30 years, have not yet to see any mankind's of being suitable for long-term taking, toxic and side effects is low, effective percentage is high related drugs is asked city.
In prior art, the Remeron of the classes such as the SSRI in Yi Wen city, SNRI, NDRI, by absorbing again of first messenger's neurotransmitteies such as concentration calibration ordinary person is low 5-HT, NE, DA in inhibition melancholia sufferer body, treat first messenger's neurotransmitter concentration and with receptor in conjunction with after trend compared with normal, thereby could make the transduce generation of mediator of cAMP second message,second messenger in sufferer cell tend to compared with normal; But side effect is high, effective percentage is low, but makes Remeron make us forbidding.So the people who never hears unsoundness is long-term taking Remeron in order to improve one's memory.
3,000 5 hundred ten thousand dollars of study on psychological health institute (NIMH) costs of American National health research institute (NIH), with the time of 6 years, for surpassing 2800 melancholia's sufferers, carry out clinical effective rate (remission rat) research (STAR*D study) of 5 kinds of representative SSRI class Remerons (Celexa, Zoloft, Wellbutrin, Effexor, Buspar), outcome research report is pointed out, the effective percentage of each medicine only approximately 30%, and on average approximately must within 6 to 7 weeks, could alleviate melancholy symptom.Still more, the Remeron in Yi Wen city has side effect in various degree, such as: increase homicide rate, headache, dizziness, dizzy, insomnia, drowsiness, tinnitus, xerostomia, anorexia, appetite increases, body weight rising, increased blood pressure, gastrointestinal upset, regurgitation, nauseating, vomiting, dyspepsia, diarrhoea, constipation, leg pain, skin eruption, tremble, spasm, hyperhidrosis, edema, libido reduction, sexual dysfunction etc.The Remeron such as fluoxetine has become the serious problem of paying close attention to of society in recent years, U.S. food and FAD (Food and Drug Administration, FDA) more in 2004, require pharmaceutical factory 32 kinds of Remerons main on market to be indicated again to the part of its side effect and warning, and medical personnel are emphasized to these medicines may increase the probability of child and youth suicide.
For many years, it is low, safer, more effective that the scientists of international the world of medicine constantly makes great efforts to research and develop side effect, after can acting directly on the receptor of first messenger's neurotransmitter, improve more rapidly in cell cAMP second message,second messenger the transduce generation of mediator and the medicine of availability, to prevent and to treat the low associated conditions of cAMP in cell.Although, (phosphodiesterase 4 for four type phosphodiesterases, PDE4) inhibitor is enumerated pula (Rolipram), after belonging to receptor, mechanism of action regulates class medicine, and test shows that it has obvious anti-melancholy effect, reason is that the cAMP that generates in cell can be by four type di-phosphate ester enzymatic degradation, and suppressed the availability that four type phosphodiesterases have just improved cAMP; But, owing to taking, enumerate pula and there will be the side effect such as strong vomiting, so and fail to be widely used.
I am in order to solve the deficiency of aforementioned techniques, cooperate to dive with Mr. Zhang Zuoguang and be ground into a kind of employing Radix Ginseng of merit, 3 kinds of natural plants of Radix Glycyrrhizae and Fructus Jujubae are the pharmaceutical composition that raw material is made, not only can make cAMP content in cell raise, also can suppress phosphodiesterase and to reduce the degraded of cAMP, increase the availability of cAMP, and can improve the concentration of the neurotransmitteies such as DA and NE in brain, and long-term taking is safe, be suitable for treating the melancholia of necessary Long-term taking medicine, certainly be also suitable for prevention and treat the interior cAMP of cell low, and the associated conditions of the neurotransmitter deficiency such as DA and NE in brain.Yet, natural plants because the difference of trophophase, the difference of the difference in the place of production, collecting season, the difference of preserving type, and climatic variation temperature, rainwater, sunlight etc. factor, so in every a collection of natural plant raw material, the content that can improve the generation of cAMP and the active ingredient of availability, is all not the same; So active ingredient is clearer and more definite, more can be by controlling and the content of proportioning active ingredient, make more alignedization of effectiveness and reliability of the pharmaceutical composition produced each time, to promote the quality controllability (CMC) of pharmaceutical composition; Moreover, if can more make the kind of ginsenoside in active ingredient clear, can expand the scope that raw material is obtained, make the unlikely scarcity of raw material, because except the root of Radix Ginseng, stem, leaf, the root of plants such as Radix Notoginseng, Radix Panacis Quinquefolii, stem, leaf also contain multiple ginsenoside and can utilize.So, I and the quality controllability (CMC) of Mr. Zhang Zuoguang for further this pharmaceutical composition of lifting, and expand the Ji Yuan that raw material is obtained, then on the basis of former research and development achievement, main effective component and mechanism of action that the research that keeps punching is more made clear, and research and develop successfully the main clearer and more definite ginsenoside Rg1 of effective component, Rb1, the pharmaceutical composition of glycyrrhizic acid (enoxolone) and Cyclic adenosine-3',5'-monophosphate, and be that after multi-target receptor, mechanism of action regulates class medicine, and selection adopts ginsenoside Rg1, Rb1 is main effective component, more can strengthen the expression of BDNF.
But, except ginsenoside Rg1 and Rb1, if can further utilize again the ginsenoside of other kind that root, stem, the leaf of the plants such as Radix Ginseng, Radix Notoginseng, Radix Panacis Quinquefolii contain, assist ginsenoside Rg1, Rb1, reach the effectiveness of aforementioned pharmaceutical composition, can further increase the availability of active ingredient in natural plant raw material and reduce costs.In addition, in aforementioned pharmaceutical composition, contain Radix Glycyrrhizae acids composition, and the traditional Chinese medical science is determined already since ancient times, if there is the people of vomiting problem to take Radix Glycyrrhizae, probably can bring out the problem of its vomiting.
Therefore, I keep punching on former research and development achievement basis, concentrated research and discovery, further to improve prior art and disappearance wherein, an and spirit of working with perseverance, visualizing eventually this case it " pharmaceutical composition of cAMP content and availability in the body that can increase sharply ", is below the brief description of this case.
Summary of the invention
In order to overcome the deficiencies in the prior art, the object of the present invention is to provide one group to comprise that to take ginsenoside (Rg1+Rb1+Re), glycyrrhizic acid and Cyclic adenosine-3',5'-monophosphate be Main Ingredients and Appearance, make the pharmaceutical composition of increase sharply body internal ring adenosine monophosphate content and availability, particularly can further increase the availability of active ingredient in natural plant raw material and reduce costs, and provide and can strengthen rapidly cAMP/PKA/CREB signal transduction pathway in cell with stable quality, and the oral drugs of strengthening BDNF performance amount or the new solution of health food.
The solution of pharmaceutical composition of the present invention be through I concentrate on studies explore and adopt embodiment fully to test after the result of proof, because experimental results show that ginsenoside Rg1 and Rb1, prior art can increase the expression of BDNF in body, so can be in order to the main effective component as development related drugs; But at present technology not yet can synthetic ginsenoside Rg1 and Rb1, so must obtain from the root of the natural plants such as Radix Ginseng, Radix Notoginseng, Radix Panacis Quinquefolii, stem, leaf.Because ginsenoside's kind is nearly more than 30 kinds, in order further to increase the availability of active ingredient in natural plant raw material and to reduce costs, so after inventor concentrates on studies and explores, can adopt ginsenoside Re to work in coordination with ginsenoside Rg1 and Rb1, and as main effective component, make pharmaceutical composition with glycyrrhizic acid (enoxolone) and Cyclic adenosine-3',5'-monophosphate compatibility, proof after carrying out fully experiment, the present invention can take after 8 hours at normal rat, both improved cAMP concentration in hippocampal tissue, and it is active to strengthen PKA, and improves CREB phosphorylation level; Still can suppress the activity of PDE in rat hippocampal tissue; Waiting a moment property Repeated stress experiment, cAMP concentration in the mouse brain hippocampal tissue of taking, PKA are active, the expression of CREB phosphorylation, and the expression of BDNF, all apparently higher than the mice of the model group of not taking; And the experiment of chronic Repeated stress, cAMP, PKA in the Rat hippocampus of taking, and the expression of the monoamine neurotransmitter such as serum BDNF and hypothalamus 5-HT, NE, DA, also apparently higher than the rat of the model group of not taking; It can be confirmed the present invention's pharmaceutical composition can increase sharply body internal ring adenosine monophosphate content and availability.It serves to show that the present invention has good effectiveness, and further increase the availability of active ingredient in natural plant raw material and reduce costs than prior art, and implementation quality controllability (CMC) effectively.In addition, because long-term taking of the present invention is safe, and be suitable for treating the melancholia of necessary Long-term taking medicine, and in prevention and treatment body and in cell, cAMP is low, BDNF performance amount is low, in brain the associated conditions of the neurotransmitter deficiency such as DA and NE etc. (such as cranial nerve degenerative disease such as memory is not enough, old man is dull-witted, A Zihaimo, parkinson, and low purgation disease of cAMP etc. in the body such as psoriasis, cancer and in cell), applicable crowd is extensive; But because contain Radix Glycyrrhizae acids composition in pharmaceutical composition, and the traditional Chinese medical science is determined already since ancient times, if there is the people of vomiting problem to take Radix Glycyrrhizae, probably can bring out its vomiting; Yet the traditional Chinese medical science is also determined already since ancient times, the safe Rhizoma Zingiberis Recens of long-term taking is the holy product of emesis; So the present invention's pharmaceutical composition, can also add Rhizoma Zingiberis Recens powder or its extract, to improve the deficiency of prior art.
The present invention is the pharmaceutical composition that discloses a kind of increase sharply body internal ring adenosine monophosphate content and availability, and it is by comprising that the raw material that contains the main effective component such as ginsenoside (Rg1+Rb1+Re), glycyrrhizic acid and Cyclic adenosine-3',5'-monophosphate is made.
The pharmaceutical composition of increase sharply body internal ring adenosine monophosphate content and the availability described in description of the present invention and claim; it is the core content of realizing the object of the invention; after the present invention is open; those skilled in the art carries out conventional addition or subtraction of changes to said medicine; all belong to the general technical activity of art technology and research worker, therefore it is all within protection scope of the present invention.
The present invention obtains mat and consults and show and describe in detail and obtain better understanding as accompanying drawing.
Accompanying drawing explanation:
Fig. 1 is the method flow schematic diagram of the preparation embodiment of the present invention one medicine.
Fig. 2 is the method flow schematic diagram of preparation the present invention program two medicines.
Fig. 3 is the method flow schematic diagram of preparation the present invention program three medicines.
Fig. 4 is the method flow schematic diagram of preparation the present invention program four medicines.
After Fig. 5 is administration 8h, the changes of contents figure of Cyclic AMP in Rat hippocampus.
(swimming lane is 1-4 normal saline group from left to right for typical gel electrophoresis photo in mensuration cAMP-Dependent PKA activity test for Fig. 6; 5-8 paroxetine group; Mono-group of 9-11 embodiment; 12 positive control samples; 13 negative check samples).
After Fig. 7 is administration 8h, cAMP-Dependent PKA activity difference figure in Rat hippocampus.
After Fig. 8 is administration 8h, the changes of contents figure of p-CREB in Rat hippocampus.
Fig. 9 shows that embodiment mono-is for the impact of Repeated stress hippocampus of mice cAMP concentration.
Figure 10 shows that embodiment mono-is for the impact of chronic stress hippocampus of mice PKA activity.
Figure 11 shows that embodiment mono-is for the impact of chronic stress hippocampus of mice CREB phosphorylation.
Figure 12 shows that embodiment mono-is for the impact of chronic stress hippocampus of mice BDNF.
The specific embodiment
Below with reference to drawings and Examples, further illustrate the present invention.The present invention adopts the method that well known to a person skilled in the art to prepare medicine of the present invention in conjunction with feature of the present invention.Following examples are only used to explanation non-limiting the present invention.
In order to complete object of the present invention, the present invention proposes following technical proposal especially.
The present invention is the pharmaceutical composition that discloses increase sharply body internal ring adenosine monophosphate content and availability, and it is by comprising that the raw material that contains the main effective component such as ginsenoside (Rg1+Rb1+Re), glycyrrhizic acid and Cyclic adenosine-3',5'-monophosphate is made.
Scheme one:
To contain the raw material of ginsenoside (Rg1+Rb1+Re), glycyrrhizic acid or enoxolone and Cyclic adenosine-3',5'-monophosphate, be processed into the increase sharply pharmaceutical composition of body internal ring adenosine monophosphate content and availability of the present invention.
Scheme two:
To contain ginsenoside (Rg1+Rb1+Re), add up to the raw material of 2～26 weight portions, glycyrrhizic acid or enoxolone 3～48 weight portions and Cyclic adenosine-3',5'-monophosphate 0.002～0.5 weight portion, be processed into pharmaceutical composition of the present invention.
Scheme three:
To contain ginsenoside (Rg1+Rb1+Re), add up to the raw material of 4～13 weight portions, glycyrrhizic acid or enoxolone 5～16 weight portions and Cyclic adenosine-3',5'-monophosphate 0.01～0.1 weight portion, be processed into pharmaceutical composition of the present invention.
Scheme four:
The present invention's pharmaceutical composition comprises can add gingerade extract.
Scheme five:
The present invention's pharmaceutical composition comprises can contain pharmaceutically acceptable carrier or additive, can make known oral Pharmaceutical dosage forms on any pharmaceuticss such as lozenge, capsule, powder.
Scheme six:
Pharmaceutical composition of the present invention can be used to make increase sharply medicine, health food and the nutrient of body internal ring adenosine monophosphate content and availability.
In order to complete object of the present invention, the special manufacture method that proposes following medicine.
Method one:
Respectively in Radix Ginseng, Radix Glycyrrhizae and Fructus Jujubae, the extract that extraction contains ginsenoside (Rg1+Rb1+Re), glycyrrhizic acid and Cyclic adenosine-3',5'-monophosphate is raw material, or the raw material that contains ginsenoside (Rg1+Rb1+Re), glycyrrhizic acid or enoxolone and Cyclic adenosine-3',5'-monophosphate that directly employing has been prepared into, be processed into the increase sharply pharmaceutical composition of body internal ring adenosine monophosphate content and availability of the present invention.
Method two:
To contain the raw material that ginsenoside (Rg1+Rb1+Re) adds up to 2～26 weight portions, glycyrrhizic acid or enoxolone 3～48 weight portions and Cyclic adenosine-3',5'-monophosphate 0.002～0.5 weight portion, be processed into pharmaceutical composition of the present invention.
Method three:
To contain the raw material that ginsenoside (Rg1+Rb1+Re) adds up to 4～13 weight portions, glycyrrhizic acid or enoxolone 5～16 weight portions and Cyclic adenosine-3',5'-monophosphate 0.01～0.1 weight portion, be processed into pharmaceutical composition of the present invention.
Method four:
The present invention's pharmaceutical composition comprises can add gingerade extract.
Method five:
Pharmaceutical composition of the present invention comprises can contain pharmaceutically acceptable carrier or additive, can make known oral Pharmaceutical dosage forms on any pharmaceuticss such as lozenge, capsule, powder.
Method six:
Raw material of the present invention according to food control standard or manufacture the method for standard according to health food, is processed into the present invention increase sharply health food or the nutrient of body internal ring adenosine monophosphate content and availability.
Specific embodiment
Below with reference to accompanying drawing and concrete case study on implementation, further illustrate the present invention.
Embodiment mono-
Referring to Fig. 1, is the method flow schematic diagram of the preparation embodiment of the present invention one medicine.In the first figure, by the Radix Ginseng fragmentation of 40kg afterwards with the extraction of heating of 70% alcoholic solution, through upper column chromatographic isolation and purification, dry, must contain the Radix Ginseng extract 1.42kg of 270g ginsenoside Rg1+Rb1+Re (the about 48.4g of Rg1, the about 176.9g of Rb1, the about 44.7g of Re); And by soak at room temperature after the Radix Glycyrrhizae fragmentation of 15kg 12 hours, with the extraction of water extracting alcohol Shen method, concentrate drying, must be containing the Radix Glycyrrhizae extract 3.1kg of glycyrrhizic acid 307g; And will after the Fructus Jujubae fragmentation of 10kg, add water soak at room temperature, with the extraction of water extracting alcohol Shen method, obtain Fructus Jujubae extract again, use again macroporous resin OU-2, the successively continuous upper prop adsorbing separation of ME-2 two posts, dry, must as raw material, supply preparation medicine of the present invention containing the Fructus Jujubae extract 40g of Cyclic adenosine-3',5'-monophosphate 0.752g; Afterwards, after Radix Ginseng extract 144g, the Radix Glycyrrhizae extract 300g that said method is obtained and Fructus Jujubae extract 3.6g are pulverized and mixed evenly, obtain 447.6g (containing 27.4g ginsenoside Rg1+Rb1+Re, and 29,7g glycyrrhizic acid, and 0.067g Cyclic adenosine-3',5'-monophosphate) the present invention program one pharmaceutical composition.
Embodiment bis-
Referring to Fig. 2, is the method flow schematic diagram of the preparation embodiment of the present invention two medicines.In the second figure, after the Radix Ginseng extract 120g that embodiment mono-is obtained and Radix Glycyrrhizae extract 200g and Fructus Jujubae extract 0.5g are pulverized and mixed evenly, obtain 320.5g (containing 22.8g ginsenoside Rg1+Rb1+Re, 19.8g glycyrrhizic acid and 0.009g Cyclic adenosine-3',5'-monophosphate) the present invention program's two pharmaceutical composition.
Embodiment tri-
Referring to Fig. 3, is the method flow schematic diagram of the preparation embodiment of the present invention three medicines.In the 3rd figure, after the Fructus Jujubae extract 10g that the enoxolone that the ginsenoside Rb1 that the ginsenoside Re that the ginsenoside Rg1 that is 90% by the 3.6g purity being prepared into, 3.2g purity are 90%, 15.6g purity are 90% and 26g purity are 96% and embodiment mono-obtain is pulverized and mixed evenly, obtain 58.4g (containing 22.4g ginsenoside Rg1+Rb1,26g enoxolone and 0.188g Cyclic adenosine-3',5'-monophosphate) the present invention program's three pharmaceutical composition.
Embodiment tetra-
Referring to Fig. 4, is the method flow schematic diagram of the preparation embodiment of the present invention four medicines.In the 4th figure, the present invention program's one that embodiment mono-is obtained pharmaceutical composition 100g, after mixing homogeneously, obtains 135g the present invention program four pharmaceutical composition with commercially available Rhizoma Zingiberis Recens extract 35g.
Experimental example one: normal rat administration embodiment mono-8 hours, the zoopery on the impact of cAMP/PKA/CREB signal transduction pathway.
After normal rat gastric infusion embodiment mono-8h, divide and get hippocampal tissue, by euzymelinked immunosorbent assay (ELISA) (ELISA), measure the cyclic adenosine monophosphate (Cyclic AMP) in hippocampal tissue, phosphorylation Cyclic AMP reaction component is in conjunction with the changes of contents of albumen (p-CREB), biloluminescence method (Bioluminescent) is measured the activity change of phosphoric acid protein kinase A (cAMP-Dependent PKA), fluorescence spectrometry phosphodiesterase (Phosphodiesterase, PDE) activity change, after announcement embodiment mono-administration 8h, in the short time, improve Cyclic AMP concentration, thereby it is active to strengthen cAMP-Dependent PKA, improve CREB phosphorylation level, and the molecular pharmacology mechanism that can suppress PDE activity in cerebral hippocampal tissue.Test data adopts Oringin Pro 7.5 software statistics analysis mappings.
1. test material
1.1 experimental animal
Healthy male SD rat, body weight 180-200g,, is purchased from Beijing dimension tonneau China animal testing center by 70.
1.2 reagent
Positive control medicine, resist melancholy agent paroxetine hydrochloride (lot number: 08030078, Sino-America Tianjin Shike Pharmaceutical Co., Ltd.); Parameter Cyclic AMP Assay Kit, KGE002 (U.S. R & DSystems, Inc.); DuoSet IC Human/Mouse/Rat Phospho-CREB (S133) ELISA Kit, DYC2510-2 (U.S. R & D Systems, Inc.); PepTag Assay for Non-Radioactive Detection of cAMP-Dependent Protein Kinase Kit, V5340 (U.S. Promega Corporation.); PDE-Glo Phosphodiesterase Assay Kit, V1361 (U.S. Promega Corporation.); Pierce BCA Protein Assay Kit, 23227, (U.S. Thermo); The reference substance such as cyclic adenosine monophosphate, adenosine is purchased from Nat'l Pharmaceutical & Biological Products Control Institute; The reagent such as NaH2PO4, Na2HPO4, KH2PO4, KCl, NaCl, MgCl2, Tris Base, Tris-HCl are cell culture level biochemical reagents, purchased from U.S. Sigma company; The reagent such as E-64, APROTININ, LEUPEPTIN, Pepstatin A, PMSF, NaF, EDTA, EGTA, DTT, NaVO4, Sodium pyrophosphate, agarose, glycerol are high-purity level, purchased from Canadian BioBasic company; Acetonitrile, methanol (chromatographically pure, German MERCK company); Ultra-pure water (MilliQ pure water); Embodiment mono-.
1.3 test apparatus
The multi-functional microwell plate analyser of FlexStation 3 (U.S. Molecular Devices Corporation.); Waters600E high performance liquid chromatograph (quaternary pump, online degasser, automatic sampler, column oven, UV-detector, U.S. Waters company); Refrigerated centrifuger (U.S. BECKMAN company); Electronic ultrasonic homogenizer (U.S. UNTRASOUND TECHNOLOGY company); Electrophresis apparatus (Liuyi Instruments Plant, Beijing); Gel imaging instrument (SYN GENE company); ULTRA LOW ultra cold storage freezer (Japanese SANYO company); MLine single track pipettor, 8 road pipettors (Finland Biohit company).
2. administration
Rat adaptability was raised after three days, was divided at random 3 groups, was labeled as respectively: mono-group of A normal saline group, B paroxetine group, C embodiment.Proxetine hydrochloride tablets pulverizes, and with ultra-pure water, is made into certain density suspension, and rat oral gavage dosage is 5mg/kg; Embodiment mono-gets its content water and is made into certain density solution, and rat oral gavage dosage is 50mg/kg; Normal saline group gives isopyknic 0.9% normal saline; Before administration, all rats are weighed and use picric acid labelling, all administrations after preheating 30min at 37 ℃ of all medicines.
3. draw materials
After A, B, tri-groups of experimental animal administration 8h of C, etherization, femoral artery sacrificed by exsanguination, broken end is got brain on ice, divide and get hippocampal tissue, fine cut becomes three parts, is placed in respectively the color lid of the 1.5mL screw socket cryopreservation tube of numbering in advance labelling, after accurately weighing, drop into rapidly quick-freezing 15min in liquid nitrogen, then be placed in-80 ℃ of refrigerators and save backup.
4. pattern detection
Cyclic AMP assay in 4.1 Rat hippocampus:
Hippocampal tissue sample is thawed, use a small amount of normal saline flushing, again in 1: 20 (g: the cell pyrolysis liquid (by using after 5 times of concentrated solution dilutions) that ratio mL) adds test kit to provide, electronic ultrasonic homogenizer homogenate 30s, 10000rpm frozen centrifugation 5min at 4 ℃, get supernatant and be placed in the colored Eppendorf centrifuge tube of 1.5mL of numbering in advance, be placed in ice chest, to be measured.The application U.S. Parameter Cyclic AMP Assay ELISA of R & D Systems company test kit carries out pattern detection.Sample is returned to room temperature, by test kit description, adopt Cyclic AMP content in competitive ELISA method working sample.With porous plate analyser, under 450nm, measure OD value, according to standard curve, calculate CyclicAMP content in sample.
CAMP-Dependent PKA determination of activity in 4.2 Rat hippocampus:
Hippocampal tissue sample is thawed, use a small amount of normal saline flushing, again in 1: 10 (g: ratio mL) adds PKA extraction buffer (according to formulated in test kit), electronic ultrasonic homogenizer homogenate 30s, the centrifugal 5min of 10000rpm at 4 ℃, get supernatant and be placed in the colored Eppendorf centrifuge tube of 1.5mL of numbering in advance, be placed in ice chest, to be measured.The application U.S. PepTag Assay for Non-Radioactive Detection of cAMP-Dependent Protein Kinase of Promega company test kit detects analysis.In 200 μ L PCR eight unions of numbering in advance, according to test kit description, add the reagent of premix, get respectively each sample check mark of 9 μ L and add in each pipe, vortex mixes, centrifugal, and then room temperature reaction 30min is placed in 98 ℃ of 5min of PCR instrument enzyme is carried out to deactivation.In test, require to arrange respectively to specifications positive control and negative control tube, retinue test.The agarose gel of preparation 0.8%, respectively gets 10 μ L by the sample after enzyme reaction and adds in the comb hole of gel, 100V, and 130mA electrophoresis 30min, electrophoresis liquid is 50mMTris-HCl (pH 8.0) buffer.After electrophoresis, agarose gel is taken out, gel imaging instrument is taken a picture, and is then placed on uv analyzer, and the PepTag A1 Peptide speckle of phosphorylation reaction is cut, and is placed in respectively the color lid of the 1.5mL screw socket cryopreservation tube of numbering in advance labelling.Heating is melted agarose gel, with ultra-pure water standardize solution to 250 μ L, taking out rapidly 125 μ L adds in the colored Eppendorf centrifuge tube of the 1.5mL numbering in advance, the sol solutions and the 50 μ L glacial acetic acid that add again 75 μ L test kits to provide, vortex mixes, get 200 μ L and add in 96 hole ELISA Plate, take that to bear the positive extreme direction agarose of control tube be blank, on porous plate analyser, carry out fluorescence analysis.Set Excitation Wavelength 568nm, Emission Wavelength 592nm.With sample fluorescence intensity, represent that PKA is active.
P-CREB assay in 4.3 Rat hippocampus:
The application U.S. R & D Systems DuoSet IC Human/Mouse/Rat Phospho-CREB of company (S133) ELISA test kit carries out pattern detection.Hippocampal tissue sample is thawed, use a small amount of normal saline flushing, again in 1: 20 (g: ratio mL) adds tissue homogenate (according to IC DELUENT 6# formulated in test kit), electronic ultrasonic homogenizer homogenate 30s, the centrifugal 5min of 10000rpm at 4 ℃, get supernatant and be placed in the colored Eppendorf centrifuge tube of 1.5mL of numbering in advance, be placed in ice chest, to be measured.During mensuration, sample is returned to room temperature, by test kit description, adopt p-CREB content in sandwich ELISA method working sample.With porous plate analyser, under 450nm, measure OD value, according to standard curve, calculate p-CREB content in sample.
In 4.4 Rat hippocampus, total protein is measured:
For the amount of the contained p-CREB albumen of every milligram of albumen in accurate calibration sample more, need to measure the total protein content of sample.Get tissue homogenate in the p-CREB determination test supernatant after centrifugal, with after 25 times of PBS dilutions, as test sample book, according to Pierce BCA Protein Assay Kit reagent description, with porous plate analyser, under 562nm, measure OD value, the bovine serum albumin (BSA) of take is standard substance, according to standard curve, calculates total protein content in sample.
4.5 phosphodiesterases (PDE) determination of activity:
Use the impact of PDE activity in a pair of rat hippocampal tissue of U.S.'s Promega company biloluminescence method (Bioluminescent) PDE-GloPhosphodiesterase Assay kit measurement embodiment.
4.5.1 medicinal liquid preparation:
Embodiment mono-gets content and is mixed with 0.02mg/mL, 0.05mg/mL and tri-concentration of 1.0mg/mL.
4.5.2 sample preparation:
Get a certain amount of hippocampal tissue, after a small amount of normal saline flushing, in 1: 10 (g: ratio mL) adds PDE-Glo Reaction Buffer (Tris-HCl 40mM, MgCl2 10mM, BSA 0.1mg/ml, separately adds PMSF 1mM, leupetin 2 μ M/mL, aprotinin 2 μ M/mL, E-642 μ M/mL), the homogenate of electronic ultrasonic device, 14000rpm is centrifugal 30 minutes at 4 ℃, get supernatant as enzyme liquid, standby.
4.5.3 biloluminescence method is measured:
The method providing according to test kit description operates, and enzyme reaction solution part adds 1 μ L medicinal liquid, 1.5 μ L enzyme liquid, totally 2.5 μ L; Add the substrate solution 2.5 μ L that contain 2 μ mol Cyclic AMP, mix, 37 ℃ of reaction 30min, then add the reacting terminating solution 2.5 μ L that contain PDE potent inhibitor IBMX, mix; Add test solution 2.5 μ L, mix room temperature reaction 20min; Finally add luminescence reagent 10 μ L, after room temperature reaction 10min, on multi-functional microwell plate analyser, test.
5. result of the test
Cyclic AMP content in 5.1 Rat hippocampus:
By ELISA method, measured Cyclic AMP concentration in Rat hippocampus homogenate, divided by the tissue samples weight weighing, the content of the Cyclic AMP that obtains containing in hippocampal tissue, represents (Fig. 5) with pmol/g Tissue.
Refer to Fig. 5, mono-group of embodiment and normal saline group and the comparison of paroxetine group, in Rat hippocampus, the content of Cyclic AMP significantly raises, * P < 0.05, n=10.
In 5.2 Rat hippocampus, cAMP-Dependent PKA is active:
After enzyme reaction, sample carries out agarose gel electrophoresis, and gel imaging instrument is taken a picture, and carries out coarse analysis.
Refer to Fig. 6, the A1 peptide of phosphorylation, with negative charge, moves to positive extreme direction; Unphosphorylated A1 peptide, with positive charge, moves to negative pole direction, and the two is separated.The A1 peptide spot intensity of the phosphorylation wherein moving to positive extreme direction is higher, shows that phosphorylation level is higher, and in sample, cAMP-Dependent PKA activity is higher.In figure, the visible positive extreme direction spot intensity of mono-group of sample of embodiment is higher compared with normal saline group and the brightness of paroxetine group.
Cutting agarose gel speckle, standardize solution after melten gel, active with cAMP-Dependent PKA in fluorescence spectrometry Rat hippocampus, with fluorescence intensity, represent (Fig. 7).
Refer to Fig. 7, after administration 8h, mono-group of embodiment and blank group and the comparison of paroxetine group, in Rat hippocampus, cAMP-Dependent PKA is active significantly raises, * P < 0.05, n=10.
P-CREB content in 5.3 Rat hippocampus:
Adopt BCA method to measure the concentration of total protein in Rat hippocampus sample homogenate, to demarcate the amount that contains p-CREB in every μ g total protein.Adopt again sandwich ELISA method to measure p-CREB concentration in Rat hippocampus sample homogenization liquid, and represent p-CREB content in Rat hippocampus with p-CREB (pg)/total protein (μ g), the results are shown in Figure 8.
Refer to Fig. 8, after administration 8h, mono-group of embodiment and normal saline group and the comparison of paroxetine group, in Rat hippocampus, the content of p-CREB raises, n=10.
5.4 medicines are to phosphodiesterase in Rat hippocampus (PDE) activity influence:
With biloluminescence method, measured the active of PDE in hippocampal tissue and externally given the inhibitory action to PDE activity after medicine.With luminous intensity, represent that PDE is active, with matched group comparison, luminous intensity is higher, illustrates that PDE activity is higher; Luminous intensity is lower, and PDE activity inhibited is described; The result demonstration of measuring, compares with blank group, and embodiment mono-(0.5mg/ml) has obviously suppressed the activity of PDE in Rat hippocampus, * P < 0.05, n=4.
6, conclusion
(1) rat oral gavage administration is after 8 hours, and with normal saline group and the comparison of paroxetine group, the Cyclic AMP content in mono-group of rat hippocampal tissue of embodiment significantly raises; CAMP-Dependent PKA is active significantly to be strengthened; P-CREB content is also improved.
(2) this experiment has confirmed that embodiment mono-can be by second message,second messenger Cyclic AMP intracellular signal transduction pathway performance pharmacological action, and in administration, after 8 hours, be cAMP-PKA-CREB capable of fast starting (p-CREB) path (compare with paroxetine group with normal saline group there were significant differences, * P < 0.05).
(3) administration in same 8 hours, positive control drug paroxetine can not start cAMP-PKA-CREB (p-CREB) path.
(4) even this experimental result show, in embodiment mono-, dosage group can significantly suppress the activity of phosphodiesterase in Rat hippocampus, because phosphodiesterase is the inactivator of Cyclic AMP, it can make Cyclic AMP content in Rat hippocampus raise after being suppressed.
Experimental example two: chronic stress mice administration embodiment mono-10 days, the zoopery on cAMP/PKA/CREB signal transduction pathway and the impact of BDNF expression.
1. embodiment mono-is for the impact (Fig. 9) of Repeated stress hippocampus of mice cAMP concentration:
Fig. 9 shows result: the hippocampus of mice cAMP concentration of administration embodiment mono-, and apparently higher than the model group of administration not, * P < 0.05.
2. embodiment mono-is for the impact (Figure 10) of chronic stress hippocampus of mice PKA activity:
Figure 10 shows result: the hippocampus of mice PKA of administration embodiment mono-is active, apparently higher than the model group of administration not, and * P < 0.05.
3. embodiment mono-is for the impact (Figure 11) of chronic stress hippocampus of mice CREB phosphorylation:
Figure 11 shows result: the expression of the hippocampus of mice CREB phosphorylation of administration embodiment mono-, and apparently higher than the model group of administration not.
4. embodiment mono-is for the impact (Figure 12) of chronic stress hippocampus of mice BDNF:
Figure 12 shows result: the expression of BDNF in the hippocampus of mice of administration embodiment mono-, and apparently higher than the model group of administration not.
Experimental example three: chronic stress rat administration embodiment mono-21 days, the zoopery on expression impacts such as Hippocampus cAMP, PKA and serum BDNF and hypothalamus NE, DA, 5HT.
1. embodiment mono-is for the impact (table 1) of chronic stress rat hippocampus and cortex cAMP concentration:
Table 1: each organizes rat hippocampus and cortex cAMP performance amount
2. embodiment mono-is for the impact (table 2) of chronic stress rat hippocampus PKA content:
Table 2: each organizes rat hippocampus PKA content
3. embodiment mono-is for the impact (table 3) of chronic stress rat blood serum BDNF content:
Table 3: each organizes rat blood serum BDNF content
| Group | Number of cases | Dosage | BDNF |
| (mg/kg/d) | (pg/ml) | ||
| Normal group | 8 | - | 111.00±45.28 |
| Model group | 8 | - | 72.57±19.49 |
| Embodiment mono-small dose group | 8 | 15 | 102.90±18.70 |
| Dosage group in embodiment mono- | 8 | 30 | 110.14±31.64 |
| Heavy dose of group of embodiment mono- | 8 | 60 | 91.53±39.93 |
4. embodiment mono-is for the impact (table 4) of chronic stress the Monoamine Neurotransmitters in Hypothalamus of Rat expression:
Table 4: each organizes the Monoamine Neurotransmitters in Hypothalamus of Rat expression
5. conclusion:
Rat hippocampus cAMP, the PKA of administration embodiment mono-, and the expression of the monoamine neurotransmitter such as serum BDNF and hypothalamus 5-HT, NE, DA, apparently higher than the model group (* P < 0.05) of not administration.
Experimental example four: embodiment mono-antidepressants effect is learned zoopery.
1. behavioristics's zoopery:
The pathogenesis of depression and clinical symptoms, I have selected the antidepressant behavioristics zooperies such as mouse tail suspension, rat forced swimming, mice forced swimming, rat unpredictability long-term stress, Rat Olfactory Bulb damage model.
1.1 embodiment mono-gavages give mice 20mg/kg/d, 40mg/kg/d, 80mg/kg (rat 15mg/kg/d, 30mg/kg/d, 60mg/kg/d), continuous 1 week, can show the effect of anti-tentative depression, wherein middle dosage group (mice 40mg/kg/d, rat 30mg/kg/d) all can obviously shorten the outstanding tail mice dead time with positive drug paroxetine group (3mg/kg/d), obviously shorten the dead time of forced swimming mice, rat, compare with model group and there is obvious significant difference (P < 0.05).
1.2 embodiment mono-gavages give chronic stress depression model (CUMS) rat 15mg/kg/d, 30mg/kg/d, 60mg/kg/d, continuous 21 days, result: compare with normal group, model group (CUMS) rat body weight increasess slowly, sucrose water consumption obviously decline (P < 0.01), horizontal anomalous movement all significantly declines (P < 0.01) with vertical activity, and rat diving tower errors number obviously increases (P < 0.01).Compare with model group, embodiment mono-small dose group and the growth of positive drug paroxetine group rat body weight significantly improve, sucrose water consumption obviously increases (P < 0.01), embodiment mono-small dose group and the activity of positive drug paroxetine group rat horizontal and vertical obviously increase (P < 0.01), and embodiment mono-small dose group and positive drug paroxetine group diving tower errors number obviously reduce (P < 0.05, P < 0.01).
1.3 embodiment mono-gavages give olfactory bulb damage model rat 15mg/kg/d, 30mg/kg/d, 60mg/kg/d, continuous 24 days, in opening the test of wild case, heavy dose of group of embodiment mono-compares with model group, can obviously improve olfactory bulb and damage rat level and the minimizing that moves both vertically causing, the positive also can obviously be improved olfactory bulb with reference to medicine paroxetine (3mg/kg/d) and damage the rat horizontal movement minimizing causing; In passive avoidance test, the big or middle dosage group of embodiment mono-is compared with model group with positive drug paroxetine group, all can obviously improve olfactory bulb and damage the rat study and the memory function that cause and go down.
2. interaction model zoopery:
According to the pathogenesis of depression and clinical symptoms, I selected mice reserpine model (temperature decline, motion can not, blepharoptosis) and pentahydroxy-color ammonia inducing mouse get rid of first-class test.
2.1 embodiment mono-gavages give mice 20mg/kg/d, 40mg/kg/d, 80mg/kg/d (rat 15mg/kg/d, 30mg/kg/d, 60mg/kg/d), continuous 1 week, obviously the mouse temperature of antagonism reserpine induction decline, motion can not and blepharoptosis, show that the tentative depressed effect of embodiment primary antibodie may be with to affect monoamine neurotransmitter relevant; Can obviously increase the number of times that gets rid of after injected in mice pentahydroxy-tryptophan, show that embodiment mono-antidepressant effect may be relevant with inhibition MAO.In addition, because result of the test shows a pair of mice autonomic activities of embodiment, have no significant effect, embodiment mono-is without central excitation effect.
3. the main antidepressant drug effect interpretation of embodiment mono-is as following table (table 5):
(table 5)
4. conclusion: embodiment mono-has obviously anti-tentative depressed effect.
The result of every experimental example shows:
(1) rat oral gavage administration embodiment is after mono-8 hours, with normal saline group and the comparison of paroxetine group, hippocampal tissue cAMP significantly raises, active significantly strengthen (the * P < 0.05) of PKA, p-CREB content also raises to some extent, and the activity of PDE4 is subject to obvious inhibition (* P < 0.05).
(2) chronic stress mouse stomach administration embodiment, after mono-10 days, can significantly improve the Hippocampus cAMP causing due to Repeated stress, the decline of PKA, promotes the expression (* P < 0.05) of the interior phosphorylation CREB of hippocampus of mice and BDNF.
(3) chronic stress rat oral gavage administration embodiment is after mono-21 days, can significantly improve the Hippocampus cAMP causing due to Repeated stress, the decline of PKA, promote the expression (* P < 0.05) of the monoamine neurotransmitters such as serum BDNF and hypothalamus NE, 5-HT, lower serum GSC.
(4) embodiment mono-has obviously anti-tentative depressed effect.
The increase sharply range of application of pharmaceutical composition of body internal ring adenosine monophosphate content and availability of the present invention:
1. in the pharmaceutical composition of increase sharply body internal ring adenosine monophosphate content and availability of the present invention, can contain acceptable additive on materia medica;
The pharmaceutical composition that increases sharply body internal ring adenosine monophosphate content and availability of the present invention can be processed into powder, capsule, tablet, etc. various known dosage forms; And
3. cAMP/PKA/CREB signal transduction pathway in the disease that the pharmaceutical composition that increases sharply body internal ring adenosine monophosphate content and availability of the present invention can be made in prevention and treatment body and in cell, cAMP content and availability lowly cause, strengthening BDNF performance amount, strengthening cell, and the medicine, health food and the nutrient that increase DA, NE and 5HT neurotransmitter content and memory reinforcing in brain.
Comprehensive speech, the present invention's embodiment is as follows:
1. a pharmaceutical composition that increases body internal ring adenosine monophosphate content and availability, comprising:
One first Main Ingredients and Appearance: comprise ginsenoside Rg1 and Rb1 and Re;
One second Main Ingredients and Appearance: comprising a Radix Glycyrrhizae acids, is to be selected from one of a glycyrrhizic acid, an enoxolone and combination thereof; And
One the 3rd Main Ingredients and Appearance: comprise a Fructus Jujubae ring adenosine monophosphate and make.
2. pharmaceutical composition as described in Example 1, wherein this pharmaceutical composition comprises this ginsenoside Rg1 and Rb1, this Radix Glycyrrhizae acids of 3～48 weight portions and this Fructus Jujubae ring adenosine monophosphate of 0.002～0.5 weight portion of 2～26 weight portions.
3. the pharmaceutical composition as described in embodiment 1 or 2, wherein this pharmaceutical composition comprises this ginsenoside Rg1 and Rb1, this Radix Glycyrrhizae acids of 5～16 weight portions and this Fructus Jujubae ring adenosine monophosphate of 0.01～0.1 weight portion of 4～13 weight portions.
4. as embodiment 1 to 3 pharmaceutical composition as described in any one, wherein this pharmaceutical composition contains and is selected from one of a pharmaceutically acceptable carrier, an additive and combination thereof.
5. as embodiment 1 to 4 pharmaceutical composition as described in any one, wherein this pharmaceutical composition is made a dosage form, this dosage form system be selected from an oral Pharmaceutical dosage forms on a lozenge, a capsule, a powder, a tablet, a powder, a solution, a microcapsule, a suspensoid, an Emulsion, a granule, a drop pill, a pill and pharmaceutics one of them.
6. as embodiment 1 to 5 pharmaceutical composition as described in any one, wherein this pharmaceutical composition can be made cAMP content in prevention and treatment body and in cell and availability is low, cAMP/PKA/CREB signal transduction pathway, strengthening BDNF performance amount in strengthening cell, increase medicine, health food and the nutrient of DA, NE and 5HT neurotransmitter content and memory reinforcing in brain.
7. as embodiment 1 to 6 pharmaceutical composition as described in any one, wherein this pharmaceutical composition also comprises one the 4th main component, and it is to be selected from a Rhizoma Zingiberis Recens powder and one of Rhizoma Zingiberis Recens extract and combination thereof.
8. a pharmaceutical composition that increases body internal ring adenosine monophosphate availability, comprising:
One first Main Ingredients and Appearance: comprise ginsenoside Rg1 and Rb1 and Re;
One second Main Ingredients and Appearance: comprising a Radix Glycyrrhizae acids, is to be selected from one of a glycyrrhizic acid, an enoxolone and combination thereof; And
One the 3rd Main Ingredients and Appearance: comprise a Fructus Jujubae ring adenosine monophosphate and make.
9. manufacture a method that increases one of body internal ring adenosine monophosphate content pharmaceutical composition, comprising:
One first Main Ingredients and Appearance is provided, and wherein this first main component comprises ginsenoside Rg1 and Rb1 and Re;
One second Main Ingredients and Appearance is provided, and wherein this second main component comprises a Radix Glycyrrhizae acids, is to be selected from one of a glycyrrhizic acid, an enoxolone and combination thereof; And
One the 3rd Main Ingredients and Appearance is provided, and wherein the 3rd main component comprises a Fructus Jujubae ring adenosine monophosphate, to make this medical composition.
In sum; these are only preferred embodiment of the present invention, be not intended to limit protection scope of the present invention, therefore; all any modifications of doing within the spirit and principles in the present invention, be equal to replacement, improvement etc., within protection scope of the present invention all should be included in.
Claims (9)
1. a pharmaceutical composition that increases body internal ring adenosine monophosphate content and availability, comprising:
One first Main Ingredients and Appearance: comprise ginsenoside Rg1 and Rb1 and Re;
One second Main Ingredients and Appearance: comprising a Radix Glycyrrhizae acids, is to be selected from one of a glycyrrhizic acid, an enoxolone and combination thereof; And
One the 3rd Main Ingredients and Appearance: comprise a Fructus Jujubae ring adenosine monophosphate and make.
2. pharmaceutical composition as claimed in claim 1, wherein this pharmaceutical composition comprises this ginsenoside Rg1 and Rb1, this Radix Glycyrrhizae acids of 3～48 weight portions and this Fructus Jujubae ring adenosine monophosphate of 0.002～0.5 weight portion of 2～26 weight portions.
3. pharmaceutical composition as claimed in claim 1, wherein this pharmaceutical composition comprises this ginsenoside Rg1 and Rb1, this Radix Glycyrrhizae acids of 5～16 weight portions and this Fructus Jujubae ring adenosine monophosphate of 0.01～0.1 weight portion of 4～13 weight portions.
4. pharmaceutical composition as claimed in claim 1, wherein this pharmaceutical composition contains and is selected from one of a pharmaceutically acceptable carrier, an additive and combination thereof.
5. pharmaceutical composition as claimed in claim 1, wherein this pharmaceutical composition is made a dosage form, this dosage form system be selected from an oral Pharmaceutical dosage forms on a lozenge, a capsule, a powder, a tablet, a powder, a solution, a microcapsule, a suspensoid, an Emulsion, a granule, a drop pill, a pill and pharmaceutics one of them.
6. pharmaceutical composition as claimed in claim 1, wherein this pharmaceutical composition can be made cAMP content in prevention and treatment body and in cell and availability is low, cAMP/PKA/CREB signal transduction pathway, strengthening BDNF performance amount in strengthening cell, increase medicine, health food and the nutrient of DA, NE and 5HT neurotransmitter content and memory reinforcing in brain.
7. pharmaceutical composition as claimed in claim 1, wherein this pharmaceutical composition also comprises one the 4th main component, and it is to be selected from a Rhizoma Zingiberis Recens powder and one of Rhizoma Zingiberis Recens extract and combination thereof.
8. a pharmaceutical composition that increases body internal ring adenosine monophosphate availability, comprising:
One first Main Ingredients and Appearance: comprise ginsenoside Rg1 and Rb1 and Re;
One second Main Ingredients and Appearance: comprising a Radix Glycyrrhizae acids, is to be selected from one of a glycyrrhizic acid, an enoxolone and combination thereof; And
One the 3rd Main Ingredients and Appearance: comprise a Fructus Jujubae ring adenosine monophosphate and make.
9. manufacture a method that increases one of body internal ring adenosine monophosphate content pharmaceutical composition, comprising:
One first Main Ingredients and Appearance is provided, and wherein this first main component comprises ginsenoside Rg1 and Rb1 and Re;
One second Main Ingredients and Appearance is provided, and wherein this second main component comprises a Radix Glycyrrhizae acids, is to be selected from one of a glycyrrhizic acid, an enoxolone and combination thereof; And
One the 3rd Main Ingredients and Appearance is provided, and wherein the 3rd main component comprises a Fructus Jujubae ring adenosine monophosphate, to make this medical composition.
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