NZ705363B2 - Pharmaceutical composition increasing cyclic amp content and availability in vivo, and preparation method thereof - Google Patents
Pharmaceutical composition increasing cyclic amp content and availability in vivo, and preparation method thereof Download PDFInfo
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- NZ705363B2 NZ705363B2 NZ705363A NZ70536312A NZ705363B2 NZ 705363 B2 NZ705363 B2 NZ 705363B2 NZ 705363 A NZ705363 A NZ 705363A NZ 70536312 A NZ70536312 A NZ 70536312A NZ 705363 B2 NZ705363 B2 NZ 705363B2
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Abstract
The present invention is related to a pharmaceutical composition to increase a content and an availability of a cyclic adenosine monophosphate (cAMP) in a body. The pharmaceutical composition comprises a first main component comprising 2~26 parts by weight of ginsenosides Rg1, Rb1 and Re, a second main component comprising 3~48 parts by weight of a glycyrrhiza related acid being one selected from a group consisting of a glycyrrhizic acid, a glycyrrhetinic acid and a combination thereof, and a third main component comprising 0.002~0.5 parts by weight of a jujuba cyclic adenosine monophosphate (jujuba cAMP). main component comprising 3~48 parts by weight of a glycyrrhiza related acid being one selected from a group consisting of a glycyrrhizic acid, a glycyrrhetinic acid and a combination thereof, and a third main component comprising 0.002~0.5 parts by weight of a jujuba cyclic adenosine monophosphate (jujuba cAMP).
Description
English Translation of Publication for PCT Application No.
PHARMACEUTICAL COMPOSITION INCREASING CYCLIC AMP CONTENT
AND AVAILABILITY IN VIVO, AND PREPARATION METHOD THEREOF
FIELD OF THE INVENTION
The present invention is related to a pharmaceutical composition,
specifically to an oral medicine and health food.
BACKGROUND OF THE INVENTION
Earl Wilbur Sutherland Jr., a scientist who was awarded a Nobel
Prize in Physiology or Medicine in 1971, discovered a mechanism of cyclic
adenosine monophosphate (cAMP) in cells. Edmond H. Fischer and Edwin G.
Krebs, the scientists who were awarded a Nobel Prize in Physiology or
Medicine in 1992, further discovered a mechanism of cAMP → PKA (protein
kinase A, a cAMP dependent protein kinase) in cells. Eric Kandel, a scientist
who was awarded a Nobel Prize in Physiology or Medicine in 2000, further
discovered a mechanism of cAMP → PKA → CREB (cAMP response element-
binding protein) in cells. It is apparent that there is an absolute and very
significant relationship between the relative functions of cAMP and the
physiology and medicine in human beings. For example, ever since Eric
Kandel discovered that the mechanism for the formation of short-term memory
and long-term memory is dependent on a “cAMP → PKA → CREB” signaling
pathway (the second messenger signal transduction pathway) in cells and was
awarded the Nobel Prize, scientists consider that these results are keys for
inventing memory-enhancing drugs. Scientists have continuously endeavored
and attempted to develop a drug to rapidly activate the cAMP → PKA → CREB
signal transduction pathway in brain cells to enhance memory, improve learning
ability, prevent and cure neurodegenerative diseases, such as amnesia, dementia,
Alzheimer’s disease, Parkinson’s disease and so on, and further prevent and cure
other diseases (such as depression) relevant to low cAMP content and low
cAMP availability in organisms. However, there is no relevant medicine
commercially available with suitable long-term use for humans, low side effects
and high effectiveness, even though Earl Wilbur Sutherland Jr. was awarded the
Nobel Prize in Physiology or Medicine over 30 years ago.
In the current technology, the marketed anti-depression drugs, e.g.
selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine
reuptake inhibitors (SNRIs), and norepinephrine-dopamine reuptake inhibitors
(NDRIs), etc., inhibit the re-uptake of the first messenger neurotransmitters,
such as 5-hydroxytryptamine (5-HT), norepinephrine (NE), dopamine (DA), etc.,
in depression patients, who have a lower concentration of the first messenger
neurotransmitter than people without depression. After the concentration of
the first messenger neurotransmitter and its combination with the receptor
approached to normal levels, it may be possible to enable the production of a
second messenger transmitter for cAMP in the patients’ cells to be reached a
normal level. However, high side effects and low remission rates make the
anti-depression drugs undesirable. Therefore, there has never been a report
announcing that healthy persons are taking depression drugs over a long time for
the purpose of memory enhancement.
The National Institute of Mental Health (NIMH) of the National
Institutes of Health (NIH) of the United States spent US$ 35 million and 6 years
on remission rate research (STAR*D study) for 5 representative types of SSRI
anti-depression drugs (Celexa®, Zoloft®, Wellbutrin®, Effexor® and Buspar®)
with over 2800 depression patients. The research report indicated that the
remission rate for each drug is only about 30%, and it requires 6-7 weeks on
average to relieve the symptoms of depression. Furthermore, the marketed
anti-depression pharmaceuticals have different levels of side effects, such as
increased suicide rate, headache, giddiness, vertigo, insomnia, hypersomnia,
tinnitus, thirst, apocleisis, increased orexis, increased body weight, increased
blood pressure, stomach upset, regurgitation nausea, emesis, dyspepsia, diarrhea,
constipation, leg pain, skin rash, dither, convulsions, hyperhidrosis, edema, loss
of libido and impotence, etc. In recent years, anti-depression pharmaceuticals,
such as Prozac®, have become a serious social problem. In 2004, the Food and
Drug Administration (FDA) of the United States further mandated that
pharmaceutical companies had to revise product labels to clearly state the side
effects and warnings on the instructions of 32 major anti-depression
pharmaceuticals on the market, and emphasized to physicians and nurses that
these pharmaceuticals might increase children’s and adolescents’ suicide rates.
Over the years, scientists in the worldwide pharmaceuticals
industry have continuously endeavored to develop a safer and more effective
pharmaceutical with low side effects, which can directly function on the receptor
of the first messenger neurotransmitter to more rapidly increase the production
and the availability of intracellular second messenger transmitters for cAMP, to
prevent and cure the diseases related to a low intracellular cAMP level.
Rolipram®, a phosphodiesterase 4 (PDE4) inhibitor, belongs to a type of post-
receptor mechanism mediated drug, and the experimental results also indicate
that Rolipram® has a significant anti-depression effect because the cAMP
generated in the cells will be degraded by PDE4. That is to say, the availability
of cAMP is increased by inhibiting PDE4. However, Roligram® is not broadly
administered because Rolipram® may cause side effects such as severe emesis
and so on.
The inventor developed a pharmaceutical composition that is
prepared using three natural plants, i.e. ginseng, liquorice and jujuba, as the raw
materials in order to solve the deficiencies in the prior art. The pharmaceutical
composition not only increases the level of cAMP in cells, but also inhibits
PDE4 to decrease the degradation of cAMP and increase the availability of
cAMP, and increase the concentration of DA and NE neurotransmitters in the
brain. The pharmaceutical composition is high safe for long-term use, is
suitable for treating depression patients who need to take medicine for a long
duration, and is suitable to prevent and cure diseases relevant to low intracellular
cAMP levels and the deficiency of DA and NE neurotransmitters. However,
the effective amount of the components that can increase the generation and
availability of cAMP may be different in each batch of the natural plants
because of differences in factors, such as the growth period, the place of origin,
the harvest time and the preservation mode, climate change, temperature,
rainwater, sun exposure, and so on. Therefore, the more definite of the active
components, the more the amount of active components can be controlled and
formulated, so that the efficacy and safety of the pharmaceutical composition
maintain consistency batch by batch to improve the quality control (i.e.
chemistry, manufacture and control (CMC)) of the pharmaceutical composition.
Moreover, if the types of ginsenosides among the active components can be
more definite, the range of the acquired raw materials can be broadened without
reducing the supply. That is to say, in addition to the roots, stems and leaves of
ginseng, those parts of other plants (such as Panax notoginseng and Panax
quinquefolius) also contain various types of ginsenosides which can be used.
Therefore, the inventor has continuously endeavored to search for more
definitely-defined main effective components and their mechanisms on the basis
of original research results in order to promote the quality control (i.e. CMC) of
the pharmaceutical composition and broaden the origins of the acquired raw
materials. He successfully developed a pharmaceutical composition having
more definitely-defined main effective components, which contains
ginsenosides Rg1 and Rb1, glycyrrhizic acid (or glycyrrhetinic acid) and jujuba
cAMP, wherein the pharmaceutical composition is a multi-targeted post-receptor
mechanism mediated drug, and the ginsenosides Rg1 and Rb1 are the main
active components to enhance the expression of the brain-derived neurotrophic
factor (BDNF).
However, in addition to the ginsenosides Rg1 and Rb1, if the other
types of ginsenosides contained in the roots, stems and leaves of the plants (such
as ginseng, Panax notoginseng, Panax quinquefolius and so on) are used to
solve the supply/insufficiency of the ginsenosides Rg1 and Rb1 to achieve the
effectiveness of the pharmaceutical composition above, the availability of the
main active components in the natural plants can be further increased and the
cost is reduced. In addition, the pharmaceutical composition above includes
glycyrrhiza-related acids which may induce emesis symptoms if a person prone
to emesis takes liquorice. This issue was confirmed by traditional Chinese
physicians since ancient times.
It is therefore the inventor’s invention to deal with the above
limitations in the prior art.
SUMMARY OF THE INVENTION
To overcome the deficiencies in the prior art, the present invention
discloses a pharmaceutical composition including ginsenosides (Rg1, Rb1 and
Re), glycyrrhizic acid and jujuba cAMP as the main active components to
rapidly increase the content and the availability of cAMP in the body. In
particular, the present invention discloses an oral pharmaceutical or a health
food that can further increase the availability of the main active components in
the natural plants, reduce the cost, enhance the cAMP/PKA/CREB signal
transduction pathway by providing such products’ stable quality, and enhance
the expression of BDNF.
The scheme of the pharmaceutical composition in the present
invention is the result of endeavors by the inventor. Because the prior art
proved that the ginsenosides Rg1 and Rb1 can increase the BDNF expression in
an organism, the ginsenosides Rg1 and Rb1 can be used to develop the main
active components of the related pharmaceuticals. However, the ginsenosides
Rg1 and Rb1 cannot be artificially synthesized using current technology, and
hence they must be obtained from the roots, stems and leaves of natural plants,
such as ginseng, Panax notoginseng, Panax quinquefolius and so on. Because
there are more than 30 types of ginsenosides, to further increase the availability
of the main active components in the natural plants and reduce the cost, the
inventor incorporated ginsenoside Re with ginsenosides Rg1 and Rb1, and
paired with glycyrrhizic acid (or glycyrrhetinic acid) and jujuba cAMP to form
the main active components to prepare a pharmaceutical composition. After
completing a substantial number of experiments, it was proven that the
pharmaceutical composition of the present invention can increase the
concentration of cAMP in the hippocampus, enhance the activity of PKA,
promote the level of CREB phosphorylation, and inhibit the activity of PDE in
the hippocampus in normal rats, 8 hours after they have been administered with
the pharmaceutical composition. In a chronic repetitive stress experiment, the
cAMP concentration, the PKA activity, the expression of CREB phosphorylation
and the BDNF expression in the mice that were administered with the
pharmaceutical composition were significantly higher than those of the mice in
the control group which were not administered with the pharmaceutical
composition, and the expressions of cAMP and PKA in the hippocampus, BDNF
in the serum and the monoamine neurotransmitters (e.g. 5-HT, NE, DA and so
on) in the hypothalamus of the “administered” mice were significantly higher
than those in the “control” mice. Therefore, it was proven that the
pharmaceutical composition in the present invention can rapidly increase the
content and availability of cAMP in an organism. It is apparent that the
pharmaceutical composition in the present invention demonstrates good
effectiveness, increases the availability of the main active components in the
natural plants and reduces the cost compared to the prior art, and the quality
control (i.e. CMC) can be effectively performed. Furthermore, the
pharmaceutical composition in the present invention is suitable for people
worldwide because it is highly safe for long-term use, is suitable for treating
depression patients who need long-term administration, and prevents and treats
the diseases relevant to the low expressions of cAMP and BDNF and the
insufficiency of the DA and NE neurotransmitters in the brain (e.g.
neurodegenerative diseases such as amnesia, dementia, Alzheimer's disease,
Parkinson's disease and so on, and diseases such as psoriasis, cancer and so on,
where the patients have low cAMP expression in their bodies and cells).
However, because the pharmaceutical composition includes a glycyrrhiza-
related acid, it may induce emesis symptoms if a person prone to emesis takes
liquorice (which is an issue confirmed by traditional Chinese physicians since
ancient times). Nevertheless, traditional Chinese physicians also confirmed
since ancient times that ginger is an excellent antiemetic food. Therefore,
ginger powder or its extract is further added to the pharmaceutical composition
of the present invention to improve the deficiencies in the prior art.
Disclosed is a pharmaceutical composition that rapidly increases
the content and availability of cAMP in an organism, wherein it is prepared
using raw materials containing the active components, including ginsenosides
(Rg1, Rb1 and Re), glycyrrhizic acid, jujuba cAMP, and others. The present
invention provides a pharmaceutical composition to increase a content and an
availability of a cyclic adenosine monophosphate (cAMP) in a body,
comprising: a first main component comprising 2~26 parts by weight of
ginsenosides Rg1, Rb1 and Re; a second main component comprising 3~48
parts by weight of a glycyrrhiza related acid being one selected from a group
consisting of a glycyrrhizic acid, a glycyrrhetinic acid and a combination
thereof; and a third main component comprising 0.002~0.5 parts by weight of a
jujuba cyclic adenosine monophosphate (jujuba cAMP).discloses a
pharmaceutical composition that rapidly increases the content and availability of
cAMP in an organism, wherein it is prepared using raw materials containing the
active components, including ginsenosides (Rg1, Rb1 and Re), glycyrrhizic acid,
jujuba cAMP, and others.
[0011A] The invention also provides a pharmaceutical composition for
increasing an availability of a cyclic adenosine monophosphate (cAMP) in a
body, comprising: a first main component comprising 2~26 parts by weight of
ginsenosides Rg1, Rb1 and Re; a second main component comprising 3~48
parts by weight of a glycyrrhiza related acid being one selected from a group
consisting of a glycyrrhizic acid, a glycyrrhetinic acid and a combination
thereof; and a third main component comprising 0.002~0.5 parts by weight of a
jujuba cyclic adenosine monophosphate (cAMP).
The pharmaceutical composition described in this specification and
the claims of the present invention which can rapidly increase the content and
the availability of cAMP in an organism, is the core content of the present
invention. After the present invention is published, one skilled in the art can
modify the drugs above using common techniques, and this is a regular technical
activity for one skilled in the art. Therefore, any substitutions fall within the
protective scope of the present invention.
The above objectives and advantages of the present invention will
become more readily apparent to those ordinarily skilled in the art after
reviewing the following detailed descriptions and accompanying drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is a flowchart showing a preparation method for a
pharmaceutical composition in accordance with a first preferred embodiment of
the present invention.
Figure 2 is a flowchart showing a preparation method for a
pharmaceutical composition in accordance with a second preferred embodiment
of the present invention.
Figure 3 is a flowchart showing a preparation method for a
pharmaceutical composition in accordance with a third preferred embodiment of
the present invention.
Figure 4 is a flowchart showing a preparation method for a
pharmaceutical composition in accordance with a fourth preferred embodiment
of the present invention.
Figure 5 is a diagram showing the level of cAMP in the
hippocampus of rats, 8 hours after they were administered with the
pharmaceutical composition.
Figure 6 is a gel electrophoresis photo showing the activity of
cAMP-dependent PKA (lanes from left to right: Lanes 1-4: saline, Lanes 5-8:
Paroxetine, Lanes 9-11: the embodiment 1, Lane 12: the positive control, and
Lane 13: the negative control).
Figure 7 is a diagram showing the activity of cAMP-dependent
PKA in the hippocampus of rats, 8 hours after they were administered with the
pharmaceutical composition.
Figure 8 is a diagram showing the level of p-CREB in the
hippocampus of rats, 8 hours after they were administered with the
pharmaceutical composition.
Figure 9 shows the effect of embodiment 1 on the cAMP
concentration in the hippocampus of repetitively stressed mice.
Figure 10 shows the effect of embodiment 1 on the PKA activity in
the hippocampus of chronically stressed mice.
Figure 11 shows the effect of embodiment 1 on the CREP
phosphoryplation in the hippocampus of chronically stressed mice.
Figure 12 shows the effect of embodiment 1 on the level of BDNF
in the hippocampus of chronically stressed mice.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The present invention will now be described more specifically with
reference to the following embodiments. It is to be noted that the following
descriptions of preferred embodiments of this invention are presented herein for
purpose of illustration and description only; they are not intended to be
exhaustive or to be limited to the precise form disclosed.
In order to accomplish the purpose of the present invention, the
technical schemes of the present invention are specifically described as follows.
The present invention discloses a pharmaceutical composition that
rapidly increases the content and the availability of cAMP in an organism,
wherein it is prepared using the main active components, including the
ginsenosides (Rg1, Rb1 and Re), glycyrrhizic acid and jujuba cyclic adenosine
monophosphate (jujuba cAMP).
Example 1:
The pharmaceutical composition to rapidly increase the content and
the availability of cAMP in an organism in the present invention is prepared
using the raw materials including ginsenosides (Rg1, Rb1 and Re), glycyrrhizic
acid or glycyrrhetinic acid, and jujuba cAMP.
Example 2:
The pharmaceutical composition to rapidly increases the content
and the availability of cAMP in an organism in the present invention is prepared
using the raw materials including 2~26 parts by weight of ginsenosides (Rg1,
Rb1 and Re), 3~48 parts by weight of glycyrrhizic acid or glycyrrhetinic acid,
and 0.002~0.5 parts by weight of jujuba cAMP.
Example 3:
The pharmaceutical composition in the present invention is
prepared using the raw materials including 4~13 parts by weight of ginsenosides
(Rg1, Rb1 and Re), 5~16 parts by weight of glycyrrhizic acid or glycyrrhetinic
acid, and 0.01~0.1 parts by weight of jujuba cAMP.
Example 4:
The pharmaceutical composition in the present invention further
includes a ginger water extract.
Example 5:
The pharmaceutical composition in the present invention can
include pharmacologically acceptable carriers or additives, and can be
manufactured in an oral pharmaceutical dosage form that is pharmaceutically
known, such as a tablet, capsule, powder and so on.
Example 6:
The pharmaceutical composition of the present invention can be
manufactured as a pharmaceutical, health food or nutrient supplement to rapidly
increase the content and availability of cAMP in an organism.
In order to accomplish the purposes of the present invention, the
preparation methods for the pharmaceutical composition are described as
follows.
Method 1:
The extracts containing ginsenosides (Rg1, Rb1 and Re),
glycyrrhizic acid (or glycyrrhetinic acid) and jujuba cAMP respectively
extracted from ginseng, liquorice and jujuba act as the raw materials to be
manufactured as the pharmaceutical composition to rapidly increases the content
and availability of cAMP in an organism in the present invention.
Alternatively, the prepared raw materials containing ginsenosides (Rg1, Rb1 and
Re), glycyrrhizic acid (or glycyrrhetinic acid) and jujuba cAMP are
manufactured as the pharmaceutical composition in the present invention.
Method 2:
The pharmaceutical composition in the present invention is
manufactured using the raw materials containing 2~26 parts by weight of
ginsenosides (Rg1, Rb1 and Re), 3~48 parts by weight of glycyrrhizic acid (or
glycyrrhetinic acid), and 0.002~0.5 parts by weight of jujuba cAMP.
Method 3:
The pharmaceutical composition in the present invention is
manufactured using the raw materials containing 4~13 parts by weight of
ginsenosides (Rg1, Rb1 and Re), 5~16 parts by weight of glycyrrhizic acid (or
glycyrrhetinic acid), and 0.01~0.1 parts by weight of jujuba cAMP.
Method 4:
The pharmaceutical composition in the present invention further
includes a ginger water extract.
Method 5:
The pharmaceutical composition in the present invention can
include pharmacologically acceptable carriers or additives, and can be
manufactured in an oral pharmaceutical dosage form that is pharmaceutically
known, such as a tablet, capsule, powder and so on.
Method 6:
The health food or nutrient supplement to rapidly increases the
content and availability of cAMP in an organism in the present invention is
manufactured using the raw materials in accordance with food management
standards or methods of health food producing/manufacturing standards.
THE PREFERRED EMBODIMENT
The present invention is further illustrated as follows by combining
the figures with the preferred embodiments.
Embodiment 1:
Please refer to Figure 1, which is a flowchart showing a preparation
method for a pharmaceutical composition in accordance with a first preferred
embodiment of the present invention. In Figure 1, 40 kg of ginseng is fractured
followed by extraction in heat using a 70% ethanol solution. The ethanol
extract is separated and purified using column chromatography, and dried to
obtain 1.42 kg of the ginseng extract containing 270 g of ginsenoside
Rg1+Rb1+Re (about 48.4 g of Rg1, about 176.9 g of Rb1 and about 44.7 g of
Re) (step 101). Furthermore, 15 kg of liquorice is fractured followed by
soaking at room temperature for 12 hours. The soaked liquorice is extracted
using decoction and alcohol sedimentation, concentrated and dried to obtain 3.1
kg of the liquorice extract containing 307 g of glycyrrhizic acid (step 102). In
addition, 10 kg of jujuba is fractured and then soaked in water at room
temperature, and then the soaked jujuba is extracted using decoction and alcohol
sedimentation to obtain the jujuba extract, which is further absorbed and
separated using OU-2 and ME-2 macroporous resins sequentially, and dried.
The jujuba extract (40 g) containing 0.752 g of jujuba cAMP is obtained and
acts as the raw material for preparing the pharmaceutical composition of the
present invention (step 103). Afterwards, 144 g of the ginseng extract, 300 g
of the liquorice extract and 3.6 g of the jujuba cAMP obtained from the method
above are pulverized and mixed to obtain 447.6 g of the pharmaceutical
composition (containing 27.4 g of ginsenoside Rg1+Rb1+Re, 29.7 g of
glycyrrhizic acid and 0.067 g of jujuba cAMP) in Example 1 in the present
invention (step 104).
Embodiment 2:
Please refer to Figure 2, which is a flowchart showing a preparation
method for a pharmaceutical composition in accordance with a second preferred
embodiment of the present invention. In Figure 2, 120 g of the ginseng extract
(step 201), 200 g of the liquorice extract (step 202) and 0.5 g of the jujuba
extract (step 203) obtained from Embodiment 1 are pulverized and mixed to
obtain 320.5 g of the pharmaceutical composition (containing 22.8 g of
ginsenoside Rg1+Rb1+Re, 19.8 g of glycyrrhizic acid and 0.009 g of jujuba
cAMP) of Example 2 in the present invention (step 204).
Embodiment 3:
Please refer to Figure 3, which is a flowchart showing a preparation
method of a pharmaceutical composition in accordance with a third preferred
embodiment of the present invention. In Figure 3, 3.6 g of the prepared
ginsenoside Rg1 with 90% purity (step 301), 3.2 g of the prepared ginsenoside
Re with 90% purity (step 302), 15.6 g of the prepared ginsenoside Rb1 with
90% purity (step 303), 26 g of glycyrrhetinic acid with 96% purity (step 304)
and 10 g of the jujuba extract obtained in Embodiment 1 (step 305) are
pulverized and mixed to obtain 58.4 g of the pharmaceutical composition
(containing 22.4 g of ginsenoside Rg1+Rb1+Re, 26 g of glycyrrhetinic acid and
0.188 g of jujuba cAMP) of Example 3 in the present invention (step 306).
Embodiment 4:
Please refer to Figure 4, which is a flowchart showing a preparation
method for a pharmaceutical composition in accordance with a fourth preferred
embodiment of the present invention. In Figure 4, 100 g of the pharmaceutical
composition of Example 1 in the present invention obtained in Embodiment 1
(step 401) and 35g of commercially available ginger extract (step 402) are
mixed to obtain 135 g of the pharmaceutical composition of Example 4 in the
present invention (step 403).
Experiment 1: An animal experiment for the influence on the
cAMP/PKA/CREB signal transduction pathway 8 hours after normal rats
were administered with the pharmaceutical composition of Embodiment 1.
8 hours after normal rats were intragastrically administered with the
pharmaceutical of Embodiment 1, their hippocampi were taken out. The
variations in the levels of cAMP and phospho-CREB (p-CREB) in the
hippocampus were determined using enzyme-linked immunosorbent assay
(ELISA), the variations on the activities of the cAMP-dependent PKA were
determined using bioluminescent assay, and the variations in the activities of
PDE were determined using a fluorescence method. 8 hours after
administering the pharmaceutical composition of Embodiment 1, it shows a
molecular pharmacological mechanism wherein the cAMP concentration rises
during a short time period, thereby enhance the cAMP-dependent PKA activity,
promoting the level of the CREB phosphorylation and inhibiting the PDE
activity in the hippocampus. The experimental data were statistically analyzed
and plotted using Origin Pro 7.5 software.
1. Experimental materials:
1.1 Experimental animals: Seventy (70) healthy male SD rats with
180~200 g of body weight were purchased from Vital River Laboratories
(VRL), Beijing.
1.2 Reagents: positive control drug: anti-depression Paroxetine
hydrochloride (lot number: 08030078, Zhong Mei Tianjin Smith Kline
pharmaceuticals Co. Ltd.); Parameter™ Cyclic AMP Assay Kit, KGE002 (R&D
Systems, Inc., U.S.); DuoSet IC Human/Mouse/Rat Phospho-CREB (S133)
ELISA Kit, DYC2510-2 (R&D Systems, Inc., U.S.); PepTag® Assay for Non-
Radioactive Detection of cAMP-Dependent Protein Kinase Kit, V5340
(Promega Corporation, U.S.); PDE-Glo™ Phosphodiesterase Assay Kit, V1361
(Promega Corporation, U.S.); Pierce™ BCA Protein Assay Kit, 23227, (Pierce
Biotechnology, U.S.); the standards such as cAMP and adenosine were
purchased from the National Institutes for Food and Drug Control, China; the
chemicals such as NaH PO , Na HPO , KH PO , KCl, NaCl, MgCl , Tris Base,
2 4 2 4 2 4 2
Tris-HCl and so on were the biochemical reagents for the cell culture grade and
purchased from Sigma, U.S.; the reagents such as E-64, aprotinin, leupeptin,
pepstatin A, phenylmethylsulfonyl fluoride (PMSF), NaF,
ethylenediaminetetraacetic acid EDTA), ethylene glycol tetraacetic acid
(EGTA), dithiothreitol (DTT), NaVO , sodium pyrophosphate, agarose, glycerol
and so on were a high purity grade were purchased from BioBasic Inc., Canada;
acetonitrile and methanol (the HPLC grade, Merck & Co., Inc., Germany);
ultrapure water (Milli-Q® pure water); and the pharmaceutical composition of
Embodiment 1.
1.3 Experimental equipment: FlexStation® 3 multi-mode
microplate reader (Molecular Devices Corp., U.S.); Waters® 600E high-
performance liquid chromatography (including the quaternary pump, on-line
degasser, autosampler, column oven, and UV detector; Waters Corp., U.S.);
refrigerated centrifuger (Backmen Coulter, Inc., U.S.); electronic ultrasonic
homogenizer (Ultrasound Technology Inc., U.S.); electrophoresis apparatus
(Beijing Liuyi Instrument Factory, China); gel imager (SYN GENE); ultra-low
temperature freezer (SANYO Electric Co., Ltd., Japan); and mLine single-
channel pipette and 8-channel pipette (Biohit, Finland).
2. Administration: After adaptive feeding for three days, the rats
were randomly divided into three groups, and labeled as follows: group A −
saline, group B − Paroxetine, and group C − Embodiment 1. Paroxetine
hydrochloride tablets were crushed and formulated into a suspension at a
specific concentration using ultrapure water, and the intragastrically
administered dose was 5 mg/kg per rat. The pharmaceutical composition of
Embodiment 1 was formulated to a solution at a specific concentration using
ultrapure water, and the intragastrically administered dose was 50 mg/kg per rat.
The rats in the saline group were administrated with the equivoluminal 0.9%
saline. All the rats were weighed and marked with picric acid prior to
administration, and all drugs were administered after heating at 37 ℃ for 30
minutes in advance.
3. Collection of tissues: 8 hours after the experimental animals in
groups A, B and C were administered, the rats were anesthetized with ethyl ether
and sacrificed by bleeding from their femoral arteries. The brains were collected
on ice via the removal of the head, and the hippocampus was harvested and
divided into three parts. Each part was placed in a 1.5 −mL cryotube with a
colored screw cap and labeled in advance, accurately weighed, rapidly frozen in
liquid nitrogen for 15 minutes, and then stored in the refrigerator at -80ºC for
further use.
4. Sample determination:
4.1 Determination of the level of cAMP in the rat’s hippocampus:
The sample of hippocampus tissue was unfrozen and washed with a small
amount of saline, and then the cell lysis solution (where the concentrated
solution was diluted 5 times for use) provided by the kit was added at a ratio of
1:20 (weight: volume (g: mL)) . The sample was homogenized in an electronic
ultrasonic homogenizer for 30 seconds, centrifuged at 10000 rpm for 5 minutes
at 4ºC. The supernatant was placed in a 1.5 −mL colored Eppendorf and
labeled in advance and stored in an ice box for testing. The sample was
determined using the Parameter™ Cyclic AMP Assay ELISA kit (R&D Systems,
Inc., U.S.). The sample was defrosted to room temperature, and the level of
cAMP in the sample was determined using competitive ELISA. The value of
optical density (OD) of the sample was determined at 450 nm using the multi-
mode microplate reader, and the level of cAMP in the sample was calculated
according to the standard curve.
4.2 Determination of the activity of cAMP-dependent PKA in the
rat’s hippocampus: The sample of hippocampus tissue was unfrozen and washed
with a small amount of saline, and then the PKA extraction buffer (which was
prepared according to the formulation in the manufacturer’s manual) was added
at a ratio of 1:10 (weight: volume (g: mL)) ratio. The sample was
homogenized in an electronic ultrasonic homogenizer for 30 seconds,
centrifuged at 10000 rpm for 5 minutes at 4ºC. The supernatant was transferred
to a 1.5 −mL colored Eppendorf and labeled in advance and stored in an ice box
for testing. The sample was determined using the PepTag® Assay for Non-
Radioactive Detection of cAMP-Dependent Protein Kinase Kit (Promega
Corporation, U.S.). According to the instruction manual in the kit, the pre-
mixed reagent was added to 200 −μL 8-tube PCR tubes and labeled in advance,
and 9 μL of each sample was added to the corresponding tube. The tube was
vortexed, centrifuged and reacted at room temperature for 30 minutes, and then
placed in a PCR machine to inactivate the enzyme at 98ºC for 5 minutes. A
positive control and a negative control were determined together with the tested
samples according to the instruction manual. A 0.8% agarose gel was prepared,
and 10 μL of each sample after the enzymatic denaturation was injected into the
hole of the agarose gel, and electrophoresis was run at 100 V and 130 mA for 30
minutes. The electrophoresis buffer was 50 mM Tris-HCl (pH 8.0) buffer.
After electrophoresis, the agarose gel was removed from the apparatus and
photographed under the gel imager. The agarose gel was placed on the UV
analyzer, the phosphorylated PepTag A1 Peptide spots were cut and placed in a
1.5 mL cryotube with a colored screw cap and labeled in advance. The
agarose gel was heated to melt, and pure water was added to a volume of 250 μL.
The hot agarose of 125 μL was quickly transferred to another 1.5 −mL Eppendorf
and labeled in advance, and 75 μL of the gel solubilization solution and 50 μL of
glacial acetic acid were added. The mixture was vortexed, and 200 μL of the
mixture was added to a 96 −well microtiter plate. The agarose toward the
positive electrode in the negative control was the blank. Fluorescent analysis
was conducted on a multi-mode microplate reader, and the excitation
wavelength of 586 nm and the emission wavelength of 592 nm were set. The
fluorescent intensity of the sample refers to the PKA activity.
4.3 Determination of the level of p-CREB in the rat’s hippocampus:
The samples were determined using DuoSet IC Human/Mouse/Rat Phospho-
CREB (S133) ELISA Kit (R&D Systems, Inc., U.S.). The sample of
hippocampus tissue was unfrozen and washed with a small amount of saline,
and then the tissue homogenization solution (which was prepared according to
the IC Diluent #6 in the manufacturer’s manual) was added at a ratio of 1:20
(weight: volume (g: mL)). The mixture was homogenized in an electronic
ultrasonic homogenizer for 30 seconds, centrifuged at 10000 rpm for 5 minutes
at 4ºC, the supernatant was transferred to a 1.5 −mL colored Eppendorf and
labeled in advance and stored in an ice box for testing. The level of p-CREB in
the sample was determined using the sandwich ELISA according to the
instruction manual in the kit. The OD value of the sample was determined at
450nm using the multi-mode microplate reader, and the level of p-CREB in the
sample was calculated according to the standard curve.
4.4 Determination of the total protein in the rat’s hippocampus: In
order to more accurately calculate the amount of p-CREB protein per milligram
of protein contained in the sample, it is essential to determine the amount of the
total protein in the sample. The supernatant after the tissue was homogenized
and centrifuged in the p-CREB determination experiment was diluted with PBS
times to form the test samples. In accordance with the instruction manual
inthe Pierce™ BCA Protein Assay Kit, the OD value of the sample was
determined at 450nm using the multi-mode microplate reader, and bovine serum
albumin (BSA) is the standard. The amount of total protein in the sample was
determined according to the standard curve.
4.5 Determination of the PDE activity: The influence of the
pharmaceutical composition of Embodiment 1 on the PDE activity in the rat’s
hippocampus was determined by bioluminescent assay using a PDE-Glo™
Phosphodiesterase Assay Kit (Promega Corporation, U.S.).
4.5.1 Preparation of the medical solution: The pharmaceutical
composition of Embodiment 1 was prepared to the concentrations of 0.02 mg/ml,
0.05 mg/ml and 1.0 mg/ml.
4.5.2 Preparation of the sample: After a specific amount of the
hippocampus tissue was washed with a small amount of saline, and the PDE-
Glo™ Reaction Buffer (Tris-HCl of 40 mM, MgCl of 10 mM, and bovine
serum albumin (BSA) of 0.1 mg/mlsupplemented with PMSF of 1 mM, leupetin
of 2 μM/mL, aprotinin of 2 μM/mL, and E-64 of 2 μM/mL) was added at a ratio
of 1:10 (weight: volume (g: mL)). The mixture was homogenized using an
electronic ultrasonic homogenizer and centrifuged at 10000 rpm for 5 minutes at
4ºC, and the supernatant was the enzymatic solution for use.
4.5.3 Protocol of the bioluminescent assay: The protocol was
conducted according to the method provided in the instruction manual. As to
the enzymatic reaction solution, 1 μL medical solution was added to 1.5 μL
enzymatic solution to a total volume of 2.5 μL. The substrate solution of 2.5
μL containing 2 μmol cAMP was added to 2.5 μL of the mixture, and the
reaction mixture was mixed and reacted at 37ºC for 30 minutes. Next, 2.5 μL
of the stop solution containing 3-isobutylmethylxanthine (IBMX) (which is a
strong PDE inhibitor) was added and mixed. A test solution of 2.5 μL was
added and mixed, and the reaction mixture was reacted at room temperature for
minutes. Finally, 10 μL of the luminescent reagent was added to the
reaction mixture, which then was reacted at room temperature for 10 minutes.
The bioluminescence was determined using the multi-mode microplate reader.
5. Experimental results:
.1 The level of cAMP in the rat’s hippocampus: The cAMP
concentration in the homogenate of the rat’s hippocampus was determined using
the ELISA assay, and the level of cAMP contained in the hippocampus tissue
was obtained by dividing the weight of the measured tissue sample by the
concentration of cAMP, and is presented as pmol / g tissue (referring to Figure
Please refer to Figure 5. The level of cAMP in the rat’s
hippocampus tissue in the Embodiment 1 group significantly increased
compared to the saline group and the Paroxetine group (* P <0.05, n = 10).
5.2 The activity of cAMP-dependent PKA in the rat’s hippocampus:
After the enzymatic reaction, the samples were resolved using agarose gel
electrophoresis, developed using the gel imager, and roughly analyzed.
Please refer to Figure 6, the phosphorylated A1 peptide has a
negative charge and migrates toward the positive electrode, while the
unphosphorylated A1 peptide has a positive charge and migrates toward the
negative electrode. These two peptides were separated from each other.
When the brightness of the phosphorylated A1 peptide spot (which migrates
toward the positive electrode) is stronger, this indicates that the level of
phosphorylation and the activity of cAMP-dependent PKA are higher in the
sample. It is shown in Figure 6 that the brightness of the spot in the
Embodiment 1 group is stronger than those in the saline group and the
Paroxetine group.
The spots on the agarose gel were cut and melted, and the volume
of the melted gel was determined. The activity of cAMP-dependent PKA in
the rat’s hippocampus was determined using the fluorescent assay and was
presented as fluorescent intensity (referring to Figure 7).
Please refer to Figure 7. 8 hours after administration, the activity
of cAMP-dependent PKA in the rat’s hippocampus in the Embodiment 1 group
is significantly increased compared to the blank control group and the
Paroxetine group (*P <0.05, n = 10).
5.3 The level of p-CREB in the rat’s hippocampus: The
concentration of total protein in the homogenate of the rat’s hippocampus
sample was determined using the BCA method to assess the amount of p-CREB
per μg of total protein. Next, the concentration of p-CREB in the homogenate
of the rat’s hippocampus sample was determined using the sandwich ELISA
assay, and p-CREB (pg) / total protein (μg) referred to the level of p-CREB in
the rat’s hippocampus (referring to the data in Figure 8).
Please refer to Figure 8. 8 hours after administration, the level of
p-CREB in the rat’s hippocampus in the Embodiment 1 group significantly
increased compared to the saline group and the Paroxetine group (n = 10).
5.4 The influence of the pharmaceutical composition on the PDE
activity in the rat’s hippocampus: The PDE activity in the rat’s hippocampus and
the inhibition against the PDE activity after in vitro administration were
determined using the bioluminescent assay. The luminous intensity refers to
the PDE activity. Compared with the control group, the higher luminous
intensity indicates higher PDE activity, and the lower luminous intensity
indicates that the PDE activity was inhibited. The measured results show that
the pharmaceutical composition (0.5mg/ml) in the Embodiment 1 group
significantly inhibited the PDE activity in the rat’s hippocampus compared to
the blank control group (* P <0.05, n = 4).
6. Conclusion:
(1) 8 hours after the intragastric administration to the rats,
compared with the saline group and the Paroxetine group, the level of cAMP in
the rat’s hippocampus in the Embodiment 1 group significantly increased, the
cAMP-Dependent PKA activity therein was significantly enhanced, and the
level of p-CREB therein also increased.
(2) The experiments demonstrate that the pharmaceutical
composition of Embodiment 1 can perform its pharmacological functions via the
second messenger cAMP signaling pathway, and can rapidly initiate the cAMP-
PKA-CREB (p-CREB) pathway 8 hours after administration (where the
significant difference (*P <0.05) was done by comparison with the saline group
and the Paroxetine group).
(3) 8 hours after administration, the positive control drug,
Paroxetine, cannot initiate the cAMP-PKA-CREB (p-CREB) pathway.
(4) The experimental result also indicates that the PDE activity can
be significantly inhibited by a medium dose of the pharmaceutical composition
in Embodiment 1. Because PDE is an inactivated enzyme for cAMP, the
inhibition of PDE can cause the increased level of cAMP in the rat’s
hippocampus.
Experiment 2: An animal experiment for the influence to the
cAMP/PKA/CREB signal transduction pathway and the BDNF expression
after the chronically stressed mice were administered with the
pharmaceutical composition of Embodiment 1 for 10 days.
1. The effect of the pharmaceutical composition of Embodiment 1
on the cAMP concentration of the hippocampus in the repetitively stressed mice
(referring to Figure 9):
The results in Figure 9 show that the cAMP concentration in the
hippocampus of the mice that were administered with the pharmaceutical
composition of Embodiment 1 is significantly higher than that in the control
group without administration (*P <0.05).
2. The effect of the pharmaceutical composition of Embodiment 1
on the PKA activity of the hippocampus in the repetitively stressed mice
(referring to Figure 10):
The results in Figure 10 show that the PKA activity in the
hippocampus of the mice that were administered with the pharmaceutical
composition of Embodiment 1 is significantly higher than that in the control
group without administration (*P <0.05).
3. The effect of the pharmaceutical composition of Embodiment 1
on the CREB phosphorylation of the hippocampus in the repetitively stressed
mice (referring to Figure 11):
The results in Figure 11 show that the expression of the CREB
phosphorylation in the hippocampus of the mice that were administered with the
pharmaceutical composition of Embodiment 1 is significantly higher than that in
the control group without administration.
4. The effect of the pharmaceutical composition of Embodiment 1
on the BDNF expression of the hippocampus in the repetitively stressed mice
(referring to Figure 12):
The results in Figure 12 show that the BDNF expression in the
hippocampus of the mice that were administered with the pharmaceutical
composition of Embodiment 1 is significantly higher than that in the control
group without administration.
Experiment 3: An animal experiment for the influence on the
expressions of hippocampal cAMP and PKA, serum BDNF, and
hypothalamic NE, DA and 5HT after the chronically stressed rats were
administered with the pharmaceutical composition of Embodiment 1 for 21
days.
1. The effect of the pharmaceutical composition of Embodiment 1
on the cAMP concentration of the hippocampus and cortex in the chronically
stressed rats (referring to Table 1).
Table 1. The cAMP expression in the hippocampus and cortex of the rats in each
group.
Sample Dose Hippocampus Cortex
Group
size (mg/kg/d) (pmol/ml) (pmol/ml)
Normal 8 - 72.650±2.9017 67.650±4.0715
Control 8 - 64.950±7.6459 57.825±5.8004
High dose of
8 60 69.887±7.2155 66.850±5.0844
Embodiment 1
Medium dose of
8 30 71.400±6.0233 66.975±6.6626
Embodiment 1
Low dose of
8 15 69.113±5.4286 65.388±8.0920
Embodiment 1
2. The effect of the pharmaceutical composition of Embodiment 1
on the PKA level of the hippocampus in the chronically stressed rats (referring
to Table 2).
Table 2. The PKA level in the hippocampus of the rats in each group.
Sample Dose Hippocampus
Group
size (mg/kg/d) (pmol/ml)
Normal 8 - 26.4988±2.75623
Control 8 - 21.4936±3.01990
High dose of Embodiment 1 8 60 25.8763±3.48088
Medium dose of Embodiment 1 8 30 25.9150±4.77464
Low dose of Embodiment 1 8 15 26.0025±4.87687
3. The effect of the pharmaceutical composition of Embodiment 1
on the serum BDNF level in the chronically stressed rats (referring to Table 3).
Table 3. The serum BDNF level of the rats in each group
Sample Dose BDNF
Group
size (mg/kg/d) (pg/ml)
Normal 8 - 111.00±45.28
Control 8 - 72.57±19.49
Low dose of Embodiment 1 8 15 102.90±18.70
Medium dose of Embodiment 1 8 30 110.14±31.64
High dose of Embodiment 1 8 60 91.53±39.93
4. The effect of the pharmaceutical composition of Embodiment 1
on the expression of monoamine neurotransmitters of the hypothalamus in the
chronically stressed rats (referring to Table 4).
Table 4. The expression of monoamine neurotransmitters in the hypothalamus of
the rats in each group
5HT DA
Sample Dose NE
Group (ng/g wet (ng/g wet
size mg/kg/d (ng/g wet tissue)
tissue) tissue)
Normal 11 - 1038.03±458.63 4254.74±1334.95 546.04±329.18
Control 11 - 324.22±89.44 2572.61±707.43 229.40±109.74
Low dose of
11 15 990.45±261.38 4128.42±1608.56 477.27±274.74
Embodiment 1
Medium dose
of 11 30 857.52±273.55 3822.10±1295.65 473.60±269.23
Embodiment 1
High dose of
11 60 857.28±293.29 3566.67±501.30 373.03±141.25
Embodiment 1
5. Conclusion:
The expressions of hippocampal cAMP and PKA, serum BDNF,
and hypothalamic monoamine neurotransmitters (5-HT, NE and DA) in the rats
that were administered with the pharmaceutical composition of Embodiment 1
are significantly higher than those in the control group without administration
(*P <0.05).
Experiment 4: An animal experiment for the anti-depression
pharmacodynamics of Embodiment 1.
1. Animal behavior experiment:
The inventor conducted animal behavior experiments, including the
tail-hang experiment on mice, the forced-swim experiment on rats, the forced-
swim experiment on mice, the unpredictable long-term stimulus experiment on
rats, the olfactory bulb lesion experiment on rats and others, according to the
pathogenetic mechanism and clinical symptoms of depression.
1.1 The pharmaceutical composition of Embodiment 1 was
intragastrically administered to mice with the dose of 20 mg/kg/d, 40 mg/kg/d
and 80 mg/kg/d (the dose of 15 mg/kg/d, 30 mg/kg/d and 60 mg/kg/d for rats)
for one week to determine an effect against the experimental depression,
wherein the medium dose group (40 mg/kg/d for mice and 30 mg/kg/d for rats)
and the positive control group (Paroxatine) demonstrated significantly shorter
non-movement time for the tail-hanged mice, the forced-swim mice and the
forced-swim rats. The data show a statistically significant difference compared
to the control group (P < 0.05).
1.2 The pharmaceutical composition of Embodiment 1 was
intragastrically administered to rats under the chronic unpredictable mild stress
(CUMS) model with the dose of 15 mg/kg/d, 30 mg/kg/d and 60 mg/kg/d for 21
consecutive days. The results show that, compared to the normal group, the
body weight of the CMUS model rat group gained slowly, the sucrose
consumption significantly decreased (P < 0.01), the horizontal movement and
vertical movement significantly decreased (P < 0.01), and the number of errors
in rat jumping trials significantly increased (P < 0.01). Compared to the
control group, the body weight gains of the low dose of Embodiment 1 and the
positive group (Paroxetine) significantly increased, the sucrose consumption in
both groups significantly increased (P < 0.01), the horizontal movement and
vertical movement in both groups significantly increased (P < 0.01), and the
number of errors in rat jumping trial in both groups significantly decreased (P <
0.01 for the small dose group, and P < 0.01 for the positive group (Paroxetine)).
1.3 The pharmaceutical composition of Embodiment 1 was
intragastrically administered to olfactory bulb lesion model rats with the dose of
mg/kg/d, 30 mg/kg/d and 60 mg/kg/d for 24 consecutive days. In the open
field box test, compared to the control group, the high dose of Embodiment 1
significantly improved the decrease of the horizontal movement and vertical
movement caused by the olfactory bulb lesion. The positive control
(Paroxetine of 3 mg/kg/d) also significantly improved the decrease of the
horizontal movement and vertical movement caused by the olfactory bulb lesion.
In the passive avoidance experiment, compared to the control group, the high
dose and the medium dose of Embodiment 1 significantly improved the
decrement of rat study and memory capacity caused by the olfactory bulb lesion.
2. The animal experiment on interaction model:
The inventor conducted animal behavior experiments, including the
reserpine-induced model experiments (body temperature drop, akinesia and
blepharoptosis) on mice, the serotonin-induced head shaking experiment on
mice and others, according to the pathogenetic mechanism and clinical
symptoms of depression.
2.1 The pharmaceutical composition of Embodiment 1 was
intragastrically administered to mice with the dose of 20 mg/kg/d, 40 mg/kg/d
and 80 mg/kg/d (the dose of 15 mg/kg/d, 30 mg/kg/d and 60 mg/kg/d for rats)
for one week. The reserpine-induced body temperature drop, akinesia and
blepharoptosis in mice can be significantly inhibited by the pharmaceutical
composition of Embodiment 1, indicating that the effect against the
experimental depression of Embodiment 1 may be relevant to the effect of the
monoamine neurotransmitters. The amount of head-shaking of the serotonin-
injected mice can be significantly increased, indicating that the anti-depression
effect of Embodiment 1 may be relevant to the inhibition of monoamine oxidase
(MAO). Moreover, because the experimental results show that the
pharmaceutical composition of Embodiment 1 has no significant effect on the
self-regulated activity of mice, the pharmaceutical composition of Embodiment
1 had no stimulation effect on the central nervous system.
3. The experimental results for the major anti-depression
pharmacodynamics are summarized as follows (referring to Table 5):
Administrated condition
Dose
Item Model/Method (route/time/frequency/ Major result
(mg/kg)
effective dose)
Significantly shortened the
Oral/7 days/2 times a
60 accumulative non-
Forced-swim
day/15 mg/kg
1.1 30 movement time in the
experiment on rats
forced-swim experiment on
(* P ＜0.05)
rats
Significantly shortened the
Oral/7 days/2 times a day
Forced-swim 80 accumulative non-
/40 mg/kg
1.2 experiment on 40 movement time in the
mice 20 forced-swim experiment on
(** P ＜0.01)
mice
Oral/7 days/2 times a day
Significantly shortened the
Tail-hang 80
/20 mg/kg
accumulative non-
1.3 experiment on 40
movement time of tail-
(* P ＜0.05)
mice 20
hanged mice
Self-regulated
80 No significant effect on the
activity
1.4 40 Oral/7 days/2 times a day self-regulated activity of
experiment on
mice
mice
Unpredictable
Oral/7 days/1 time a day
long-term Significantly increased the
/15 mg/kg
stimulus body weight gain in the
2.1 30
experiment on unpredictably long-term
(** P ＜0.01)
rats: body weight stressed rats
measurement
Unpredictable
long-term
Significantly improved the
Oral/7 days/1 time a day
stimulus 60
decrease of sucrose uptake
/15 mg/kg
2.2 experiment on 30
in the unpredictably long-
rats: sucrose 15
(** P ＜0.01)
term stressed rats
intake
measurement
Unpredictable Significantly improved the
Oral/7 days/1 time a day
long-term decrease of horizontal and
/15 mg/kg
2.3 30
stimulus vertical movements in the
(* P ＜0.05)
experiment on unpredictably long-term
rats: open field stressed rats
box test to
measure self-
regulated
activityof the
model rats
Unpredictable
long-term
Oral/7 days/1 time a day
stimulus Significantly decreased the
/15 mg/kg
experiment on number of jumping errors
2.4 30
(* P ＜0.05)
rats: jumping test of the unpredictably long-
to measure the term stressed rats
rats’ behavior
changes
The determination
of the monoamine
neurotransmitters
Oral/7 days/1 time a day
Significantly increased the
(NE and 5-HT, 60
/15 mg/kg
levels of NE, 5-HT and DA
2.5 etc.) in the brain 30
in the model rat’s cerebral
(** P ＜0.01)
of the 15
cortex
unpredictable
long-term
stimulus model rat
Olfactory bulb
Oral/7 days/1 time a day
lesion experiment: Significantly improved the
/30 mg/kg
open field box test rat’s horizontal and vertical
3.1 30
(* P ＜0.05)
to measure the movements caused by the
self-regulated olfactory bulb lesion
activity of mice
Oral/7 days/1 time a day
Olfactory bulb
Significantly improved the
/30 mg/kg
lesion experiment: 60
decrement of rat study and
3.2 determination of 30
(* P ＜0.05)
memory capability caused
passive avoidance 15
by the olfactory bulb lesion
experiment on rats
Oral/7 days/2 times a day
Reserpine model
80 Significantly inhibited
/40 mg/kg
experiment: body
4.1 40 reserpine-induced body
temperature drop
(** P ＜0.01)
temperature drop
on mice
Oral/7 days/2 times a day
Reserpine model
80 Significantly inhibited
/40mg/kg
experiment:
4.2 40 reserpine-induced akinesia
akinesia (stupor)
(** P ＜0.01)
on mice
Reserpine model 80 Oral/7 days/2 times a day Significantly inhibited
experiment: 40 /40 mg/kg reserpine-induced
blepharoptosis on 20 blepharoptosis
(** P ＜0.01)
mice
Oral/7 days/1 time a day
Serotonin-induced Significantly increased the
/40 mg/kg
head-shake amount of head-shaking of
4.4 40
experiment on the serotonin-injected
(** P ＜0.01)
mice mice
Note: 1. Embodiment 1 v.s. control *P <0.05,**P <0.01.
2. Positive control: Paroxetine, 3 mg/kg/d for mice, 2 mg/kg/d for rats (In addition to
that the tail-hang experiment refers to the label “**”, others refer to the label “*”).
4. Conclusion: The pharmaceutical composition of Embodiment 1
has significant experimental effects against depression.
The results in the various experiments show:
(1) 8 hours after intragastrically administering the pharmaceutical
composition of Embodiment 1 to rats, compared to the saline group and the
Paroxetine group, the hippocampal cAMP significantly increased, the PKA
activity was significantly enhanced (*P <0.05), the p-CREB level also increased,
and the PDE4 activity was significantly inhibited (*P <0.05).
(2) After intragastrically administering the pharmaceutical
composition of Embodiment 1 to chronically stressed mice for 10 days, the
decrease of the hippocampal cAMP and PKA caused by repetitive stress
significantly increased to promote the expression of the phosphorylated CREB
and BDNF in the mice hippocampus.
(3) After intragastrically administering the pharmaceutical
composition of Embodiment 1 to chronically stressed rats for 21 days, the
decrease of the hippocampal cAMP and PKA caused by repetitive stress
significantly increased to promote the expression of monoamine
neurotransmitters, including serum BDNF, hypothalamic NE and 5-HT and so
on , while GSC was down-regulated.
(4) The pharmaceutical composition of Embodiment 1 has
significant experimental effects against depression.
The application scopes of the pharmaceutical composition of the
present invention for rapidly increasing the content and availability of cAMP in
vivo are described as follows.
1. The pharmaceutical composition of the present invention to
rapidly increase the content and availability of cAMP in vivo can include
pharmacologically acceptable additives.
2. The pharmaceutical composition of the present invention to
rapidly increase the content and availability of cAMP in vivo can be
manufactured in known dosage forms, such as a powder, capsule, tablet and so
3. The pharmaceutical composition of the present invention to
rapidly increase the content and availability of cAMP in vivo can be
manufactured as a drug, a health food or a nutrient to prevent and cure diseases
caused by low availability and level of cAMP in an organism and cells, enhance
the level of BDNF, enhance the cAMP/PKA/CREB signaling pathway in cells,
enhance the levels of neurotransmitters including DA, NE and 5-HT, and
enhance memory.
There are further embodiments disclosed as follows.
Embodiment 1. In a pharmaceutical composition to increase a
content and an availability of a cyclic adenosine monophosphate in a body,
including: a first main component including ginsenosides Rg1, Rb1 and Re; a
second main component including a glycyrrhiza related acid being one selected
from a group consisting of a glycyrrhizic acid, a glycyrrhetinic acid and a
combination thereof; and a third main component including a jujuba cyclic
adenosine monophosphate.
Embodiment 2. In the pharmaceutical composition according to
Embodiment 1, the pharmaceutical composition includes 2~26 parts by weight
of the ginsenosides Rg1 and Rb1, 3~48 parts by weight of the glycyrrhiza
related acid, and 0.002~0.5 parts by weight of the jujuba cyclic adenosine
monophosphate.
Embodiment 3. In the pharmaceutical composition according to
Embodiment 1 or 2, the pharmaceutical composition includes 4~13 parts by
weight of the ginsenosides Rg1 and Rb1, 5~16 parts by weight of the
glycyrrhiza related acid, and 0.01~0.1 parts by weight of the jujuba cyclic
adenosine monophosphate.
Embodiment 4. In the pharmaceutical composition according to
one of Embodiments 1-3, the pharmaceutical composition includes a
pharmacologically acceptable carrier, an additive or a combination thereof.
Embodiment 5. In the pharmaceutical composition according to
one of Embodiments 1-4, the pharmaceutical composition has a dosage form
being one selected from a group consisting of a tablet, a capsule, a powder, a
pill, a dust, a solution, a microcapsule, a suspension, an emulsion, a particle, a
dropping pill, a roll and a pharmacological oral medication dosage.
Embodiment 6. In the pharmaceutical composition according to
one of Embodiments 1-5, the pharmaceutical composition is manufactured as a
drug, a health food or a nutrient which is used to prevent and treat low
availability and content of the cAMP in the body and a cell, enhance a
cAMP/PKA/CREB signaling pathway in the cell, enhance an expression of a
BDNF, increase content of DA, NE and 5HT neurotransmitters, or enhance
memory.
Embodiment 7. In the pharmaceutical composition according to
one of Embodiments 1-6, the pharmaceutical composition further includes a
fourth main component being one selected from a ginger, a ginger extract or a
combination thereof.
Embodiment 8. In a pharmaceutical composition to increase an
availability of a cyclic adenosine monophosphate in a body, including: a first
main component including ginsenosides Rg1, Rb1 and Re; a second main
component including a glycyrrhiza related acid being one selected from a group
consisting of a glycyrrhizic acid, a glycyrrhetinic acid and a combination
thereof; and a third main component including a jujuba cyclic adenosine
monophosphate.
Embodiment 9. In a method for preparing a pharmaceutical
composition to increase a content of a cyclic adenosine monophosphate in a
body, including: providing a first main component, wherein the first main
component includes ginsenosides Rg1, Rb1 and Re; providing a second main
component, wherein the second main component includes a glycyrrhiza related
acid being one selected from a group consisting of a glycyrrhizic acid, a
glycyrrhetinic acid and a combination thereof; and providing a third main
component, wherein the third main component includes a jujuba cyclic
adenosine monophosphate, to manufacture the pharmaceutical composition.
While the invention has been described in terms of what is
presently considered to be the most practical and preferred embodiments, it is to
be understood that the invention needs not be limited to the disclosed
embodiments. Therefore, it is intended to cover various modifications and
similar configurations included within the spirit and scope of the appended
claims, which are to be accorded with the broadest interpretation so as to
encompass all such modifications and similar structures.
Industrial Applicability
1. The pharmaceutical composition of the present invention to
rapidly increase content and availability of cAMP in vivo can include
pharmacologically acceptable additives.
2. The pharmaceutical composition of the present invention to
rapidly increase the content and availability of cAMP in vivo can be
manufactured in known dosage forms, such as a powder, capsule or tablet.
3. The pharmaceutical composition of the present invention to
rapidly increase the content and availability of cAMP in vivo can be
manufactured as a drug, a health food or a nutrient which is used to prevent and
treat diseases caused by low availability and content of the cAMP in an
organism and cells, enhance a cAMP/PKA/CREB signaling pathway in the cell,
enhance an expression of a BDNF, increase content of DA, NE and 5-HT
neurotransmitters, or enhance memory.
Claims (16)
1. A pharmaceutical composition to increase a content and an availability of a cyclic adenosine monophosphate (cAMP) in a body, comprising: a first main component comprising 2~26 parts by weight of ginsenosides Rg1, Rb1 and Re; a second main component comprising 3~48 parts by weight of a glycyrrhiza related acid being one selected from a group consisting of a glycyrrhizic acid, a glycyrrhetinic acid and a combination thereof; and a third main component comprising 0.002~0.5 parts by weight of a jujuba cyclic adenosine monophosphate (jujuba cAMP).
2. The pharmaceutical composition as claimed in Claim 1, wherein the pharmaceutical composition comprises 4~13 parts by weight of the ginsenosides Rg1, Rb1 and Re, 5~16 parts by weight of the glycyrrhiza related acid, and 0.01~0.1 parts by weight of the jujuba cyclic adenosine monophosphate.
3. The pharmaceutical composition as claimed in Claim 1, wherein the ginsenosides Rg1, Rb1 and Re are extracted from a ginseng, the glycyrrhiza related acid is extracted from a liquorice, and the jujuba cAMP is extracted from a jujuba.
4. The pharmaceutical composition as claimed in Claim 1, wherein the pharmaceutical composition comprises one selected from a group consisting of a pharmacologically acceptable carrier, an additive and a combination thereof.
5. The pharmaceutical composition as claimed in Claim 1, wherein the pharmaceutical composition has a dosage form being one selected from a group consisting of a tablet, a capsule, a powder, a pill, a dust, a solution, a microcapsule, a suspension, an emulsion, a particle, a dropping pill, a roll and a pharmacological oral medication dosage.
6. The pharmaceutical composition as claimed in Claim 1, wherein the pharmaceutical composition is manufactured as one selected from a group consisting of a drug, a health food and a nutrient which is used to one selected from a group consisting of prevent and treat low availability and content of the cAMP in one of the body and a cell, enhance a cAMP/PKA/CREB signaling pathway in the cell, enhance an expression of a BDNF, increase content of DA, NE and 5HT neurotransmitters, and enhance memory.
7. The pharmaceutical composition as claimed in Claim 1, wherein the pharmaceutical composition further comprises a fourth main component selected from a group consisting of a ginger, a ginger extract and a combination thereof.
8. The pharmaceutical composition as claimed in Claim 7, wherein the ginger extract is a ginger water extract.
9. A pharmaceutical composition for increasing an availability of a cyclic adenosine monophosphate (cAMP) in a body, comprising: a first main component comprising 2~26 parts by weight of ginsenosides Rg1, Rb1 and Re; a second main component comprising 3~48 parts by weight of a glycyrrhiza related acid being one selected from a group consisting of a glycyrrhizic acid, a glycyrrhetinic acid and a combination thereof; and a third main component comprising 0.002~0.5 parts by weight of a jujuba cyclic adenosine monophosphate (cAMP).
10. The pharmaceutical composition as claimed in Claim 9, wherein the pharmaceutical composition comprises 4~13 parts by weight of the ginsenosides Rg1, Rb1 and Re, 5~16 parts by weight of the glycyrrhiza related acid, and 0.01~0.1 parts by weight of the jujuba cyclic adenosine monophosphate.
11. The pharmaceutical composition as claimed in Claim 9, wherein the ginsenosides Rg1, Rb1 and Re are extracted from a ginseng, the glycyrrhiza related acid is extracted from a liquorice, and the jujuba cAMP is extracted from a jujuba.
12. The pharmaceutical composition as claimed in Claim 9, wherein the pharmaceutical composition comprises one selected from a group consisting of a pharmacologically acceptable carrier, an additive and a combination thereof.
13. The pharmaceutical composition as claimed in Claim 9, wherein the pharmaceutical composition has a dosage form being one selected from a group consisting of a tablet, a capsule, a powder, a pill, a dust, a solution, a microcapsule, a suspension, an emulsion, a particle, a dropping pill, a roll and a pharmacological oral medication dosage.
14. The pharmaceutical composition as claimed in Claim 9, wherein the pharmaceutical composition is manufactured as one selected from a group consisting of a drug, a health food and a nutrient which is used for one selected from a group consisting of preventing and treating low availability of the cAMP in one of the body and a cell, enhancing a cAMP/PKA/CREB signaling pathway in the cell, enhancing an expression of a BDNF, increasing contents of DA, NE and 5HT neurotransmitters, and enhancing memory.
15. The pharmaceutical composition as claimed in Claim 9, wherein the pharmaceutical composition further comprises a fourth main component selected from a group consisting of a ginger, a ginger extract and a combination thereof.
16. The pharmaceutical composition as claimed in Claim 15, wherein the ginger extract is a ginger water extract.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/CN2012/080191 WO2014026341A1 (en) | 2012-08-15 | 2012-08-15 | Pharmaceutical composition increasing cyclic amp content and availability in vivo, and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| NZ705363A NZ705363A (en) | 2017-05-26 |
| NZ705363B2 true NZ705363B2 (en) | 2017-08-29 |
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