CN114832006B - Application of ginsenoside Rh4 in preparation of medicine for inhibiting sleep - Google Patents
Application of ginsenoside Rh4 in preparation of medicine for inhibiting sleep Download PDFInfo
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- OZTXYFOXQFKYRP-TXRYYSRHSA-N Ginsenoside Rh4 Chemical compound O([C@@H]1[C@H]2C(C)(C)[C@@H](O)CC[C@]2(C)[C@H]2C[C@@H](O)[C@H]3[C@@]([C@@]2(C1)C)(C)CC[C@@H]3C(/C)=C/CC=C(C)C)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O OZTXYFOXQFKYRP-TXRYYSRHSA-N 0.000 title claims abstract description 62
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/26—Psychostimulants, e.g. nicotine, cocaine
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Abstract
The application discloses application of ginsenoside Rh4 in preparing a medicament for inhibiting sleep. The application also discloses application of ginsenoside Rh4 in preparing medicines for improving glutamic acid content in peripheral blood, medicines for treating hypersomnia and central nervous system excitation medicines. Wherein ginsenoside Rh4 is used as an active ingredient of the medicine.
Description
Technical Field
The invention relates to the field of biological medicine, in particular to application of rare ginsenoside Rh4 in preparation of a medicine for inhibiting sleep.
Background
Natural products are widely used worldwide and have been recognized as an important source of pharmaceuticals. In recent years, active ingredients extracted from certain medicinal plants with high safety coefficient have become an important source of new drugs for treating nerve dysfunction. Ginseng belongs to perennial herb of Araliaceae, and is a high-value herb for treating various diseases for a long time. Ginsenoside is the main active ingredient of ginseng and has been demonstrated to have various pharmacological effects including antioxidant, anti-inflammatory, antiallergic, antidiabetic and anticancer. In recent years, there is growing evidence that some kinds of ginsenosides have a protective effect on the nervous system. For example, ginsenoside Rg5 and ginsenoside Rk1, which have similar structures to ginsenoside Rh4, are central nervous system inhibitors, and can reduce excitatory neurotransmitter Glu and promote sleep (see reference 1). Reference 1: shao, j., zheng, x., qu, l., zhang, H. & Fan, d.ginsenoside Rg5/Rk1 ameliorated sleep via regulating the GABAergic/serotoninergic signaling pathway in rodent model.
Disclosure of Invention
The inventor has conducted intensive studies on the physiological action of ginsenoside Rh4 and found that: 1. ginsenoside Rh4 is similar to ginsenoside Rg5/Rk1 in structure, but is opposite to ginsenoside Rg5/Rk1 in physiological effect, namely ginsenoside Rh4 is not reduced, but rather increases excitatory neurotransmitter Glu;2. ginsenoside Rh4 also does not have the activity of up-regulating the expression of GABAA receptors and GABAB receptors, and up-regulating the expression of 5-HT1A receptors; 3. ginsenoside Rh4 is central nervous system stimulant and can inhibit sleep.
Accordingly, an object of the present invention is to provide the use of ginsenoside Rh4 as an active ingredient in the preparation of a medicament for inhibiting sleep. Furthermore, the present invention aims to provide the use of ginsenoside Rh4 as an active ingredient in the preparation of a central nervous system stimulant. Furthermore, the present invention also aims to provide the use of ginsenoside Rh4 as an active ingredient in the preparation of a medicament for increasing the glutamic acid content in peripheral blood. Furthermore, the invention also aims to provide the application of ginsenoside Rh4 as an active ingredient in preparing medicines for treating hypersomnia.
Namely, the present invention includes:
1. use of ginsenoside Rh4 in the manufacture of a medicament for inhibiting sleep, wherein the ginsenoside Rh4 is used as an active ingredient of the medicament.
2. Use of ginsenoside Rh4 in the manufacture of a medicament for increasing the glutamic acid content in peripheral blood, wherein the ginsenoside Rh4 is used as an active ingredient of the medicament.
3. Use of ginsenoside Rh4 in the manufacture of a medicament for the treatment of hypersomnia, wherein the ginsenoside Rh4 is the active ingredient of the medicament.
In the present specification, excessive sleep means that the sleep time is 110% or more, 120% or more, 130% or more, 140% or more, 150% or more, 200% or more of the normal sleep time.
4. Use of ginsenoside Rh4 in the preparation of a central nervous system stimulant, wherein the ginsenoside Rh4 is used as an active ingredient of the drug.
5. The use according to any one of claims 1 to 4, wherein the ginsenoside Rh4 is the only active ingredient of the medicament.
6. The use according to any one of claims 1 to 4, wherein the pharmaceutical is in the form of an oral preparation, an injection or a instillation.
7. The use according to any one of claims 1 to 4, wherein the oral preparation is a tablet, capsule, granule, powder, drop, fruit juice, pill or syrup.
8. The use according to any one of claims 1 to 4, wherein the injection or instillation is in the form of a solution, suspension, emulsion or lyophilized powder.
Drawings
FIG. 1 shows the structural formula of ginsenoside Rh 4.
FIG. 2 is a graph showing the effect of ginsenoside Rh4 on the GABA related receptor and the 5-HT1A receptor of CUMS mice.
FIG. 3 is a graph showing the effect of ginsenoside Rh4 on the glutamic acid content in serum.
Fig. 4 is a graph showing the physiological effect of ginsenoside Rh4 in inhibiting sleep.
Detailed Description
The present invention will be described in detail with reference to specific examples. It should be particularly pointed out that these descriptions are merely exemplary descriptions and do not constitute limitations on the scope of the invention.
Example 1: ginsenoside Rh4 capsule
Making into capsule (6000 granules, ginsenoside Rh4 content: 100 mg/granule) according to the following proportion
Example 2: ginsenoside Rh4 tablet
Is prepared into tablets (5000 tablets, ginsenoside Rh4 content: 100 mg/tablet) according to the following proportion
Example 3: ginsenoside Rh4 syrup
Syrup (2000 pieces, 10 mL/piece, ginsenoside Rh4 content: 100 mg/piece) is prepared according to the following proportion
EXAMPLE 4 ginsenoside Rh4 granule
Syrup (6000 bags, 6 g/bag, ginsenoside Rh4 content: 100 mg/bag) is prepared according to the following proportion
EXAMPLE 5 ginsenoside Rh4 gel
Making into ointment (1000 tubes, 10 g/tube, ginsenoside Rh4 content: 100 mg/tube) according to the following proportion
Example 6: influence of ginsenoside Rh4 on sodium pentobarbital-induced sleep state of mice
1. Experimental materials
Ginsenoside Rh4 capsule prepared in example 1; imipramine tablet (Shandong Xinyi pharmaceutical Co., ltd.); sodium pentobarbital (Shanghai chemical reagent Co., ltd., chinese medical group); C57/BL mice, males, body weight 20-25g
2. Experimental method
2.1 grouping of animals and modes, dosages, times of administration
The animals were dosed by gavage, and C57/BL mice were randomly divided into a blank group, imipramine group (15 mg/kg), ginsenoside Rh4 low dose group (20 mg/kg), ginsenoside Rh4 high dose group (40 mg/kg), ginsenoside Rg5 high dose group (40 mg/kg) and ginsenoside Rk1 high dose group (40 mg/kg). The administration time is 9:00-11:00 am.
The mice of groups 2.2 and above were each dosed for 7 days continuously and experiments were performed 30 minutes after the last dose.
For mice of each of the blank group, imipramine group, ginsenoside Rh4 low dose group, and ginsenoside Rh4 high dose group, half of the mice were euthanized, orbital blood was rapidly collected and centrifuged (12000 r,4 ℃) and the supernatant after centrifugation was extracted, and Glu content was measured using a glutamic acid detection kit (Shanghai enzyme-linked biology Co., ltd.) according to the procedure of the specification. For the other half of the mice of the previous group, and all mice of the ginsenoside Rg5 high dose group and the ginsenoside Rk1 high dose group, sleep was induced by intraperitoneal injection of sodium pentobarbital (45 mg/kg), and sleep latency and sleep duration of each mouse were recorded. Sleep latency is the time from injection of sodium pentobarbital to disappearance of positive response in mice; sleep duration is the time between when the mice lose their positive response to turnover and when they wake up. Mice that did not go to sleep 30 minutes after injection of pentobarbital sodium were knocked out.
2.3 statistical methods
All experimental data were analyzed using Statistical Package for Social Science version 19.0 (SPSS 19.0). The differences between groups were analyzed using a one-way analysis of variance (ANOVA) and a multiple comparison test of Turkey. All experimental data are expressed as mean ± standard deviation.
3. Experimental results
Reference 1 as the prior art shows that ginsenoside Rg5 and ginsenoside Rk1, which have similar structures to ginsenoside Rh4, are central nervous system inhibitors, and can reduce excitatory neurotransmitter Glu and promote sleep. In contrast, the Glu content measurement result of this example shows that the content of glutamic acid in serum is significantly increased after administration of ginsenoside Rh4, and there is no significant difference from the positive drug imipramine (see fig. 3). Glutamate is an excitatory neurotransmitter, and thus it is speculated that ginsenoside Rh4 may have effects of exciting the nervous system and inhibiting sleep, which are in contrast to the effects of ginsenoside Rg5 and ginsenoside Rk 1.
The results of the sleep latency and sleep duration measurement experiments are shown in fig. 4. To evaluate the effect of ginsenoside Rh4 on mouse sleep, we treated mice with pentobarbital sodium (45 mg/kg) to verify the effect of ginsenoside Rh4 on mouse sleep quality. The sleep latency and sleep duration of mice were mainly examined. The results show that ginsenoside Rh4 prolonged the sleep latency of mice in a dose-dependent manner and was not significantly different from the positive drug imipramine (P < 0.01) compared with the blank control group. Meanwhile, ginsenoside Rh4 significantly reduces the sleep duration of mice and has no significant difference (P < 0.0001) from the positive drug imipramine. In addition, we also evaluated the sleep effect of ginsenoside Rg5 and ginsenoside Rk1 on mice, and the results show that ginsenoside Rg5 and Rk1 can significantly reduce the sleep latency (P < 0.01) and significantly increase the sleep duration (P < 0.001) of mice compared with the blank control group.
The experimental result shows that compared with a blank control group, the ginsenoside Rh4 can remarkably increase the sleep latency of mice and reduce the sleep duration of the mice, and shows the effects of exciting the nervous system and inhibiting sleep. And after the ginsenoside Rg5 and the ginsenoside Rk1 are applied, the sleep latency of the mice is obviously reduced and the sleep duration is obviously increased, so that the effects of inhibiting the nervous system and promoting the sleep are shown.
Example 7: influence of ginsenoside Rh4 on GABA related receptor, 5-HT1A receptor of chronically unpredictable stress induced depressed mice
Ginsenoside Rg5 and ginsenoside Rk1, which are known to have similar structures to ginsenoside Rh4, are central nervous system inhibitors, and can reduce excitatory neurotransmitter Glu and promote sleep, and the physiological mechanisms thereof also include: up-regulating the expression of GABAA receptors and GABAB receptors; up-regulating the expression of the 5-HT1A receptor (5-HT, 5-hydroxytryptamine, an inhibitory neurotransmitter). See reference 1. This example investigated whether ginsenoside Rh4 has the above physiological mechanism.
1. Experimental materials
Ginsenoside Rh4 capsules prepared in example 1 were used; imipramine tablet (Shandong Xinyi pharmaceutical Co., ltd.); C57/BL mice, male, weight 20-25g; GABAA α1 antibody (Abcam); GABAB antibodies (PTG); 5-HT1A antibody (Abwax).
2. Experimental method
2.1 Normal mice 30 were equally divided into 3 groups, namely, a normal group (blank control in FIG. 2), a model group (CUMS in FIG. 2), and a CUMS+Rh4 group (Rh 4 in FIG. 2). CUMS operation: mice were given a stimulus daily for 8 consecutive weeks comprising: breaking food, breaking water, clamping tail for 4 min, binding for 4h, wetting padding for 4h, tilting the cage for 45 DEG for 4h, shaking the cage for 10 min and the like. The capsules were dissolved in physiological saline and each group was administered by intragastric administration at a weight of 0.2mL/10 g. Rh4 group was dosed at 40mg/kg. Once daily, administration was continued for 14 days, and physiological saline was administered to the blank group.
2.2 for protein expression assays, 14 days of continuous dosing, bilateral hippocampal ice cubes were dissected and stored at-80 ℃ until use. The tissues were crushed with liquid nitrogen and lysed with ice Ripa lysate. The supernatant was centrifuged and the protein concentration was determined using BCA kit. The samples were mixed with SDS sample buffer and boiled for 5 minutes. An equal amount of protein sample (20 mg) was separated by 10% SDS/PAGE gel electrophoresis and transferred onto PVDF membrane. Incubate overnight with the corresponding primary antibody. The membrane was then placed in horseradish peroxidase (HRP) -conjugated secondary antibodies, incubated for 1 hour at room temperature, and detected on a gel imaging system (Tanon 5200, shanghai, china) using ECL primers. The bands were quantified using a gel imaging system (Tanon 5200, shanghai, china).
3. Experimental results
All experimental results are shown in figure 2.
In terms of behavioral regulation, the role of GABA in the fear circuit has been widely studied, with GABA playing a key role in the acquisition, storage and elimination of fear. Since GABA binds to the corresponding receptor on the premise of exerting its action in the brain, we examined the protein expression of GABA in the corresponding receptor in the hippocampus, and as a result, it was revealed that the protein expression levels of GABAAa1 and GABAB receptors in the model group were significantly decreased as compared with the normal group, and that the expression levels of both proteins were not significantly increased after administration of ginsenoside Rh 4. In addition, we examined the protein expression level of 5-HT1A receptor, which is a regulator for maintaining serotonin activity, and maintaining the dynamic balance of 5-HT1A receptor in brain can affect various functions such as cognition and emotion of organism, and is considered to play a key role in neuronal migration, neural dendritic growth and synapse formation inherent to neural development process. The results showed that the protein expression level of 5-HT1A was significantly reduced in the model group compared to the normal group; the protein expression level of 5-HT1A did not increase significantly after administration of ginsenoside Rh 4. The above demonstrates that ginsenoside Rh4 has a similar structure to Rg5/Rk1, but does not have biological activity affecting GABAergic neurotransmission and maintaining expression of 5-HT1A receptor protein.
Finally, it should be noted that while the above describes embodiments of the invention in terms of drawings, the invention is not limited to the particular embodiments and fields of application described above, which are illustrative, instructive, and not limiting. Those skilled in the art, having the benefit of this disclosure, may effect numerous forms of the invention without departing from the scope of the invention as claimed.
Claims (4)
1. Use of ginsenoside Rh4 in the manufacture of a medicament for inhibiting sleep, wherein the ginsenoside Rh4 is the sole active ingredient of the medicament for increasing sleep latency and decreasing sleep duration.
2. The use according to claim 1, wherein the medicament is in the form of an oral formulation, an injection or a instillation.
3. The use according to claim 2, wherein the oral formulation is a tablet, capsule, granule, powder, drop, fruit juice, pill or syrup.
4. The use according to claim 2, wherein the injection or instillation is in the form of a solution, suspension, emulsion or lyophilized powder.
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| CN1875975A (en) * | 2006-07-06 | 2006-12-13 | 复旦大学 | Application of ocotillol type ginsenoside and its glucoside |
| KR20130115951A (en) * | 2012-04-13 | 2013-10-22 | 경희대학교 산학협력단 | Composition comprising ginsenoside re as an active ingredient for treatment of depression, anxiety or learnig and memory impairments |
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| CN1875975A (en) * | 2006-07-06 | 2006-12-13 | 复旦大学 | Application of ocotillol type ginsenoside and its glucoside |
| KR20130115951A (en) * | 2012-04-13 | 2013-10-22 | 경희대학교 산학협력단 | Composition comprising ginsenoside re as an active ingredient for treatment of depression, anxiety or learnig and memory impairments |
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