CN114832006A - 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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Images
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
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- 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
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Abstract
The application discloses application of ginsenoside Rh4 in preparing a medicine for inhibiting sleep. The application also discloses application of the ginsenoside Rh4 in preparing a medicine for increasing the content of glutamic acid in peripheral blood, a medicine for treating hypersomnia and a central nervous system excitation medicine. Wherein ginsenoside Rh4 is used as the 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 preparing 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 factors have become an important source of new drugs for treating neurological dysfunction. Ginseng belongs to the Araliaceae family, is a high-value herbaceous plant for long-term use in treating various diseases. Ginsenosides are the main active ingredient of ginseng and have been shown to have various pharmacological effects including antioxidant, anti-inflammatory, antiallergic, antidiabetic and anticancer. In recent years, there has been increasing evidence that some classes 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.G. Sensenoside Rg5/Rk1 associated slide vision aligning the GABAergic/serotonergic signaling path in cadent model.food & Function 11(2020).
Disclosure of Invention
The inventor carries out intensive research on the physiological action of the ginsenoside Rh4 to find that: 1. the ginsenoside Rh4 is similar to ginsenoside Rg5/Rk1 in structure, but is quite opposite to ginsenoside Rg5/Rk1 in physiological action, namely the ginsenoside Rh4 not only does not reduce but also increases excitatory neurotransmitter Glu; 2. ginsenoside Rh4 also has no activity of up-regulating the expression of GABAA and GABAB receptors, and up-regulating the expression of 5-HT1A receptor; 3. ginsenoside Rh4 is a central nervous system stimulant and can inhibit sleep.
Therefore, the invention aims to provide the application of ginsenoside Rh4 as an active ingredient in preparing a medicament for inhibiting sleep. Moreover, the invention aims to provide the application of the ginsenoside Rh4 as an active ingredient in preparing a central nervous system stimulant. Furthermore, the invention also aims to provide the application of the ginsenoside Rh4 as an active ingredient in preparing a medicament for increasing the content of glutamic acid in peripheral blood. Moreover, the invention also aims to provide the application of the ginsenoside Rh4 as an active ingredient in preparing a medicament for treating hypersomnia.
Namely, the present invention comprises:
1. the application of ginsenoside Rh4 in preparing a medicine for inhibiting sleep, wherein the ginsenoside Rh4 is used as an active ingredient of the medicine.
2. The application of ginsenoside Rh4 in preparing a medicine for increasing the content of glutamic acid in peripheral blood is disclosed, wherein the ginsenoside Rh4 is used as an active ingredient of the medicine.
3. Use of ginsenoside Rh4 in the preparation of a medicament for the treatment of hypersomnia, wherein ginsenoside Rh4 is used as an active ingredient of the medicament.
In the present specification, the excessive sleep means that the sleep time is 110% or more, 120% or more, 130% or more, 140% or more, 150% or more, or 200% or more of the normal sleep time.
4. The application of ginsenoside Rh4 in preparing a central nervous system excitation medicament, wherein the ginsenoside Rh4 is used as an active ingredient of the medicament.
5. The use according to any one of claims 1 to 4, wherein the ginsenoside Rh4 is used as the only active ingredient of the medicament.
6. The use according to any one of items 1 to 4, wherein the medicament is in the form of an oral preparation, an injection or a drip.
7. The use according to any one of items 1 to 4, wherein the oral formulation is a tablet, capsule, granule, powder, drop, juice, pill or syrup.
8. The use according to any one of items 1 to 4, wherein the injection or instillation is a solution, a suspension, an emulsion or a lyophilized powder.
Drawings
FIG. 1 is the structural formula of ginsenoside Rh 4.
FIG. 2 is a graph showing the effect of ginsenoside Rh4 on GABA-related receptors, 5-HT1A receptors in 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 suppressing sleep.
Detailed Description
The present invention will be described in detail below by way of specific examples. It is to be expressly understood that the description is illustrative only and is not intended as a definition of the limits of the invention.
Example 1: ginsenoside Rh4 capsule
Making into capsule (6000 granules, ginsenoside Rh4 content: 100 mg/granule)
Example 2: ginsenoside Rh4 tablet
Making into tablet (5000 tablets, ginsenoside Rh4 content: 100 mg/tablet)
Example 3: ginsenoside Rh4 syrup
Making into syrup (2000 pieces, 10 mL/piece, ginsenoside Rh4 content: 100 mg/piece)
Example 4 ginsenoside Rh4 granule
Making into syrup (6000 bags, 6 g/bag, ginsenoside Rh4 content: 100 mg/bag)
Example 5 ginsenoside Rh4 gel
Making into ointment (1000 tubes, 10 g/tube, ginsenoside Rh4 content: 100 mg/tube)
Example 6: effect of ginsenoside Rh4 on sleep state of mice induced by sodium pentobarbital
1. Experimental Material
The ginsenoside Rh4 capsule prepared in example 1; imipramine tablets (shandong comobian pharmaceutical limited); sodium pentobarbital (Shanghai chemical Co., Ltd., pharmaceutical group, China); C57/BL mice, male, body weight 20-25g
2. Experimental methods
2.1 animal groups and administration methods, dosages, schedules
The animal administration modes are intragastric administration, and C57/BL mice are randomly divided into a blank control group, a imipramine group (15mg/kg), a ginsenoside Rh4 low-dose group (20mg/kg), a ginsenoside Rh4 high-dose group (40mg/kg), a ginsenoside Rg5 high-dose group (40mg/kg) and a ginsenoside Rk1 high-dose group (40 mg/kg). The administration time is 9:00-11:00 in the morning.
2.2 the mice in the above groups were administered continuously for 7 days, and the experiment was carried out 30 minutes after the last administration.
Half of the mice in each group of the blank control group, imipramine group, ginsenoside Rh4 low dose group and ginsenoside Rh4 high dose group were euthanized, orbital blood was collected rapidly and centrifuged (12000r, 4 ℃), and the centrifuged supernatant was extracted and assayed for Glu content using a glutamic acid assay kit (shanghai enzyme-linked biology ltd) according to the procedures described therein. For the other half of the mice in the previous group, and all mice in the high dose group of ginsenoside Rg5 and the high dose group of ginsenoside Rk1, pentobarbital sodium (45mg/kg) was intraperitoneally injected to induce sleep, and the sleep latency and length of sleep were recorded for each mouse. The sleep latency period is the time from the injection of the pentobarbital sodium to the disappearance of the mouse righting reaction; the length of sleep is the time between the disappearance of the mouse righting response and the awakening of the mouse. Mice that did not enter sleep after 30 minutes of pentobarbital sodium injection were culled.
2.3 statistical methods
All experimental data were analyzed using Statistical Package for Social Science version 19.0(SPSS 19.0). Differences between groups were analyzed using one-way analysis of variance (ANOVA) and Turkey's multiple comparison test. All experimental data are expressed as mean ± standard deviation.
3. Results of the experiment
Reference 1 as a 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 results of this example show that the content of glutamic acid in serum was significantly increased after the administration of ginsenoside Rh4, and there was 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 nervous system stimulating and sleep inhibiting effects, which are in direct 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 sodium pentobarbital (45mg/kg) to verify the effect of ginsenoside Rh4 on mouse sleep quality. The sleep latency and the sleep duration of the mice are mainly detected. The results show that the ginsenoside Rh4 dose-dependently prolonged the sleep latency of mice compared to the blank control group and was not significantly different from the positive drug imipramine (P < 0.01). Meanwhile, the ginsenoside Rh4 obviously reduces the sleep duration of the mice and has no obvious difference with the positive drug imipramine (P is less than 0.0001). In addition, we also evaluated the effect of ginsenoside Rg5 and ginsenoside Rk1 on sleep in mice, and the results showed that ginsenoside Rg5 and Rk1 significantly reduced the sleep latency (P < 0.01) and significantly increased the sleep duration (P < 0.001) of mice compared to the blank control group.
The experimental result shows that compared with a blank control group, the ginsenoside Rh4 can obviously increase the sleep latency of a mouse and reduce the sleep duration of the mouse, and has the effects of exciting the nervous system and inhibiting the sleep. After the application of the ginsenoside Rg5 and the ginsenoside Rk1, the sleep latency of the mice is remarkably reduced, the sleep duration is remarkably increased, and the effects of inhibiting the nervous system and promoting sleep are shown.
Example 7: effect of ginsenoside Rh4 on GABA-related receptors, 5-HT1A receptors in chronic unpredictable stress-induced depressed mice
Ginsenoside Rg5 and ginsenoside Rk1 with similar structures to ginsenoside Rh4 are known to be central nervous system inhibitors, which can reduce excitatory neurotransmitter Glu and promote sleep, and the physiological mechanisms also include: up-regulating the expression of GABAA and GABAB receptors; up-regulates 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 Material
The ginsenoside Rh4 capsule prepared in example 1 was used; imipramine tablets (shandong comobian pharmaceutical limited); C57/BL mice, male, body weight 20-25 g; GABAA α 1 antibody (Abcam); GABAB antibodies (PTG); 5-HT1A antibody (Abways).
2. Experimental methods
2.1 Normal mice 30, evenly divided into 3 groups, i.e., normal group (white control in FIG. 2), model group (CUMS in FIG. 2), CUMS + Rh4 group (Rh 4 in FIG. 2). CUMS operation: one stimulus given to mice daily for 8 consecutive weeks included: food is stopped, water is stopped, the tail is clamped for 4 minutes, binding is carried out for 4 hours, the padding is wetted for 4 hours, the cage is inclined for 4 hours at an angle of 45 degrees, and the cage is shaken for 10 minutes. The capsules are dissolved in normal saline, and each group is administrated by intragastric administration according to 0.2mL/10g body weight. The dosage of Rh4 group administration is 40 mg/kg. The administration was once daily for 14 days, and the blank control group was given physiological saline.
2.2 for protein expression assays, administration was continued for 14 days, with double sided hippocampus ice cubes cut open and stored at-80 ℃ until use. The tissue was crushed with liquid nitrogen and lysed with ice Ripa lysate. The supernatant was centrifuged and the protein concentration was determined using the BCA kit. The samples were mixed with SDS sample buffer and boiled for 5 minutes. Equal amounts of protein samples (20mg) were separated by electrophoresis on 10% SDS/PAGE gels and transferred to PVDF membrane. The corresponding primary antibody was used for overnight incubation. Then, the membrane was placed in a horseradish peroxidase (HRP) conjugated secondary antibody, incubated at room temperature for 1 hour, and detected on a gel image system (Tanon 5200, Shanghai, China) using ECL primers. The bands were quantified using a gel imaging system (Tanon 5200, Shanghai, China).
3. Results of the experiment
All experimental results are shown in figure 2.
In terms of behavioral modulation, the role of GABA in the fear circuit has been extensively studied, with GABA playing a key role in acquisition, storage and elimination of fear. The precondition that GABA plays the role in the brain is combined with the corresponding receptor, therefore, the protein expression of the corresponding receptor of GABA in hippocampus is detected, and the result shows that compared with a normal group, the protein expression level of GABAAa1 and GABAB receptor of a model group is obviously reduced, and the protein expression level of the two proteins is not obviously increased after ginsenoside Rh4 is applied. In addition, we also examined the protein expression level of 5-HT1A receptor, 5-HT1A receptor is a regulator for maintaining serotonin activity, and maintaining the dynamic balance of 5-HT1A receptor in brain can affect multiple functions of organism such as cognition and emotion, and is thought to play a key role in neuronal migration, neurodendritic growth and synapse formation inherent in the 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 is not increased after the ginsenoside Rh4 is applied. The above proves that the ginsenoside Rh4 has a structure similar to that of Rg5/Rk1, but does not have biological activity of influencing GABAergic nerve signal paths and maintaining the expression of 5-HT1A receptor proteins.
Finally, it should be noted that while the above describes exemplifying embodiments of the invention with reference to the accompanying drawings, the invention is not limited to the embodiments and applications described above, which are intended to be illustrative and instructive only, and not limiting. Those skilled in the art, having the benefit of this disclosure, may effect numerous modifications to the disclosed embodiments without departing from the scope of the invention as defined by the appended claims.
Claims (8)
1. The application of ginsenoside Rh4 in preparing a medicine for inhibiting sleep, wherein the ginsenoside Rh4 is used as an active ingredient of the medicine.
2. The application of ginsenoside Rh4 in preparing a medicine for increasing the content of glutamic acid in peripheral blood is disclosed, wherein the ginsenoside Rh4 is used as an active ingredient of the medicine.
3. Use of ginsenoside Rh4 in the preparation of a medicament for the treatment of hypersomnia, wherein ginsenoside Rh4 is used as an active ingredient of the medicament.
4. The application of ginsenoside Rh4 in preparing a central nervous system excitation medicament, wherein the ginsenoside Rh4 is used as an active ingredient of the medicament.
5. The use according to any one of claims 1 to 4, wherein ginsenoside Rh4 is used as the sole active ingredient of the medicament.
6. The use according to any one of claims 1 to 4, wherein the medicament is in the form of an oral preparation, an injection or a drip.
7. The use according to any one of claims 1 to 4, wherein the oral formulation is a tablet, capsule, granule, powder, drop, juice, pill or syrup.
8. The use according to any one of claims 1 to 4, wherein the injection or instillation is a solution, suspension, emulsion or lyophilized powder.
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