CN117503909A - Application of lycium barbarum glycopeptide in preparing medicine for preventing or treating presbycusis - Google Patents
Application of lycium barbarum glycopeptide in preparing medicine for preventing or treating presbycusis Download PDFInfo
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Abstract
The invention belongs to the technical field of biological medicines, and particularly relates to application of wolfberry glycopeptides in preparation of medicines for preventing or treating presbycusis. Experimental results show that the medlar glycopeptide has a protective effect on the hearing loss of mice in a fast aging mouse model. In addition, the medlar glycopeptide has a protective effect on cell aging of the cochlear hair cell line of the HEI-OC1 mouse, which is cultured in vitro. Therefore, the medlar glycopeptide can be effectively used for preventing and treating senile deafness as a traditional Chinese medicinal material extract product, has the prospect of developing medicaments for preventing and treating senile deafness, provides more treatment options for clinically preventing or treating senile deafness, and has important social benefit and economic value.
Description
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to application of wolfberry glycopeptides in preparation of medicines for preventing or treating presbycusis.
Background
Hearing impairment is one of the most popular ear diseases worldwide. According to World Health Organization (WHO) statistics, it is shown that about 4.66 million people worldwide are suffering from hearing impairment, and by 2050 will rise to 9 hundred million people. China is the country with the largest hearing disabilities in the world, and the hearing disabilities are up to 2780 thousands. With aging population, abuse of ototoxic drugs, noise and environmental pollution, the population suffering from deafness and hearing impairment has a tendency to rise year by year, and deafness has become a global health problem affecting society and economy, wherein sensorineural deafness accounts for about 63% of deaf patients, and cochlear hair cell damage is one of the main causes of sensorineural deafness. At present, although the hearing of a patient is improved to a certain extent by the common clinical hearing aid and artificial cochlea transplantation, the problems cannot be fundamentally solved, and the effect of the artificial cochlea is completely dependent on the number and the quality of hair cells, so that finding out the cause of hair cell damage and the damage mechanism is important for preventing and treating sensorineural deafness.
Presbysis (presbysis), also known as Age-related hearing loss (Age-related hearing loss, AHL), is a complex degenerative disease, with the Age, the patient's binaural hearing is symmetric and progressively decreasing, characterized by decreased auditory function, including increased hearing threshold and decreased frequency. The World Health Organization (WHO) estimated that by 2025, the population over 60 years would reach 12 million people, and in this population, 5 million people were predicted to suffer presbycusis. Presbycusis has serious harm to physical and psychological health of the elderly, such as physiology, cognition, emotion, behavior, social function and the like, and can also lead to social isolation, depression and spelt.
AHL is a complex, multifactorial disease whose causative factors are related to environmental, genetic, health, and nutritional factors. Cochlear hair cell loss or spiral ganglion degeneration is a major pathological feature of presbycusis. In the occurrence of presbycusis, the main pathological condition of the cochlea is loss of hair cells, especially top-turning outer hair cells, and hair cell loss turns from top to bottom, extending from outer hair cells to inner hair cells; in mammals, the loss of such hair cells is irreversible and the molecular basis of hair cell death associated with presbycusis has not been studied completely. In the face of the current situation of severe presbycusis, the development of effective protective drugs is one of the important points of the auditory field research in recent years. However, there are no therapeutic means and drugs which are clinically effective for preventing or treating presbycusis.
The fructus Lycii is dried mature fruit of Lycium barbarum L. Of Solanaceae, has effects of nourishing liver and kidney, and replenishing essence for improving eyesight, and can be used for treating asthenia essence deficiency, soreness of waist and knees, dizziness and tinnitus, etc. The wolfberry polysaccharide is a natural macromolecular water-soluble polysaccharide extracted from wolfberry, and researches show that the wolfberry polysaccharide has pharmacological effects of regulating immunity, reducing blood sugar and blood lipid, resisting aging, resisting oxidation, resisting tumor and the like. In addition, researches show that the lycium barbarum polysaccharide can protect neuronal cell injury and exert neuroprotection effects such as anti-depression and the like. In recent years, the lycium barbarum glycopeptide (Lycium barbarum Glycopeptide, LBGP) extracted from lycium barbarum polysaccharide has been paid attention to, and compared with the lycium barbarum polysaccharide, the lycium barbarum glycopeptide has the advantages of removing inorganic salts and various monosaccharides, and the study shows that the lycium barbarum glycopeptide has stronger immune activity and anti-aging effect.
At present, no report on the aspect of preventing or treating presbycusis by using medlar glycopeptides is yet seen.
Disclosure of Invention
In order to solve the problem of insufficient medicine for effectively preventing or treating presbycusis, which is clinically used at present, the inventor adopts a modern medicine research method to deeply develop and utilize natural products, and combines a great deal of pharmacodynamics experiment research, thereby providing the application of the medlar glycopeptide in preparing the medicine for preventing or treating presbycusis.
Specifically, the invention is realized through the following technical schemes:
the invention provides application of lycium barbarum glycopeptide in preparing a medicament for preventing or treating presbycusis.
Preferably, the present invention provides the use of lycium barbarum glycopeptide as the sole active ingredient in the manufacture of a medicament for preventing or treating presbycusis.
Alternatively, in the above use, the symptoms of presbycusis include one or more of: tinnitus, hearing loss or hearing loss.
Alternatively, in the above use, the matrimony vine glycopeptide reduces the hearing threshold of presbycusis patients from moving up and increases the survival rate of cochlea hair cells.
Alternatively, in the above application, the content of the lycium barbarum glycopeptide is more than or equal to 60%, the content of uronic acid is more than or equal to 5%, and the content of protein is 20-33%, and the state of the lycium barbarum glycopeptide is powder with purity more than or equal to 90%.
Alternatively, in the above use, the wolfberry glycopeptide has a molecular weight of 88kD as determined by SDS-PAGE, a sugar content of 70% by weight and a sugar composition of ArA: GAl:glc=2.5:1.0:1.0 by mole ratio.
Alternatively, in the above use, the medicament comprises a prophylactically or therapeutically effective amount of a lycium barbarum glycopeptide and a pharmaceutically acceptable carrier.
Alternatively, in the above use, the medicament is an oral preparation, an injection or an external preparation.
Preferably, the oral preparation is selected from oral liquid, tablets, powder, capsules or granules.
Further preferably, the injection is selected from a water injection or a sterile powder for injection.
Further preferably, the external preparation is selected from drops, sprays or gels.
Alternatively, in the above use, the medicament is suitable for various modes of administration, which may be oral administration or parenteral administration or in-ear administration.
Preferably, the parenteral administration includes intravenous injection, intramuscular injection, subcutaneous injection, and the like.
Compared with the prior art, the invention has the following beneficial effects:
the invention combines the advantages of China in the research of natural products, and discovers the new application of the natural product medlar glycopeptide in preventing or treating presbycusis for the first time. Experimental results show that the medlar glycopeptide has a protective effect on the hearing loss of mice in a fast aging mouse model. In addition, the medlar glycopeptide has a protective effect on cell aging of the cochlear hair cell line of the HEI-OC1 mouse, which is cultured in vitro. Therefore, the medlar glycopeptide can be effectively used for preventing and treating senile deafness as a traditional Chinese medicinal material extract product, has the prospect of developing medicaments for preventing and treating senile deafness, provides more treatment options for clinically preventing or treating senile deafness, and has important social benefit and economic value.
Detailed Description
The inventor adopts a modern drug research method to deeply develop and utilize natural products, and discovers that the medlar glycopeptide can prevent or treat presbycusis for the first time through a large number of screening. The present invention has been completed on the basis of this finding.
The dosage form of the medicament of the invention is preferably an oral preparation, an injection or an external preparation.
Preferably, the oral preparation is selected from oral liquid, tablets, powder, capsules or granules. Further preferably, the injection is selected from a water injection or a sterile powder for injection. Further preferably, the external preparation is selected from drops, sprays or gels.
The medicament of the present invention is suitable for various modes of administration, which may be oral administration or parenteral administration or in-ear administration. Such parenteral administration includes intravenous injection, intramuscular injection, subcutaneous injection, and the like.
The pharmaceutically acceptable carrier refers to a conventional pharmaceutical carrier in the field of pharmaceutical preparations, and is selected from one or more of a filler, an adhesive, a disintegrating agent, a lubricant, a suspending agent, a wetting agent, a pigment, a flavoring agent, a solvent and a surfactant.
Fillers of the present invention include, but are not limited to, starch, microcrystalline cellulose, sucrose, dextrin, lactose, powdered sugar, dextrose, and the like; such lubricants include, but are not limited to, magnesium stearate, stearic acid, sodium chloride, sodium oleate, sodium lauryl sulfate, poloxamers, and the like; such binders include, but are not limited to, water, ethanol, starch slurry, syrup, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, sodium alginate, polyvinylpyrrolidone, and the like; such disintegrants include, but are not limited to, starch effervescent mixtures, i.e., sodium bicarbonate and citric acid, tartaric acid, low-substituted hydroxypropyl cellulose, and the like; such suspending agents include, but are not limited to, polysaccharides such as acacia, agar, alginic acid, cellulose ethers, carboxymethyl chitin and the like; such solvents include, but are not limited to, water, balanced salt solutions, and the like.
The various formulations described above may be prepared according to conventional techniques in the pharmaceutical formulation arts.
The "lycium barbarum glycopeptide" can be obtained by extracting and separating plants such as lycium barbarum containing the active ingredient by adopting a natural product extraction method conventional in the art, and can also be purchased from commercial products. In particular, lycium barbarum glycopeptides may be prepared using the preparation method described in CN 107021995B. The wolfberry glycopeptide is taken as the most effective active ingredient in wolfberry pulp and is the essence of wolfberry. Modern pharmacological tests have fully proved that the medlar glycopeptide can remarkably improve the immune function of organisms, participate in the immune regulation of the organisms and various activities of living cells, and has certain effects of reducing blood pressure, reducing blood fat, reducing blood sugar, resisting inflammation, resisting oxidation, resisting aging, resisting tumor and the like. The high biological activity of the lycium barbarum glycopeptide makes the lycium barbarum glycopeptide have hundreds of times stronger immune activity than the oral polysaccharide which is commonly used clinically at present. Experiments further prove that the medlar glycopeptide has various pharmacological activities of resisting oxidation, resisting aging, regulating immunity, inhibiting tumor cell replication and the like.
In the medical use described herein, the administration time, the administration frequency, and the like of the lycium barbarum glycopeptide are required depending on the specific diagnosis result of the condition, and are within the technical scope of those skilled in the art.
The application of an animal treatment regimen to the human body will also be readily accomplished by one of ordinary skill in the art by scaling the effective dose of all drugs to the human body by the effective dose of the drug to the animal.
In order to better understand the essence of the present invention, the novel use of lycium barbarum glycopeptides for preventing or treating presbycusis in the pharmaceutical field is further illustrated in the following detailed description section using pharmacodynamic experiments and results thereof.
The invention will be further illustrated with reference to specific examples. It should be understood that the detailed description and specific examples are intended for purposes of illustration only and are not intended to limit the scope of the invention.
The specific techniques or conditions are not identified in the examples and are described in the literature in this field or are carried out in accordance with the product specifications. The reagents or equipment used were conventional products available for purchase through regular channels, with no manufacturer noted.
The experimental methods in the following examples are conventional methods unless otherwise specified. The test materials used in the examples described below, unless otherwise specified, are all commercially available products.
Example 1: protective effect of Lycium barbarum glycopeptides on hearing loss of mice in rapidly aging mice model
1. Animal grouping and experiment
Mice of the rapid aging model, samp8 mice (purchased from hangzhou child source laboratory animal technologies limited), were randomly selected into 2 groups: samp8 control and Lycium barbarum glycopeptide administration (20 mg/kg). The Lycium barbarum glycopeptide group mice were administered by gastric administration from day 30, and Auditory Brainstem Response (ABR) audiometry was performed on the mice at 30, 45, 60, 75, 90, 105, 120, 135, 150, 165, 180 days.
2. Auditory Brainstem Response (ABR)
Mice were anesthetized by intraperitoneal injection of sodium pentobarbital according to body weight. The anesthetized mouse is placed in a constant temperature pad at 37 ℃ in a shielding chamber, a detection electrode is inserted into the central subcutaneous position of the top of the mouse, a reference electrode is inserted into the subcutaneous position below the left auricle of the mouse, and a grounding electrode is inserted into the outer skin of the thigh of the mouse. The acoustic wave device is arranged at the left ear of the mouse, then 4kHz, 8kHz, 12kHz, 16 kHz, 24kHz and 32kHz pure tones are used for stimulation respectively, the acoustic wave intensity is gradually reduced from 90dB to 10dB until the repeatable waveform is not recorded, and finally the stimulation intensity recorded to the repeatable waveform is the threshold of the hearing of the mouse.
3. Mouse cochlea hair cell immunofluorescence count
The mice were sacrificed and rapidly broken, the auditory bulb was opened, the obtained cochlear tissue was fixed with 4% Paraformaldehyde (PFA) for 24 hours, then EDTA decalcified, and after decalcification was completed, the cochlea was placed in PBS, and the basilar membrane was peeled off under an anatomic lens. Immunofluorescent staining was performed with hair cell marker (Myosin 7 a) and phalloidin (phalloidin), respectively. The count statistical analysis was performed on the cochlear hair cells of the mice by observation under a ZEISS 900 laser confocal microscope.
The statistical analysis method comprises the following steps: statistical significance differences were calculated by one-way analysis of variance (ANOVA) and Dunnett test using Graphpad prism 9.0 software, P-values <0.05 were considered significant differences.
Example 2: protective effect of matrimony vine glycopeptide on cell aging of hair cells in vitro cultured mouse cochlea
The experimental method comprises the following steps: culturing the basement membrane of a P3C 57BL/6J mouse, damaging the basement membrane for 72 hours by adopting 10mg/mL, 20mg/mL, 40mg/mL, 80mg/mL and 100mg/mL of D-gal, collecting the cultured cochlea, detecting the quantity of hair cells by immunofluorescence Myosin7a staining, detecting the change of senescence marker protein by Western blot, and detecting the copy number of mitochondrial DNA by fluorescence quantitative PCR to judge the senescence condition of the hair cells.
Example 3: protective effect of Lycium barbarum glycopeptide on cell aging of HEI-OC1 mouse cochlear hair cell line
The experimental method comprises the following steps: in HEI-OC1 cell line, add 1mg/mL, 2mg/mL, 5mg/mL, 10mg/mL and 15mg/mL of D-gal to treat OC1 cells, and detect cell death by CCK-8 and TUNEL; the appropriate D-gal concentration was selected for subsequent experiments by determining cell senescence by galactosidase staining.
It will be apparent to those skilled in the art that various modifications and variations can be made to the present invention without departing from the spirit or scope of the invention. Thus, it is intended that the present invention also include such modifications and alterations insofar as they come within the scope of the appended claims or the equivalents thereof.
Claims (8)
1. Application of fructus Lycii glycopeptide in preparing medicine for preventing or treating senile deafness is provided.
2. The use of claim 1, the symptoms of presbycusis comprising one or more of: tinnitus, hearing loss or hearing loss.
3. Use according to claim 1 or claim 2, characterized in that: the medlar glycopeptide reduces the hearing threshold of the presbycusis patient from moving upwards and improves the survival rate of cochlea hair cells.
4. Use according to any one of claims 1 to 3, characterized in that: the content of the medlar glycopeptide is more than or equal to 60 percent, the content of uronic acid is more than or equal to 5 percent, the content of protein is 20-33 percent, and the medlar glycopeptide is powder with purity more than or equal to 90 percent.
5. Use according to any one of claims 1 to 4, characterized in that: the medicament comprises a prophylactically or therapeutically effective amount of a lycium barbarum glycopeptide and a pharmaceutically acceptable carrier.
6. Use according to claim 5, characterized in that: the medicine is an oral preparation, an injection or an external preparation.
7. Use according to claim 6, characterized in that: the oral preparation is selected from oral liquid, tablets, powder, capsules or granules; the injection is selected from water injection or sterile powder for injection; the external preparation is selected from drops, spray or gel.
8. Use according to any one of claims 5 to 7, characterized in that: the medicament is suitable for oral administration or parenteral administration or for in-ear administration.
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