CN114177190A - Application of hyperin in preparing medicine for preventing and treating retinal degenerative disease - Google Patents
Application of hyperin in preparing medicine for preventing and treating retinal degenerative disease Download PDFInfo
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Abstract
The invention relates to an application of hyperin in preparing a medicament for preventing and treating retinal degenerative diseases, wherein the hyperin is a compound with the following structural formula or a pharmaceutically acceptable salt thereof,
compared with the prior art, the hyperin has obvious inhibiting effect on the photo-damage-induced photoreceptor cell death, retinal photoreceptor cell degenerative change and retinal damage-related immune inflammatory reaction, can obviously treat and improve retinal degenerative changes, and can be used for preparing and treating various diseases including age-related macular degeneration, retinitis pigmentosa, Stargardt disease, cone-rod cell dystrophy and the likeA medicine for treating retinal degenerative disease.
Description
Technical Field
The invention belongs to the technical field of medicines, and relates to application of hyperin in preparation of a medicine for preventing and treating retinal degenerative diseases.
Background
Photoreceptor cells are the first-order sensory neurons of the retina that sense light stimulation and generate nerve impulses to the central nerve, and play an extremely important role in the process that external information is transmitted to the brain through the visual system. Photoreceptor cells include rod cells, which are responsible for the formation of scotopic vision, and cone cells, which are responsible for photopic and fine vision, among others. Various environmental and genetic factors can cause irreversible damage to photoreceptor cells, and degenerative changes thereof can directly cause visual impairment and even blindness, which is the core pathological basis for diseases including age-related macular degeneration, Stargardt disease, cone-rod dystrophy, retinitis pigmentosa, and the like. The intervention of the death of the photoreceptor cells and the degeneration of the photoreceptors caused by the death of the photoreceptor cells can play an effective role in preventing and treating the occurrence and development of the relevant retinal degenerative diseases.
Age-related macular degeneration is one of the most common major types of retinal degenerative diseases worldwide that severely compromise visual health and even cause blindness. Epidemiological investigation in China shows that the prevalence rate of age-related macular degeneration of people over 50 years old is nearly 15.5%. The aging of the population directly leads to an increasing prevalence of age-related macular degeneration year by year, and has become a serious social public health problem. The clinical manifestations of age-related macular degeneration are generally classified into two types, "dry" and "wet". Dry age-related macular degeneration, which is mostly over 50 years old, occurs. The vision is expressed by slow progressive decline or deformation of visual objects, which accounts for over 90 percent of the incidence of age-related macular degeneration, and no effective treatment medicine exists at present. The cone and rod dystrophy is a group of genetic diseases, caused by ABCA4 gene mutation, mainly characterized by hypopsia, night blindness, visual field reduction and photoreceptor dysfunction, and no effective treatment medicine exists at present. Retinitis pigmentosa is a progressive, dystrophic retinal degenerative disease dominated by genetic factors and involves a diversity of genes, even where the same gene may exhibit different mutations in different patients. Mainly manifested by chronic progressive visual field loss, blindness, night blindness, abnormal electroretinogram, visual disturbance and even blindness, and no effective treatment medicine exists at present.
The hyperin compound is shown as hyperide in English, the Chinese name is hyperin for short, and the chemical structure of the hyperin compound is shown as the following formula:
the activity of hyperin in the intervention of retinal degenerative diseases such as age-related macular degeneration, retinitis pigmentosa, Stargardt disease, cone-rod dystrophy and the like in treating diseases with degeneration of photoreceptors into core pathology has not been reported in the existing literature.
Disclosure of Invention
The invention aims to provide application of hyperin in preparing a medicament for preventing and treating retinal degenerative diseases.
The purpose of the invention can be realized by the following technical scheme:
the application of hyperin in preparing the medicine for preventing and treating the retinal degenerative disease is preferred, and the prepared medicine comprises a single hyperin component or a composition formed by hyperin and other pharmaceutically acceptable components, such as other medicines for treating eye diseases, as effective components.
Further, the hyperin is a compound with the following structural formula or pharmaceutically acceptable salt thereof,
further, the prepared medicine comprises hyperin and pharmaceutically acceptable excipient, carrier or diluent.
Further, the carrier comprises at least one of an additive of an ophthalmic solvent, an additive for injection, an additive for tablet, a surfactant or a stabilizer.
Furthermore, the hyperin is used for preparing a medicament capable of treating and/or preventing retinal degenerative diseases, wherein the retinal degenerative diseases take retinal photoreceptor cell death as a core pathology.
Further, the retinal degenerative disease is retinal degenerative disease caused by at least one of age-related macular degeneration, Stargardt disease, cone-rod dystrophy and retinitis pigmentosa.
Further, the application of hyperin in inhibiting retinal light damage specifically comprises at least one of the following aspects:
1) for preventing or treating retinal photoreceptor cell death;
2) for maintaining retinal outer nuclear layer morphology;
3) for protecting retinal function;
4) for preventing a decrease in the thickness of the outer nuclear layer of the retina;
5) can be used for inhibiting immune inflammatory response related to retinal injury.
Compared with the prior art, the mouse model of retinal light injury is adopted to simulate a common pathological link in the process of generating various retinal degenerative diseases, namely photoreceptor cell death, and the effects of hyperin on resisting photoreceptor cell death, resisting the immune inflammatory response related to retinal injury and preventing and treating the retinal degenerative diseases are researched, and the result shows that the hyperin has a remarkable inhibiting effect on the photoreceptor cell death, the retinal photoreceptor cell degenerative change and the immune inflammatory response related to retinal injury induced by the light injury, and can remarkably treat and improve the retinal degenerative diseases, so that the mouse model of retinal light injury can be used for preparing various retinal degenerative diseases medicaments for treating age-related macular degeneration, retinal pigment degeneration, Stargardt disease, cone-rod cell dystrophy and the like.
Drawings
FIG. 1 shows the results of OCT analysis of the cytoprotective effect of photoreceptors by hyperin treatment;
FIG. 2 is the quantitative comparative analysis of ONL thickness for the effect of hyperoside treatment on retinal protection;
FIG. 3 shows the result of ERG identification of the protective effect of hyperoside treatment on photoreceptor cells (left: a wave, right: b wave);
FIG. 4 is an image of H & E stained sections from a histopathological study of the effects of hyperoside treatment on retinal protection;
FIG. 5 is an image of Rhodopsin/DAPI immunostaining sections, M-opsin/DAPI immunostaining sections, in an immunohistochemical study of the effects of hyperoside treatment on retinal protection;
FIG. 6 shows the GFAP/DAPI immunostaining section image and the Iba1/DAPI immunostaining section image in the study of the activated proliferation of hyperin anti-retinal immunoinflammatory cells.
The notation in the figure is:
no light: normal control group, not receiving light stimulation and not receiving hyperoside treatment;
light _ vehicle: a photodamage model control group, receiving light stimulation and receiving no hyperin treatment;
light _ HYP: the hyperin treatment group received light stimulation and hyperin treatment.
Detailed Description
The invention is described in detail below with reference to the figures and specific embodiments.
The term "acceptable" as used herein means that a prescribed component or active ingredient does not unduly adversely affect the health of the general therapeutic target.
The term "treating", as used herein, includes alleviating, inhibiting or ameliorating the symptoms or conditions of a disease; inhibiting the generation of complications; ameliorating or preventing underlying metabolic syndrome; inhibiting the development of a disease or condition, such as controlling the development of a disease or condition; alleviating the disease or symptoms; regression of the disease or symptoms; alleviating a complication caused by the disease or symptom, or preventing or treating a symptom caused by the disease or symptom. As used herein, a compound or pharmaceutical composition, when administered, can ameliorate a disease, symptom, or condition, particularly severity, delay onset, slow progression, or reduce duration of a condition. Whether fixed or temporary, sustained or intermittent, may be due to or associated with administration.
The term "pharmaceutically acceptable" as used herein refers to a substance, such as a carrier or diluent, which does not diminish the biological activity or properties of the compound and which is relatively non-toxic, e.g., a substance that is administered to an individual without causing unwanted biological effects or interacting in a deleterious manner with any of the components it contains.
The present embodiment is implemented on the premise of the technical solution of the present invention, and a detailed implementation manner and a specific operation process are given, but the scope of the present invention is not limited to the following embodiments.
Example (b):
in the embodiment, the intervention effect of hyperin on a mouse model with retinal photo-damage is determined by a non-invasive OCT (optical coherence tomography) technology, pathology and immunohistochemistry. Research results show that the hyperin can effectively interfere the death of photoreceptor cells and the occurrence of retinal degenerative disease, and has a remarkable protective effect on the structure of the retina.
Method and device
1. Medicine
Hyperin: is purchased from Shanghai leaf Biotechnology GmbH, 482-36-0, Lot # Y08N9X74602, and has purity of more than or equal to 98%.
2. Animal model
The test was performed using 6 week old female Balb/c mice (Slek, Shanghai). Mice were randomly divided into normal control group, photodamage model control group, and hyperoside-treated group. Wherein the normal control group mice and the light injury model control group mice receive 100 muL of 0.5% sodium carboxymethylcellulose solution as control treatment, the hyperin group mice receive 100 muL of hyperin treatment, the hyperin dose is 50mg/kg body weight, and all treatments are administered by intraperitoneal injection. After 30 minutes following the administration treatment, each group of mice received white light stimulation for 30 minutes using a diffuse white cold fluorescent lamp with 15,000lux illumination conditions, except for normal control mice.
3. Retinal optical correlation tomography analysis
On day 7 after drug treatment and light irradiation, the whole structure of the retina of each group of mice was subjected to non-invasive imaging analysis by using sutai 50(50mg/kg), injection seralazine hydrochloride (10mg/kg) in combination with anesthetized mice, and 0.5% tropicamide mydriasis, and optical coherence tomography (OCT 2with Micron IV, Phoenix Research Labs, USA), and the results are shown in fig. 1.
4. Photoreceptor outer nuclear layer thickness measurement analysis
After OCT imaging, the protective effect of each group of retinal structures was quantitatively analyzed by measuring the thickness of the inner and outer retinal photoreceptor outer nuclear layer (ONH) at intervals of 500 μm from the optic nerve head, and the results are shown in fig. 2.
5. Retinal function analysis
On day 7 after drug treatment and light exposure, mice were anesthetized with ketamine (66mg/kg), zeperazine hydrochloride (6.6mg/kg) for injection, and after mydriasis of 0.5% tropicamide, the mice were tested under weak red light (5lux) using ERG (ERG 2, Phoenix Research Labs, USA), and the transmission bands of a-wave and b-wave were measured at 2-1000 Hz and stimulated with different intensities of green light to measure and compare retinal function, with the results shown in fig. 3.
6. Retinal tissue pathology
On day 7 after drug treatment and light irradiation, mice were sacrificed after OCT imaging, the eyeballs were dissected out, the cornea and lens were separated and removed under a microscope, and the remaining eyeball tissues containing retina were fixed with 4% paraformaldehyde. The fixed eyeball tissue was paraffin-embedded and sectioned at a thickness of 4 μm, and further H & E staining was performed, and the results of H & E staining were photographed and analyzed by microscopic observation, and the results are shown in FIG. 4.
On day 7 after drug treatment and light irradiation, mice were sacrificed after OCT imaging, the eyeballs were dissected out, the cornea and lens were separated and removed under a microscope, and the remaining eyeball tissues containing retina were fixed with 4% paraformaldehyde. Freezing embedding and slicing the fixed eyeball tissue. Frozen tissue sections were 12 μ M thick and used for further immunohistochemical staining including Rhodopsin, M-opsin and DAPI immunostaining, immunolabeling rod outer segment, cone stromal sheath and nucleus, respectively, and microscopic imaging and analysis of immunohistochemical results, as shown in FIG. 5.
On day 3 after the light, the mice were sacrificed, the eyeballs were dissected out, the cornea and lens were separated and removed under a microscope, and the remaining eyeball tissues containing the retina were fixed with 4% paraformaldehyde. Freezing embedding and slicing the fixed eyeball tissue. Frozen tissue sections were 12 μ M thick and used for further immunohistochemical staining including GFAP, Iba1 and DAPI immunostaining, immunolabeling Muller glia cells, microglia cells and nuclei, respectively, and immunohistochemical results were photographed and analyzed by microscopic observation, as shown in FIG. 6.
7. Statistical analysis
Data are expressed as means ± s.e, data analysis using one-way ANOVA, and pairwise comparisons between groups using Dunnett-t test. p <0.05 was defined as statistically significant difference.
Second, result in
1. White light irradiation induced severe damage to mouse retina
7 days after the white light irradiation, the retinal structure was imaged with OCT. As shown in fig. 1, white light irradiation induced severe retinal degeneration with photoreceptor cell damage as the main pathological manifestation, mainly manifested as severe damage of ONL 7 days after white light irradiation.
2. Protective effect of hyperin on retina
30 minutes before white light irradiation, mice were treated with solvent or hyperin at a dose of 50mg/kg body weight and a volume of 100 μ L, and were injected intraperitoneally. Retinal structure analysis was performed 7 days after the illumination with OCT.
As shown in fig. 1, hyperin treatment significantly inhibited the occurrence of retinal photo-damage, mainly as evidenced by intact ONL morphology.
Quantitative analysis of ONL thickness (figure 2) showed that illumination resulted in a severe reduction in retinal ONL thickness compared to normal mouse retinas that did not receive illumination, whereas hyperoside treatment provided significant protection to retinal ONL with respective ONL thicknesses that were close to those of normal mouse retinas that did not receive illumination (p <0.05 in the photodamaged model group compared to the normal control group; p <0.05 in the # hyperoside-treated group compared to the photodamaged model group).
The ERG study results (fig. 3) show that the retinal a-wave and b-wave amplitudes of normal mice not receiving light increase with the increase of the stimulation of the detected light, while the retinal a-wave and b-wave amplitudes of the photo-damaged group are significantly reduced, and the retinal a-wave and b-wave amplitudes of hyperin-treated group mice are similar to those of the non-light-receiving group (p <0.05 in the photo-damaged group compared to the normal control group; p <0.05 in the # hyperin-treated group compared to the photo-damaged group).
Histopathological findings (fig. 4) showed that the retinal layers were intact in normal mice that did not receive light, whereas photodamaged mice showed severe reduction in ONL, and the retinal layers were similar in structure in hyperin treated mice to those in the non-light receiving group. Further immunohistochemical findings (FIG. 5) indicated that DAPI-labeled ONL was severely deleted in the retinas of photodamaged mice, and that only residual expression of Rhodopsin, M-opsin was seen compared to normal controls. The expression pattern of Rhodopsin and M-opsin in the hyperin treated group was similar to that of the normal control group, and no significant damage was observed in ONL (Rhodopsin: red; M-opsin: green; DAPI: blue). GFAP-labeled Muller glial cells were predominantly expressed in the nerve fiber layer in the non-illuminated normal control mice (FIG. 6), and the retinas of the photodamaged model mice showed significant GFAP expression in all ONL, IPL and INL, and the pattern of GFAP expression in the hyperin-treated group was similar to that of the normal control group (GFAP: red; DAPI: blue). The Iba1 labeled microglia were mainly expressed in IPL in normal mouse retina (FIG. 6), the retina of the photodamage model showed a large amount of positive Iba1 expression in both ONL and OPL, and the Iba1 expression pattern of the hyperin treated group was similar to that of the normal control group (Iba 1: red; DAPI: blue).
In conclusion, the research on the retinal photo-damage model by means of OCT imaging, ERG electrophysiology and retinal histopathology shows that the hyperin has a remarkable prevention and treatment effect on the death of retinal photoreceptor cells, the immune inflammatory response related to retinal damage and the occurrence of retinal degenerative disease caused by the immune inflammatory response.
The embodiments described above are described to facilitate an understanding and use of the invention by those skilled in the art. It will be readily apparent to those skilled in the art that various modifications to these embodiments may be made, and the generic principles described herein may be applied to other embodiments without the use of the inventive faculty. Therefore, the present invention is not limited to the above embodiments, and those skilled in the art should make improvements and modifications within the scope of the present invention based on the disclosure of the present invention.
Claims (10)
1. An application of hyperin in preparing medicine for preventing and treating retinal degenerative disease is provided.
2. The application of hyperin in preparing a medicament for preventing and treating retinal degenerative diseases according to claim 1, wherein the hyperin is a compound having the following structural formula, or a pharmaceutically acceptable salt thereof,
3. the use of hyperin in the preparation of a medicament for the prevention and treatment of retinal degenerative diseases as claimed in claim 1, wherein the prepared medicament comprises hyperin in combination with pharmaceutically acceptable excipients, carriers or diluents.
4. The use of hyperin in preparing a medicament for the prevention and treatment of retinal degenerative diseases according to claim 3, wherein the carrier comprises at least one of an additive for ophthalmic solvents, an additive for injection, an additive for tablets, a surfactant or a stabilizer.
5. The use of hyperin according to claim 1 in the preparation of a medicament for the prevention and treatment of retinal degenerative diseases, wherein hyperin is used in the preparation of a medicament for the treatment and/or prevention of retinal degenerative diseases.
6. The use of hyperin in the preparation of a medicament for the prevention and treatment of retinal degenerative diseases according to claim 5, wherein the retinal degenerative diseases are retinal degenerative diseases caused by age-related macular degeneration.
7. The use of hyperin in the preparation of a medicament for the prevention and treatment of retinal degenerative disease according to claim 5, wherein the retinal degenerative disease is caused by Stargardt disease.
8. The use of hyperin in the preparation of a medicament for the prevention and treatment of a retinal degenerative disease according to claim 5, wherein the retinal degenerative disease is caused by cone-rod dystrophy.
9. The use of hyperin in the preparation of a medicament for the prevention and treatment of retinal degenerative diseases according to claim 5, wherein the retinal degenerative diseases are retinal degenerative diseases caused by retinitis pigmentosa.
10. The use of hyperin according to claim 1 in the preparation of a medicament for the prevention and treatment of retinal degenerative diseases, wherein the use of hyperin is in at least one of the following aspects:
1) for preventing or treating retinal photoreceptor cell death;
2) for maintaining retinal outer nuclear layer morphology;
3) for protecting retinal function;
4) for preventing a decrease in the thickness of the outer nuclear layer of the retina;
5) can be used for inhibiting immune inflammatory response related to retinal injury.
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| JUN KIM等: "Hyperoside (quercetin-3-o-β-D-galactopyranoside) protects A2E-laden retinal pigmented epithelium cells against UVA and blue light-induced apoptosis in vitro and in vivo" * |
| 朱蓓菁等: "菟丝子明目效应相关临床应用及药理学研究进展" * |
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