CN114732805A - New application of magnolol - Google Patents
New application of magnolol Download PDFInfo
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- CN114732805A CN114732805A CN202210420973.5A CN202210420973A CN114732805A CN 114732805 A CN114732805 A CN 114732805A CN 202210420973 A CN202210420973 A CN 202210420973A CN 114732805 A CN114732805 A CN 114732805A
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- retinal
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- ocular hypertension
- microglia
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Abstract
The invention provides a new application of magnolol. The invention discloses that magnolol can reduce retinal ganglion cell loss and retinal damage caused by ocular hypertension; improving visual function reduction caused by ocular hypertension; inhibiting inflammatory factor production in retinal tissue due to ocular hypertension; reducing the activation of microglia and astrocytes in the retina caused by high intraocular pressure, reducing the polarization of the microglia to the M1 phenotype and promoting the polarization of the microglia to the M2 phenotype; relieving a decrease in blood retinal barrier associated proteins in retinal tissue caused by ocular hypertension; reduce the increase of the proportion of Th1, Th2 and Th17 cells in the reflux lymph nodes of eyes caused by high intraocular pressure. Magnolol can be used for preventing, treating or relieving optic nerve injury caused by glaucoma disease.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a new application of magnolol.
Background
Glaucoma is the first irreversible blinding eye disease worldwide, and the number of glaucoma patients is estimated to reach 1.12 hundred million by 2040 years. Glaucoma can cause optic nerve damage and visual field defect, endanger human health, reduce quality of life and influence social and economic development. Ocular hypertension is considered to be a major risk factor for glaucoma, which results in loss of retinal ganglion cells. However, strategies for lowering intraocular pressure have received little success in a significant proportion of glaucoma patients, and in recent years, neuroinflammatory injury due to ocular hypertension has received much attention.
Magnolol is a small molecular substance extracted from cortex Magnolia officinalis, which is a bisphenol structure. It has been reported to have various effects including anti-inflammatory, anti-tumor, anti-oxidant, neuroprotective, anti-angiogenic, antibacterial, etc. Currently, studies have shown that magnolol can inhibit the release of inflammatory factors from RAW 264.7 cells and down-regulate NF κ B activity. In an oxygen-induced mouse retinopathy model, magnolol can alleviate retinal vascular malformation and proliferation. In a trimethyltin-induced mouse model, magnolol can reduce hippocampus damage and inhibit inflammation and glial cell activation. However, there is no report on the optic nerve protection effect of magnolol in glaucoma diseases characterized by ocular hypertension.
Disclosure of Invention
In view of the above-mentioned deficiencies of the prior art, the present invention provides a new use of magnolol.
In a first aspect, the present invention provides the use of the compound magnolol in the manufacture of a chemical product having at least one of the following functions:
1) reducing retinal ganglion cell loss and retinal damage caused by ocular hypertension;
2) improving visual function reduction caused by ocular hypertension;
3) inhibiting inflammatory factor production in retinal tissue due to ocular hypertension;
4) reducing the activation of microglia and astrocytes in the retina caused by high intraocular pressure, reducing the polarization of the microglia to the M1 phenotype and promoting the polarization of the microglia to the M2 phenotype;
5) relieving decrease of blood retinal barrier-associated protein in retinal tissue due to ocular hypertension;
6) reduce the increase of the proportion of Th1, Th2 and Th17 cells in the reflux lymph nodes of eyes caused by high intraocular pressure.
In the invention, the magnolol is a compound shown as a formula (I) or a pharmaceutically acceptable salt of the compound shown as the formula (I)
The chemical of the invention necessarily comprises magnolol, and the magnolol is used as an effective component of the functions.
In the chemical product of the invention, the effective component for playing the functions can be magnolol only, and can also comprise other chemicals with similar functions.
The chemical product of the invention can be a single-component substance or a multi-component substance.
The form of the chemical product of the invention is not particularly limited, and can be various forms of solid, liquid, gel, semifluid, aerosol and the like.
The fields of the chemical products can be the fields of medicines, health care products, foods and the like.
In some embodiments of the invention, the chemical is a drug that prevents, treats, or reduces retinal degeneration caused by neuroinflammation.
The retinal degeneration caused by neuroinflammation includes glaucoma disease, age-related macular degeneration or diabetic retinopathy.
The optic nerve protection effect of magnolol includes, but is not limited to glaucoma disease, age related macular degeneration, and diabetic retinopathy. In the invention, the optic nerve protection effect of magnolol is realized mainly by regulating inflammatory and immune reactions, and glaucoma, age-related macular degeneration, diabetic retinopathy and the like are related to retinal degeneration caused by nerve inflammatory reactions.
In a second aspect, the present invention provides a medicament for preventing, treating or reducing optic nerve damage caused by glaucoma disease, the medicament comprising an effective amount of magnolol.
The pharmaceutical preparation also comprises a pharmaceutically acceptable carrier or auxiliary material or a composition thereof.
Compared with the prior art, the invention has the following beneficial effects:
1. existing glaucoma drugs are primarily used to lower intraocular pressure by reducing aqueous humor production, increasing aqueous humor outflow, and the like, but there is increasing evidence that controlling intraocular pressure does not address the problem of optic nerve damage in all glaucoma patients. Animal experiments show that the compound magnolol can remarkably reduce retinal ganglion cell loss of a mouse with an ocular hypertension model, relieve retinal tissue thinning, improve retinal function and reduce retinal tissue inflammation and immune response on an animal level, and can be used for preventing and treating retinal degeneration caused by neuroinflammation, particularly glaucoma diseases.
2. The compound magnolol provided by the invention is already applied to dietary supplements and cosmetics, is also clinically used as an antibacterial drug, and is simple in preparation method, stable in property, safe to use and easy to control, so that the compound magnolol is suitable for clinical application and popularization.
Drawings
Fig. 1 is a graph and statistics of retinal ganglion cell loss and retinal tissue thickness thinning in a mouse model of ocular hypertension reduced by magnolol. A is a representative diagram of immunofluorescence staining of a retinal slide; b is a statistical chart of retinal ganglion cell counts; c is a representative view of HE staining of a retinal tissue section; d is a statistical chart of the thicknesses of the retinal nerve fiber layer and the inner plexiform layer of the retinal tissue section. CON is a control group; AOH1d is one day group for ocular hypertension modeling; AOH7d was a 7-day group for ocular hypertension modeling; AOH7d + MAG was administered to the magnolol intraperitoneal injection group for 7 days at the same time for ocular hypertension modeling. Data are presented as mean ± standard deviation, single factor analysis of variance, turkey test; indicates that there is a statistical difference between the two groups, p < 0.05; indicates that there is a statistical difference between the two groups, p < 0.01; indicates that there was a statistical difference between the two groups, p < 0.001.
Fig. 2 is a diagram and statistics of results of retinal function of a mouse model for improving ocular hypertension by magnolol. A is a diagram representing the detection of electrophysiological dark adaptation of the retina; the B picture is a statistical picture of a wave and a wave B of the electrophysiological dark adaptation detection of the retina. AOH is an ocular hypertension modeling module; AOH + MAG is used for ocular hypertension molding and is simultaneously given to an intraperitoneal injection magnolol group. Data are presented as mean ± standard deviation, single factor analysis of variance, turkey test; indicates that there is a statistical difference between the two groups, p < 0.05; indicates that there was a statistical difference between the two groups, p < 0.01.
Figure 3 is a graph and statistics showing the results of magnolol reducing the level of retinal tissue inflammatory factors. A-D is a qPCR experimental data statistical chart of inflammatory factors TNF-alpha, IL-1 beta, IL-6 and INOS; e picture is a representative picture of Westernblot experimental protein expression level; f is a statistical graph of protein expression level; g picture is a representation picture of the immunofluorescence positioning and relative expression quantity of the TNF-alpha protein of the retina section; and the H picture is a representation picture of the immunofluorescence positioning and relative expression quantity of the IL-6 protein of the retina section. CON is a control group; MAG is an intraperitoneal injection magnolol group; AOH is an ocular hypertension modeling module; AOH + MAG is for high intraocular pressure molding and is given to magnolol abdominal cavity injection group at the same time; GCL is the ganglion cell layer; IPL is inner plexiform layer; INL is the inner core layer. Data are presented as mean ± standard deviation, single factor analysis of variance, turkey test; indicates that there is a statistical difference between the two groups, p < 0.05; indicates that there was a statistical difference between the two groups, p < 0.01.
FIG. 4 is a graph of the results and statistics for magnolol reducing retinal glial activation, inhibiting the microglial M1 phenotype, promoting the microglial M2 phenotype. Panel A is a representation of immunofluorescence of microglia cells (labeled with protein IBA 1) from a retinal section; b is a representation diagram of the expression level of the Westernblot experimental protein, CD86 is M1 related protein, CD206 is M2 related protein; c is a statistical graph of protein expression levels; d is a qPCR experimental data statistical chart of CD86 and CD 206; FIG. E is a representation of immunofluorescence of astrocytes (labeled with protein GFAP) on retinal sections; the F picture is a representative picture of the expression level of the Westernblot experimental protein, and ZO1 and VE-cadherin are blood retina barrier related proteins; g is a statistical graph of protein expression levels. CON is a control group; AOH is an ocular hypertension modeling module; AOH + MAG is for high intraocular pressure molding and is given to magnolol abdominal cavity injection group at the same time; data are presented as mean ± standard deviation, single factor analysis of variance, turkey test; indicates that there is a statistical difference between the two groups, p < 0.05; indicates that there was a statistical difference between the two groups, p < 0.01.
FIG. 5 is a graph showing the results of the ratio of Th1, Th2 and Th17 cells in the ocular reflux lymph node of the magnolol model for reducing ocular hypertension in mice. FIGS. A-C are cytoflow representations of ocular reflux lymph nodes; FIGS. D-F are cell flow statistics of ocular reflux lymph nodes. CON is a control group; AOH is an ocular hypertension modeling module; AOH + MAG is for high intraocular pressure molding and is given to magnolol abdominal cavity injection group at the same time; data are presented as mean ± standard deviation, single factor analysis of variance, turkey test; indicates that there was a statistical difference between the two groups, p < 0.05.
Detailed Description
The invention simulates glaucoma by preparing an ocular hypertension mouse model, adopts magnolol intervention, and detects and statistically analyzes the proportions of retinal ganglion cells, retinal tissue thickness, retinal function, retinal tissue inflammatory factors, glial cell activation, blood retinal barrier related protein and ocular reflux lymph node Th cells of the mouse to find that the magnolol intervention can reduce the retinal ganglion cell loss of the ocular hypertension mouse model, reduce the retinal tissue thickness thinning, reduce the increase of the retinal tissue inflammatory factors, relieve the microglial activation and proinflammatory polarization, promote the microglial cell anti-inflammatory polarization, maintain the blood retinal barrier related protein, and reduce the proportions of the ocular reflux lymph node Th1, Th2 and Th17 cells.
Magnolol (England name: Magnolol, MAG), brown to white fine powder, colorless needle crystal as monomer, molecular weight 266.33, chemical formula C18H18O2The sodium salt has a melting point of 99-101 ℃, is insoluble in water, is soluble in organic solvents and is easily soluble in caustic soda dilute solution to obtain sodium salt. The effective component with antibacterial effect in cortex Magnolia officinalis. Is mainly used as antibacterial and antifungal medicine clinically。
By "pharmaceutically acceptable" is meant that the molecular entities and compositions do not produce adverse, allergic, or other untoward reactions when properly administered to an animal or human.
The "pharmaceutically acceptable carrier or adjuvant" should be compatible with magnolol, i.e. capable of being blended therewith without substantially reducing the efficacy of the pharmaceutical composition under normal circumstances. Specific examples of some substances that can serve as pharmaceutically acceptable carriers or adjuvants are sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium methylcellulose, ethylcellulose and methylcellulose; powdered gum tragacanth; malt; gelatin; talc; solid lubricants, such as stearic acid and magnesium stearate; calcium sulfate; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and cocoa butter; polyols such as glycerol, sorbitol, mannitol and polyethylene glycol; alginic acid; emulsifiers, such as Tween; wetting agents, such as sodium lauryl sulfate; a colorant; a flavoring agent; tabletting agents, stabilizers; an antioxidant; a preservative; pyrogen-free water; isotonic saline solution; and phosphate buffer, and the like. These materials are used as needed to aid in the stability of the formulation or to aid in the enhancement of the activity or its bioavailability or to produce an acceptable mouthfeel or odor upon oral administration.
In the present invention, unless otherwise specified, the pharmaceutical dosage form is not particularly limited, and may be prepared into injection, oral liquid, tablet, capsule, dripping pill, spray, etc., and may be prepared by a conventional method. The choice of the pharmaceutical dosage form should be matched to the mode of administration.
The administration routes of the magnolol provided by the invention include oral administration, transdermal administration, rectal administration, ophthalmic external application, intramuscular injection and the like.
TNF-alpha is a pleiotropic proinflammatory cytokine belonging to the TNF ligand superfamily. TNF- α plays a diverse role in the regulation of a variety of developmental and immune processes, including inflammation, differentiation, lipid metabolism, and apoptosis, and is associated with a variety of diseases.
IL-1 β is an important member of the IL-1 family, which plays an important role in inflammation-related diseases. IL-1 beta has strong proinflammatory activity and can induce various proinflammatory mediators, such as cytokines and chemokines. IL-1. beta. has multiple functions. It has multiple effects on various cells and ultimately leads to a wide range of inflammatory events. Systemically, IL-1 β signaling can lead to acute phase reactions, hypotension, vasodilation, and fever. Locally, the result of IL-1 signaling leads to upregulation of adhesion molecules, thereby promoting recruitment of lymphocytes. Subsequently, immune cells are activated and inflammation is further amplified. In addition to playing an important role in innate immune responses, IL-1 β is also involved in adaptive immune responses by affecting the immune responses induced by Th17 and Th 1.
IL-6 is an activated T cell and fibroblast produced lymphokine. The expression disorder can cause a plurality of diseases, and the clinical manifestation of the diseases is mainly that the IL-6 level is increased during the onset of the diseases.
iNOS is an important catalytic enzyme in the body, and plays a biological role by catalyzing the substrate arginine to produce Nitric Oxide (NO). Research shows that iNOS is closely related to inflammation, and bacteria, viruses and various inflammatory factors can induce the expression of iNOS to generate endogenous NO, so that the iNOS plays an important biological role.
Microglia are resident immune cells of the Central Nervous System (CNS), including the retina, and are the main mediators of inflammation. Under physiological conditions, microglia are in a branched form, have small and round cell bodies and multiple branching processes, and play important roles in axon growth, synaptic remodeling, neuron survival and the like through the actions of phagocyte fragments and relieving multiple cell signaling factors. Under negative stimuli, tissue damage or free radicals, microglia are in a reactive state, and these reactive microglia can develop into phagocytic microglia. After activated, microglia can generate nutritional biomolecules, glutamate transporters and antioxidants to promote normal nerve functions; and can also produce potential side damage, such as release of nitric oxide and proinflammatory cytokines (IL-1 alpha, IL-1 beta TNF-alpha, IFN-gamma, IL-6, etc.), and participate in nervous system diseases and central nervous system disorders, etc. Meanwhile, microglia plays a certain role in the pathogenesis of glaucoma optic nerve injury.
Astrocytes participate in the formation of the central nervous system skeleton structure, are closely linked with neuronal cells, and regulate the development, metabolism, repair and other activities of the central nervous system. Various cytokines secreted by the recombinant human immunodeficiency virus also play important regulation and control roles in blood flow regulation, neuron signal transmission and synaptic transmission of the central nervous system. Astrocytes in a resting state after optic nerve injury rapidly transit to an activated state, and morphologically appear to be hypertrophied and hyperplastic. The activation process is mediated by inflammatory mediators, chemokines, growth factors, transcription factors, and the like.
Before the present embodiments are further described, it is to be understood that the scope of the invention is not limited to the particular embodiments described below; it is also to be understood that the terminology used in the examples is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In addition to the specific methods, devices, and materials used in the examples, any methods, devices, and materials similar or equivalent to those described in the examples may be used in the practice of the invention in addition to the specific methods, devices, and materials used in the examples, in keeping with the knowledge of one skilled in the art and with the description of the invention.
Unless otherwise indicated, the methods of testing, methods of preparation, and methods of preparation disclosed herein employ techniques conventional in the art of molecular biology, biochemistry, chromatin structure and analysis, analytical chemistry, cell culture, recombinant DNA technology, and related arts.
Example 1: preparation of mouse ocular hypertension model and magnolol intervention
1. Establishing a mouse ocular hypertension model:
all experiments were performed under general anesthesia of mice, which were purchased from shanghai jester laboratory animals ltd. A6-8 week-old female C57BL/6 mouse is selected, anesthetized by a mixture of azolitel and dexmedetomidine, and the right eye is injured by ocular hypertension, a 30-gauge needle is inserted into the anterior chamber, the needle is connected with a 100ml sterile isotonic physiological saline bag, the height of the saline bag is 120 cm from the eyeball of the mouse, and the injury is induced for 60 minutes. At this time the intraocular pressure was measured at approximately 90 mmHg. Mice that did not induce ocular hypertension damage served as a control group.
2. Intervention of magnolol:
mice were injected intraperitoneally daily with magnolol (25mg/kg, Selleckchem, Houston, TX, USA) until the material was obtained.
Example 2: magnolol can improve survival rate of retinal ganglion cells
1. Optic nerve injury assessment
Optic nerve damage was detected 7 days after ocular hypertension injury. The heart of the mouse is perfused with normal saline for 5 minutes to remove blood cells, and then is injected with 4% paraformaldehyde for 15 minutes to be fixed in situ, and then the eyeball is taken. The eyes were fixed with 4% PFA for 2 hours. The retinas were dissected to a flat condition, fixed with 4% PFA for 15 minutes, and permeabilized with 0.3% triton x-100 in PBS for 15 minutes. The retinas were blocked with 5% goat serum (Boster, CA, USA) -0.3% triton x-100 in PBS for 2 hours at room temperature, then incubated with β -III tubulin (markers for RGCs; 1: 1000; Abcam) overnight at 4 ℃, and inoculated with Alexa Fluor594 anti-mouse secondary antibody (1: 200; CA Abbkine, USA). Confocal microscopy 4 images were taken of each retinal middle area and immune positive cells were counted using ImageJ software, counting the mean. Observed with a confocal microscope and photographed.
2. Evaluation results
As shown in FIGS. 1A-B, in the AOH7d group, the survival rate of retinal ganglion cells was significantly decreased (P < 0.05) to about 40% in the AOH7d group compared to the CON group at day 7 after ocular hypertension injury, whereas the survival rate of retinal ganglion cells was significantly increased (P < 0.05) in the AOH7d + MAG group compared to the AOH7d group (P < 63%) and the survival rate of retinal ganglion cells in the AOH7d + MAG group was increased to about 63%. The experimental result shows that the ocular hypertension can cause the loss of retinal ganglion cells, and the injection of magnolol can obviously improve the survival rate of the retinal ganglion cells.
Example 3: magnolol can inhibit retinal tissue thinning
1. Tissue morphology analysis
The mouse eyes were removed 1 and 7 days after ocular hypertension injury and fixed overnight with 4% PFA. Morphological analysis was performed on hematoxylin and eosin (H & E) stained retinal frozen or paraffin sections to assess retinal thickness. The thickness of the Retinal Nerve Fiber Layer (RNFL) and the Inner Plexiform Layer (IPL) was measured on H & E images at the same distance from the optic nerve head and expressed as an average value.
2. Analysis results
As shown in fig. 1C-D, the thicknesses of the Retinal Nerve Fiber Layer (RNFL) and the Inner Plexiform Layer (IPL) of the AOH1D group were not significantly changed compared to the CON group, the RNFL and IPL of the AOH7D group were significantly thinned compared to the CON group, and the RNFL and IPL of the AOH7D + MAG group were increased in thickness compared to the AOH7D group. Experimental results show that the thickness of RNFL and IPL in the reversible part of magnolol treatment is thinner.
Example 4: magnolol can reduce mRNA level of inflammatory factor
1. Real-time quantitative PCR
Total retinal RNA was extracted using TRIzol reagent (Invitrogen, CA, USA) and reverse transcription was performed using PrimeScript RT reagent kit (Takara, Kyoto, Japan). Quantitative PCR was performed for gene expression using LightCycler 480II (Roche, Switzerland) and UNICON qPCR SYBR Green Master Mix (Yeasen, Shanghai, China). The specific primers used in this study were from PrimerBank. Fold changes between different transcript levels were calculated using 2- Δ Δ CT with β -actin as an endogenous control.
2. Results of the experiment
As shown in FIGS. 3A-D, different inflammatory cytokines were detected to be involved in ocular hypertension injury, mRNA levels of inflammatory factors were significantly elevated (P < 0.05) in the AOH group compared to the CON group, and ocular hypertension significantly up-regulated mRNA levels of inflammatory cytokines TNF- α, IL-1 β, IL6, iNOS in retinal tissues 1 day after modeling; the AOH + MAG group showed significantly lower mRNA levels of inflammatory factors (P < 0.01) compared to the AOH group, indicating that magnolol treatment significantly reduced mRNA levels of inflammatory factors. In addition, as shown in fig. 4D, the AOH group showed a significant increase in mRNA expression of CD86 (P < 0.01) compared to the CON group, while CD206 expression was not significantly changed. The AOH + MAG group showed significantly reduced mRNA expression of CD86 (P < 0.05) and significantly increased mRNA expression level of CD206 (P < 0.05) compared to the AOH group. The results indicate that magnolol treatment can reduce CD86 and increase the mRNA expression level of CD 206.
Example 5: magnolol can relieve the decrease of blood retina barrier related protein level
1. Western blot analysis
Proteins were extracted from retinas using RIPA (Sangon, shanghai, china) and protein concentration was measured using BCA protein assay kit (Beyotime, shanghai, china). Proteins were separated on 10% SDS-PAGE, transferred to polyvinylidene fluoride membranes, which were then closed with 5% skim milk in tris buffered saline containing Tween-20 and incubated with antibodies. Primary antibodies to TNF α (1: 1000; Abcam, cambridge, UK), IL-1 β (1: 1000; Proteintech, chicago, IL, usa), IL-6(1: 1000; Protectech, chicago, illinois, usa), iNOS (1: 1000; affinity, usa), β -actin (1: 1000; Bioss, beijing), CD86 (1: 1000; Abcam, cambridge, UK), CD206(1: 1000; affinity, usa), ZO1(1: 1000; Proteintech, chicago, IL, usa), VE-Cadherin (1: 1000; affinity, usa) overnight at 4 ℃. Then, a second antibody rabbit (1: 1000; Shanghai, China) or mouse (1: 1000; Beyotime, Shanghai, China) was incubated with the membrane at room temperature for 1 hour. Protein bands were visualized by Tanon viewer system (Shanghai, China) and BeyoECL Moon (Beyotime, Shanghai, China) and analyzed by ImageJ.
2. Results of the experiment
As shown in FIGS. 3E-F, the protein levels of inflammatory cytokines TNF- α, IL-1 β, IL6, iNOS were significantly increased in the AOH group compared to the CON group (P < 0.05 or P < 0.01), and the protein levels of inflammatory cytokines TNF- α, IL-1 β, IL6, iNOS in retinal tissues were significantly upregulated after 1 day of modeling in ocular hypertension; the AOH + MAG group showed significantly reduced levels of the inflammatory cytokines TNF-alpha, IL-1 beta, IL6, iNOS (P < 0.05 or P < 0.01) compared to the AOH group, indicating that magnolol treatment significantly reduced levels of the inflammatory factors. In addition, as shown in fig. 4D, protein expression of CD86 was increased after ocular hypertension, while expression of CD206 was not significantly changed. Magnolol treatment can reduce CD86 and increase CD206 mRNA expression levels. As shown in FIGS. 4F-G, ocular hypertension also decreased the expression levels of ZO-1, VE-cadherin, while magnolol treatment reduced the level of the protein associated with the blood retinal barrier.
Example 6: magnolol can reduce fluorescence intensity of TNF alpha and IL6 in retina
1. Immunofluorescence staining
At 7 days after ocular hypertension injury, the heart of the mouse is perfused with normal saline for 5 minutes to remove blood cells, and then injected with 4% paraformaldehyde for 15 minutes for in situ fixation, and then the eyeball is taken. The eyes were fixed with 4% PFA overnight, embedded with OCT, and frozen and cut into 10 μm pieces. Tissue sections were infiltrated with 0.3% triton x-100 in PBS for 15 minutes at room temperature, and then washed 3 times with PBS for 5 minutes each. Sections were blocked with 5% bovine serum albumin in PBS for 1 hour, then incubated with anti-TNF α primary antibody (1: 200; Abcam, Cambridge, UK), IL6(1: 200; protein technology, Chicago, IL, USA), IBA1(1: 100, Severe, Wuhan, China), glial fibrillary acidic protein (GFAP; 1: 2000; Invitrogen, CA, USA) overnight at 4 ℃. Sections were washed 3X 5 min with 0.1% tween PBS (PBST) and then incubated with Alexa Fluor 488 anti-rabbit or Alexa Fluor594 anti-mouse secondary antibody (1: 200; Abbkine, Calif., USA) for 1 hour at room temperature. Sections incubated without primary anti-PBS served as negative controls. Nuclear staining was performed using DAPI (Invitrogen, CA, USA), and sections were observed with a confocal microscope (Nikon, Tokyo, Japan) and photographed. All photographs were taken under 20 x magnification.
2. Results of the experiment
As shown in FIGS. 3G-H, the fluorescence intensity of TNF α and IL6 in the Ganglion Cell Layer (GCL), Inner Plexiform Layer (IPL) and Inner Nuclear Layer (INL) of retina was significantly increased in the AOH group compared to the CON group, while the fluorescence intensity of TNF α and IL6 in the Ganglion Cell Layer (GCL), Inner Plexiform Layer (IPL) and Inner Nuclear Layer (INL) of retina was significantly decreased in the AOH + MAG group compared to the AOH group. The results show that magnolol treatment reduced the fluorescence intensity of TNF α and IL6 in mouse ocular hypertension model retinas. As shown in fig. 4A, the AOH group showed rounding of microglia shape and shortened synapses compared to the CON group, while the AOH + MAG group showed significantly reduced rounding of microglia shape and shortened synapses compared to the AOH group. As shown in FIG. 4E, the synapsis of astrocytes in the AOH group was lengthened and extended to the outer retina compared to the CON group, while the synapsis of astrocytes in the AOH + MAG group was lengthened and extended to the outer retina compared to the AOH group, which was significantly relieved.
Example 7: magnolol can relieve the decrease of electrophysiological function level of mouse retina membrane caused by ocular hypertension
1. Retinal electrophysiological analysis
The retinal electrophysiological analysis was performed on 7-day molded mice 24 hours after dark adaptation. The mice were placed on a darkroom cushion with a red safety light under isoflurane anesthesia (induction concentration 3%, 1.0L/min; maintenance, 1.5% at 0.6L/min). The ground electrode was inserted into the tail of the mouse and the reference electrode was inserted into the forehead of the mouse. Two ring-shaped metal electrodes were attached to the mouse cornea and the response of the retina to light stimuli was recorded using an Espion E3 instrument (Diagnosys, Boxborough, MA, USA). 10.0cd/m2 induces dark adaptation to retinal electrophysiology. ERG a waves go from baseline to lowest negative peak, b waves go from lowest negative peak to main positive peak. Data from ocular hypertension modeling eyes or magnolol-intervened ocular hypertension modeling eyes were measured and the ratio to the contralateral eye was presented as data.
4. Results of the experiment
As shown in FIG. 2, the level of retinal electrophysiological function of the AOH + MAG group was significantly higher than that of the AOH group. The results show that magnolol treatment can obviously relieve the reduction of the electrophysiological function level of the retina of a mouse caused by high intraocular pressure and improve the amplitudes of a wave and b wave.
Example 8: magnolol can reduce the immune response of lymph nodes around the eye
1. Cell flow analysis
Flow cytometry analysis was performed after the mouse ocular draining lymph nodes were isolated. The isolated cells were used with BD GolgiPlugTMProtein transport inhibitor (containing Brefeldin A) was incubated at 37 ℃ for 4h and detectedT helper cells (Th) secreting IFN γ -, IL 4-and IL 17. The isolated cells were immunolabeled with primary antibodies against IFN γ (BD biosciences, NJ, USA), IL4(BD biosciences, NJ, USA), IL17(BD biosciences, NJ, USA) protected from light for 30 minutes. Corresponding isotype antibodies served as controls. Data acquisition and recording was performed using BD FACScalibur (usa) and analysis was performed using Flowjo.
2. Results of the experiment
As shown in FIG. 5, the proportions of Th1, Th2 and Th17 cells in the refluxing lymph node of the eye of the mice in the AOH group are obviously higher than those in the CON group (P < 0.05), which indicates that the high intraocular pressure can cause the proportion of Th1, Th2 and Th17 cells in the refluxing lymph node of the eye of the mice, while the proportions of Th1, Th2 and Th17 cells in the refluxing lymph node of the eye of the mice in the AOH + MAG group are obviously lower than those in the AOH group (P < 0.05), which indicates that the magnolol treatment can obviously reduce the proportions of Th1, Th2 and Th17 cells and reduce the immune response of the lymph node around the eye.
The foregoing embodiments are merely illustrative of the principles and utilities of the present invention and are not intended to limit the invention. Those skilled in the art can modify or change the above-described embodiments without departing from the spirit and scope of the present invention. Accordingly, it is intended that all equivalent modifications or changes which can be made by those skilled in the art without departing from the spirit and technical spirit of the present invention be covered by the claims of the present invention.
Claims (10)
1. Use of the compound magnolol in the manufacture of a chemical product having at least one of the following functions:
1) reducing retinal ganglion cell loss and retinal damage caused by ocular hypertension;
2) improving visual function reduction caused by ocular hypertension;
3) inhibiting inflammatory factor production in retinal tissue due to ocular hypertension;
4) reduce the activation of microglia and astrocytes in the retina caused by high intraocular pressure, reduce the polarization of the microglia to the M1 phenotype and promote the polarization of the microglia to the M2 phenotype;
5) relieving a decrease in blood retinal barrier associated proteins in retinal tissue caused by ocular hypertension;
6) reduce the increase of the proportion of Th1, Th2 and Th17 cells in the reflux lymph nodes of eyes caused by high intraocular pressure.
2. The use of claim 1, wherein the magnolol is a compound of formula (I) or a pharmaceutically acceptable salt of a compound of formula (I)
3. The use of claim 1, wherein the retinal damage comprises a thinning of the thickness of the retinal nerve fiber layer and the inner plexiform layer.
4. The use of claim 1, wherein the visual function comprises a level of retinal electrophysiological function.
5. The use of claim 1, wherein said inflammatory factors include TNF- α, IL-1 β, IL-6, iNOS.
6. The use of claim 1, wherein said blood retinal barrier associated protein comprises ZO-1, VE-cadherin.
7. The use according to claim 1, wherein the chemical product is a medicament for preventing, treating or reducing retinal degeneration caused by neuroinflammation.
8. The use of claim 7, wherein the retinal degeneration caused by neuroinflammation comprises glaucoma disease, age-related macular degeneration, or diabetic retinopathy.
9. A medicament for preventing, treating or reducing optic nerve damage caused by glaucoma disease, the medicament comprising an effective amount of magnolol.
10. The medicament of claim 9, further comprising a pharmaceutically acceptable carrier or adjuvant, or a combination thereof.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| KR20040108500A (en) * | 2003-06-17 | 2004-12-24 | 한국 한의학 연구원 | Extract of unprocessed- and processed Magnolia bark, Magnolol and pharmaceutical compositions and functional food containing the same for prevention and treatment of diabetic complications |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| KR20040108500A (en) * | 2003-06-17 | 2004-12-24 | 한국 한의학 연구원 | Extract of unprocessed- and processed Magnolia bark, Magnolol and pharmaceutical compositions and functional food containing the same for prevention and treatment of diabetic complications |
Non-Patent Citations (3)
| Title |
|---|
| RAJGOPAL A ET AL.: "Magnolia bark extract is a potent Nrf2 activator" * |
| WEN-HSIN HUANG ET AL.: "Synthesis and Ocular Hypotensive Activity of Magnolol" * |
| 雷晓溪等: "厚朴酚对兔视网膜缺血再灌注神经元凋亡和bcl-2、caspase-3表达的影响" * |
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