CN107787912B - Induction method of primate model with dry age-related macular degeneration - Google Patents
Induction method of primate model with dry age-related macular degeneration Download PDFInfo
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Abstract
The invention discloses an induction method of a primate model with dry age-related macular degeneration, which is characterized in that high-sugar high-fat semifluid diet is poured into the stomach of a primate to induce the primate to generate hypercholesterolemia so as to obtain the primate model with dry age-related macular degeneration. The invention can quantify the amount of high-sugar and high-fat intake of each animal every day, has no worry about insufficient intake of the animals caused by the change of mouthfeel, and can regularly and quantitatively take the high-sugar and high-fat, thereby greatly accelerating the formation of hypercholesterolemia and accelerating the induction process of a dry AMD model. The primate dry AMD animal model prepared by the invention has incomparable advantages compared with AMD models induced by other methods, and can be used for research and evaluation of anti-dry AMD drugs, particularly research and development and evaluation of biotechnology drugs unsuitable for rodent animal models.
Description
The technical field is as follows:
the invention belongs to the field of macular degeneration research, and particularly relates to a method for inducing age-related macular degeneration (AMD) of primates through high-sugar high-fat diet.
Background art:
age-related macular degeneration (AMD) is an irreversible disease of decreased or lost vision caused by degenerative changes of retinal pigment epithelial cells and neural retina, which is mostly caused by middle-aged and elderly people over 50 years old, and progressive damage appears in both eyes, thus being an eyeground disease seriously threatening the visual function of middle-aged and elderly people. It has been reported that AMD has progressed to the first blinding disease in western countries due to earlier aging, and asian countries have currently lower incidence of this disease than western countries due to a slightly later aging process, but with the increasing aging of the population, the incidence of AMD in asian countries, particularly china, also shows an increasing trend year by year. Because AMD causes are many, the specific causes are difficult to determine, the current treatment means are relatively limited, most AMD has no very effective treatment means at present, the AMD is developed into an intractable disease in the ophthalmology diseases at present, and the AMD is a hotspot researched in the ophthalmology diseases and a difficulty mainly overcome by research and development of ophthalmology medicines in the ophthalmology diseases at present. According to the nature of the disease, AMD can be divided into dry AMD and wet AMD, the AMD with soft drusen, pigment abnormality and geographic atrophy is generally called dry AMD, most patients are dry AMD, and the dry AMD accounts for 80-90% of the total disease number of AMD; AMD with choroidal neovascularization, retinal pigment epithelial detachment, or discoidal fibrosis is commonly referred to as wet or neovascular AMD, with wet AMD accounting for about 10-20% of the total morbidity, usually more women than men.
The incidence of AMD is a major factor, such as age, sex, genetics, drugs, eye factors, cardiovascular disease, blood lipid levels, diabetes, environmental factors, and the like, associated with the incidence of AMD. Apart from the age factors, the onset of AMD is not clearly causative, and therefore, it is very difficult to prevent it in advance in daily life. In the aspect of treatment, the current means for treating AMD is limited, and the drugs for treatment include anti-angiogenic endothelial factor drugs (currently, lucentis, macugen and small interfering RNA are mainly used, which can prevent the formation of neovascularization and the proliferation of vascular endothelial cells, so that the vascular leakage can be effectively intervened and controlled), corticosteroid hormones (mainly triamcinolone acetonide injection, which has the effects of inhibiting the formation of neovascularization, inhibiting inflammatory reaction, stabilizing the blood retinal barrier, resisting proliferation, reducing vascular leakage and the like), antioxidant vitamin drugs (mainly, vitamins C and E and carotene, which have the effects of resisting oxidation, inhibiting lipid peroxidation reaction, so that a significant inhibitory effect is generated), vascular statins (which can inhibit endogenous cholesterol, promote the synthesis of rate-limiting enzyme reductase, reduce the synthesis of moderate cholesterol in cells, stabilize atheromatous plaque, block the progression of diseases), traditional Chinese medicine syndrome differentiation treatment and the like. In addition, non-drug surgical therapy, photodynamic therapy, and the like are available. The foregoing drugs and methods are mostly used for the treatment of wet AMD, and the treatment of dry AMD is limited.
Although there is a certain choice of methods and drugs for treating AMD, the therapeutic effects of the above treatments on AMD are generally very limited, and there is an urgent need to develop specific drugs for AMD to relieve the pain of many AMD patients and improve their quality of life. It is well known that good drugs are not developed from good animal models of diseases, and most of the animal models currently used for developing anti-AMD drugs are wet AMD models induced by various methods, such as laser-induced wet AMD models (mouse, rat, pig, monkey), which have certain similarity to human wet AMD, but are accompanied by retinal damage, which is not present in humans and the cause of which is far from the cause of human AMD. A basic fibroblast growth factor (bFGF) -induced AMD model which is free of human choroidal neovascularization such as basement membrane deposits, drusen, RPE detachment and subretinal hemorrhage, and is unstable to bFGF with a short half-life in vivo; a Vascular Endothelial Growth Factor (VEGF) -induced AMD model, wherein the model has high modeling rate, but the model does not have retinal degeneration corresponding to AMD, and Bruch membranes also have no sediment formation; in addition, there are models of AMD induced by intravitreal injection, lipid peroxide induced AMD, and AMD obtained by genetic modification, most of which cause damage to the retina of animals but are still in a gap from human AMD. Moreover, most AMD models are wet AMD models, the dry AMD model research reports are relatively few, the incidence rate of dry AMD is far higher than that of wet AMD clinically, and the dry AMD model research is far from meeting the clinical requirement. At this time of the rapid advance of biotechnology, the above models have not been able to fully satisfy the needs of drug development due to the specificity of drugs (e.g., biotechnological drugs have a high selectivity of animal species). Therefore, establishing animal models similar to the onset of dry AMD in humans is of great importance in the development of novel anti-AMD drugs.
With the progress of society and the improvement of living standard of substances, the dietary structure of human beings is greatly changed, and the dietary structure mainly takes vegetarian diet to be gradually transited to the dietary structure mainly taking high fat and high sugar. The development of AMD is changed due to the improvement of living standard of the substances and the intake of a large amount of high fat and high sugar, and one of the causes of AMD is high fat diet and cardiovascular diseases, and researchers think that hyperlipemia is deposited on choroid when the vascular diseases are induced, thereby forming AMD. At present, no report of inducing dry AMD of the cynomolgus monkey by using a high-fat diet method exists, and the study induces the dry AMD of the cynomolgus monkey by using the high-fat diet method according to a high-fat pathogenicity theory. Primates are considered to be born and have been taken with feed when they are ingested. If high-fat components are mixed into the feed in the copying process of the model, most of the feed is wasted due to being played and discarded by the cynomolgus monkeys, the amount of the feed taken by each animal every day cannot be accurately calculated, and quantification cannot be realized. And because the feed has higher caloric content and the mouthfeel of the feed per se has changed greatly, the animals can feel plump after taking a certain amount of feed, and due to the self-protection effect, the animals can stop taking a larger amount of feed, so that the high fat intake can be reduced relatively, and the molding time is greatly prolonged.
The invention content is as follows:
it is a first object of the present invention to provide a method for inducing dry AMD in primates by infusing a high-fat, high-sugar, semi-fluid diet into the stomach of the primate to induce hypercholesterolemia in the primate, the high-fat, high-sugar, semi-fluid diet being prepared by: mixing sucrose, lard, cholesterol and cholate = 5-15 by mass ratio, wherein the ratio is as follows.
As a preferred technical scheme, the induction method is that the high-sugar high-fat semifluid diet of the primate model for inducing the dry age-related macular degeneration is administrated by gavage tube according to the weight of 9.2-17.2g/kg of the weight of the primate, and the dry AMD model of the cynomolgus monkey can be induced and is accompanied with hypercholesterolemia by being administrated once a day, 6 days a week and continuously for 15 months.
In a preferred embodiment, the primate is preferably a cynomolgus monkey.
The second purpose of the invention is to provide a method for screening and evaluating the dryness-resistant age-related macular degeneration medicine, which is to administer the dryness-resistant age-related macular degeneration primate model induced by the induction method of the dryness-resistant age-related macular degeneration primate model according to the characteristics of the candidate medicine and a certain dosage and frequency, and evaluate whether the candidate medicine has the dryness-resistant age-related macular degeneration effect according to the effect, thereby providing the screening and/or evaluating research results for the candidate medicine.
Compared with the prior art, the invention has the following beneficial effects:
(1) The invention induces that the carbohydrate and fat used in the high-fat high-sugar semi-fluid diet of the dry AMD model of the primate are respectively sucrose, lard, cholesterol and cholate which have larger intake in daily life of the human, the four substances are mixed according to a certain proportion to prepare the semi-fluid diet, and the semi-fluid diet is poured into the stomach of the primate through a nasal feeding tube, so that the primate can passively take the high-fat high-sugar mixture according to the weight and a certain time and frequency, and the diseases caused by diet disorder of the human due to the improvement of the living conditions of the substances are simulated.
(2) The invention can quantify the amount of high-fat and high-sugar intake of each animal every day, can relieve the worry of insufficient feed intake of the animals caused by the change of the mouthfeel of ingested substances, and can regularly and quantitatively take the high-fat and high-sugar, thereby greatly accelerating the formation of hypercholesterolemia and accelerating the induction process of a dry AMD model. The primate dry AMD animal model prepared by the invention has incomparable advantages of AMD models induced by other methods, and can be used for research and evaluation of anti-dry AMD medicines, particularly research and evaluation of biotechnology medicines unsuitable for rodent animal models.
Description of the drawings:
FIG. 1 shows fundus photographs (A01) of animals in a negative group before molding, after 7 months and after 15 months;
fig. 2 is fundus photographs (B01) of animals with low sugar and low fat in the period of 7 months and 15 months before molding;
fig. 3 is fundus photos (No. C01) of animals in low-sugar and high-fat groups before molding, in 7 months and in 15 months after molding from left to right;
fig. 4 is fundus photographs (No. D01) of high-sugar and low-fat animals in the months before molding, 7 months after molding, and 15 months after molding, from left to right;
fig. 5 shows fundus photographs (E01) of animals in the high-sugar and high-fat group from left to right in the following order before molding, after 7 months of molding, and after 15 months of molding.
The specific implementation mode is as follows:
the following examples are further illustrative of the present invention and are not intended to be limiting thereof.
Example 1:
1. experimental Material
1.1 of sucrose: 500 g/bottle, analytically pure, chemical industry of Xilonga.
1.2 lard oil: 15 kg/barrel, food grade, dingsheng food Co., ltd, hainan province.
1.3 Cholesterol: 500 g/bottle, analytical grade, shanghai Bo ao Biotech Ltd.
1.4 cholate: 500 g/bottle, analytically pure, hengxing chemical reagent manufacturing Co., ltd.
1.5 cynomolgus monkey: the health care product is 10-18 years old, 29 male animals and ordinary animals, which are purchased from Guangdong island biotechnology limited and are excluded before purchase.
1.6 triglyceride assay kit, zhejiang Yilikang biotechnology Limited.
1.7 Cholesterol determination kit, yilikang biotechnology Limited, zhejiang.
1.8 high density lipoprotein assay kit: erikang, zhejiang, biotech.
1.9 Low Density lipoprotein assay kit: yilikang, zhejiang, biotech Ltd.
2. Main instrument
2.1 7020 biochemical analyzer: model 7020, hitachi, japan.
2.2 hand-held fundus camera: model number GENESIS-Df, kowa company.
3. Experimental methods
3.1 preparation of a semi-fluid, high-fat and high-sugar diet: mixing sucrose, lard, cholesterol and cholate according to the following mass percentage: the preparation method comprises the following steps of mixing lard, sucrose, cholesterol and cholate = 5-15, and the ratio of the weight of the mixture is (1) to the weight of the mixture is (0.1-1.0).
3.2 selecting 29 normal male middle-aged and old cynomolgus monkeys of 10-18 years old, randomly dividing the cynomolgus monkeys into 5 groups according to body weight, wherein the groups are respectively a negative control group, a low-fat low-sugar group, a low-fat high-sugar group, a high-fat low-sugar group and a high-fat high-sugar group, 5 animals in the negative group and 6 animals in the rest groups. The formula of the high-fat high-sugar group diet comprises the following components in percentage by mass: lard, sucrose, cholesterol, cholate =10:10:1:0.5, uniformly mixing the components according to the content, heating to about 70 ℃, uniformly stirring and emulsifying to obtain the compound premix, wherein the dietary dosage is 17.2g/kg; the low-fat high-sugar group diet comprises the following components in percentage by mass: lard, sucrose, cholesterol, cholate =5:10:1:0.5, uniformly mixing the components according to the content, heating to about 70 ℃, uniformly stirring and emulsifying to obtain the compound premix, wherein the dietary dosage is 13.2g/kg; the formula of the high-fat low-sugar diet comprises the following components in percentage by mass: lard, sucrose, cholesterol, cholate =10:5:1:0.5, uniformly mixing the components according to the content, heating to about 70 ℃, uniformly stirring and emulsifying to obtain the feed additive, wherein the dietary dosage is 13.2g/kg; the low-fat and low-sugar diet formula comprises the following components in percentage by mass: lard, sucrose, cholesterol, cholate =5:5:1:0.5, uniformly mixing the components according to the content, heating to about 70 ℃, uniformly stirring and emulsifying to obtain the feed additive, wherein the dietary dosage is 9.2g/kg; after each test group of animals was divided into groups, the animals were gavaged with a high-fat high-sugar diet according to a set schedule, once a day, 6 days a week, for 15 months. The fundus oculi pathological changes and fasting cholesterol (TC), triglyceride (TG), high density lipoprotein (HDL-C), low density lipoprotein (LDL-C) and other indexes of the cynomolgus monkey are measured according to requirements.
The fundus oculi lesion observation method comprises the following steps: after the cynomolgus monkey is anesthetized, the head is fixed, the eyelid of the monkey is manually separated, the atropine eye drops are scattered on the pupil, and then the eyeground pathological changes are observed by using a handheld eyeground camera and eyeground pictures are stored.
The blood fat determination method comprises the following steps: after the cynomolgus monkey is anesthetized by ketamine, about 2.0ml of blood is collected from the cephalic vein and/or the saphenous vein, and serum is taken after centrifugation and is measured by a Hitachi 7020 biochemical analyzer.
4. Results of the experiment
4.1 fundus oculi lesion study results (see specifically fig. 1-5): before molding, the sizes of the optic discs of all experimental groups are similar, and the boundaries are clear; the ratio of retinal artery to retinal vein is about 2:3, the diameter of the arteriovenous vessels is uniform, and the shapes and colors of the arteriovenous vessels are not obviously abnormal and have no pulsation or cross compression; no obvious abnormality is seen in the macula and foveal reflex; the retina does not have bleeding, exudation, pigment hyperplasia or loss. No obvious difference is observed in the fundus before animal modeling of each experimental group. After 7 months of molding, the fundus structure of the negative control group has no obvious difference compared with that before molding; the low-sugar and low-fat group comprises 3 animals, the low-sugar and high-fat group comprises 2 animals, the high-sugar and low-fat group comprises 3 animals, and the high-sugar and high-fat group comprises 1 animal, wherein uneven pigment spots appear in the macular region of the eyeground, the macular region is gray and reflective, the diameter of the pigment spots is small and is about 0.5-2mm, and other structures of the eyeground are not obviously changed. After 15 months of modeling, compared with the negative control group before modeling, the fundus structure of the negative control group is not obviously changed, the fundus structures of 5 cases, 3 cases, 5 cases and 2 cases of animals in the low sugar and low fat group, the low sugar and high fat group, the high sugar and low fat group and the high sugar and high fat group are respectively changed, uneven pigment spots appear in the macular area, part of the animal fundus structures are gray and reflective, pigment spots are smaller and about 1-2mm, part of round spot pigments are separated, the gold foil type is reflective, the diameter of the round spot can reach 3-4mm, part of animals even have white choroid, blood vessels become thinner, the color of the optic disc is light, and the like.
4.2 Cholesterol study results show (see tables 1-2 specifically): compared with a negative control group, the cholesterol level of each experimental group is increased to a certain extent in 1 month of modeling, and the statistical difference (P <0.05 or 0.01) is realized, but the biological significance is avoided. After 3-13 months of modeling, the serum cholesterol content of each test group of the cynomolgus monkey is obviously increased, and the cynomolgus monkey has statistical significance (P < 0.01) and biological significance.
TABLE 1 Macaca fascicularis plasma Cholesterol Change Table
P <0.05, P <0.01, as compared to the negative control group
TABLE 2 Macaca fascicularis plasma cholesterol content change table
P <0.05, P <0.01, as compared to the negative control group
4.3 results of triglyceride studies show that (see tables 3-4 in particular): and (3) molding for 1-3 months, and compared with a negative control group, the serum TG level of the cynomolgus monkey in each test group is not obviously increased and has no statistical difference (P > 0.05). The serum TG levels of the low-sugar low-fat group and the high-sugar high-fat group in the model 5 month are increased and have statistical difference (P is less than 0.05), and the serum TG levels of the low-sugar low-fat group and the high-sugar low-fat group in the model 5 month are not obviously changed. After 7 months of molding, the serum TG level of each test group is not obviously changed; the cynomolgus monkey TG levels in each test group of 9-13 months of modeling have different degrees of increase and statistical difference (P <0.05 or 0.01), but the TG level is overall lower, so the cynomolgus monkey TG level has no biological significance.
TABLE 3 Macaca fascicularis plasma triglyceride content variation table
Indicates P <0.05, as compared to the negative control group
TABLE 4 Macaca fascicularis plasma triglyceride content variation table
Indicates P <0.05, as compared to the negative control group
4.4 results of high density lipoprotein cholesterol study (see tables 5-6): compared with a negative control group, the model is made for 1-3 months, the content of the HDL-C in the serum of the cynomolgus monkey in each test group is obviously increased, and the statistic difference is realized (P is less than 0.05); and (5) molding for 5-13 months, wherein the serum HDL-C content of the cynomolgus monkey in each test group is not obviously increased, and no statistical difference is seen (P > 0.05).
TABLE 5 Macaca fascicularis plasma HDL cholesterol level change table
P <0.05, P <0.01, as compared to the negative control group
TABLE 6 Macaca fascicularis plasma HDL cholesterol level change table
Indicates P <0.05, as compared to the negative control group
4.5 results of low density lipoprotein cholesterol study (see tables 7-8): compared with a negative control group, the cynomolgus monkey serum LDL-C level of each experimental group is increased to a certain degree within 1 month after modeling, and the results are statistically different (P is less than 0.05 or 0.01) but have no biological significance. After 3-13 months of modeling, the content of LDL-C in the cynomolgus monkey serum of each test group is obviously increased, the statistical significance (P is less than 0.01) and the biological significance are achieved, and the serum LDL-C of the cynomolgus monkey serum of each test group is gradually increased along with the extension of modeling time.
TABLE 7 cynomolgus monkey plasma low density lipoprotein cholesterol content change table
P <0.05, P <0.01, as compared to the negative control group
TABLE 8 Macaca fascicularis plasma LDL cholesterol content variation table
P <0.05, P <0.01, as compared to the negative control group
According to the research results, the low-sugar low-fat group, the low-fat high-sugar group, the high-sugar low-fat group and the high-sugar high-fat group can successfully induce the AMD model of the primate, but the incidence rates of the low-sugar low-fat group and the high-sugar low-fat group are the highest, the incidence rate of dry AMD after 13 months is induced can reach more than 80%, the incidence rate of the dry AMD after 13 months is induced by the low-sugar high-fat group can reach more than 50%, the incidence rates of the dry AMD after 13 months are induced by the high-sugar low-fat group and the high-sugar high-fat group again can reach more than 30%, and the dry AMD models in the invention are all accompanied with hypercholesterolemia with different degrees. It can also be judged from the results of the previous studies that the intake of fat (cholesterol, lard, cholate) has a decisive influence on the increase of cholesterol in cynomolgus monkeys, but the intake of fat does not positively correlate with the formation of AMD, but the intake of fat and sugar in a certain proportion has the greatest influence on the formation of AMD. Namely, when the administration proportion of the sucrose, the lard, the cholesterol and the cholate is 4g-8g:4g:0.8g: at 0.4g/kg, dry AMD is most likely to develop in cynomolgus monkeys.
Claims (2)
1. An induction method of primate model with dry age-related macular degeneration is characterized in that high-sugar high-fat semifluid diet is poured into the stomach of a primate to induce the primate to generate hypercholesterolemia so as to obtain the primate model with dry age-related macular degeneration; the high-sugar high-fat semi-fluid diet is prepared by the following method: mixing sucrose, lard, cholesterol and cholate according to the mass ratio of (5-15);
the high-sugar high-fat semi-fluid diet of the primate model for inducing the dry age-related macular degeneration is administrated by nasogastric feeding tube according to the weight of 9.2-17.2g/kg of the primate animal, and is administrated once a day, 6 days a week and continuously for 15 months;
the primate is a cynomolgus monkey.
2. A method for screening and evaluating a drug for dry-type age-related macular degeneration, which comprises administering the primate model with dry-type age-related macular degeneration induced by the induction method of the primate model with dry-type age-related macular degeneration according to claim 1 at a dose and frequency according to the characteristics of the drug candidate, and evaluating whether the drug candidate has the effect of dry-type age-related macular degeneration according to the effect, thereby providing the results of screening and/or evaluating research for the drug candidate.
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| CN111869625A (en) * | 2020-09-18 | 2020-11-03 | 四川大学华西医院 | High-fat high-sugar diet-induced dry age-related macular degeneration pigment rabbit model |
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| CN112219788A (en) * | 2020-09-29 | 2021-01-15 | 四川大学华西医院 | Construction method and application of high-fat diet-induced anterior ischemic optic neuropathy chromogen rabbit model |
| CN113796354A (en) * | 2021-09-29 | 2021-12-17 | 湖北天勤生物技术研究院有限公司 | Method for establishing cynomolgus monkey hypertriglyceridemia model and application thereof |
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