Application of atractylenolide II in preparation of medicine for treating diabetic retinopathy

Abstract

The invention discloses an application of atractylenolide II in preparation of a medicine for treating diabetic retinopathy. The application of the atractylenolide II in preparing the medicine for treating the diabetic retinopathy has the following beneficial effects that 1, a non-invasive and multi-target treatment strategy is provided by virtue of the effects of reducing blood sugar, resisting inflammation, resisting oxidation and protecting blood vessels of the atractylenolide II, and the diabetic metabolic disorder and the retina microangiopathy are improved at the same time, so that the curative effect of the atractylenolide II on the diabetic retinopathy is improved; the singleness and limitation of the prior art are made up; 2, atractylenolide II can effectively reduce the blood sugar of diabetic mice; 3, atractylenolide II can effectively improve the glucose tolerance of diabetic mice; 4, atractylenolide II can relieve the vascular atresia condition of the retina of the diabetic mouse, and enables the vascular morphology of the diabetic mouse to be closer to that of a control group mouse; 5, atractylenolide II can relieve the pathological injury degree of retinal tissues of diabetic mice.

Description

Technical Field

[0001] The present invention belongs to the field of biomedicine, and particularly relates to the use of atractylenolide II in the preparation of a drug for treating diabetic retinopathy. Background Art

[0002] Diabetic retinopathy (DR) is the most common microvascular complication of diabetes, characterized by retinal vascular leakage, occlusion, and neovascularization, ultimately leading to vision loss. The global number of diabetic patients has exceeded 640 million, and approximately 1 / 3 of them will develop diabetic retinopathy, becoming the main cause of blindness in adults. The pathogenesis of diabetic retinopathy is closely related to hyperglycemia-induced oxidative stress, inflammatory response, overexpression of vascular endothelial growth factor (VEGF), and disruption of the blood-retinal barrier.

[0003] The main treatment methods for diabetic retinopathy are intervened as follows: Drug treatment: 1. Anti-VEGF drugs (such as ranibizumab, bevacizumab): By intravitreal injection to inhibit neovascularization, it can effectively relieve macular edema, but it needs to be injected repeatedly and has a high cost, resulting in high treatment costs and poor patient compliance. Long-term use has significant side effects (it may cause complications such as increased intraocular pressure or retinal fibrosis). 2. Microcirculation-improving drugs (such as calcium dobesilate): It works by antioxidant and reducing vascular leakage, but the curative effect is limited and it is only applicable to early lesions.

[0004] Laser photocoagulation: By destroying the peripheral retina to reduce oxygen consumption demand and protect macular function, but it will sacrifice part of the visual field and has limited effect on mid-late stage lesions.

[0005] Surgical treatment: Vitrectomy is applicable to severe vitreous hemorrhage or retinal detachment, but the surgical risk is high and the postoperative vision recovery is limited, especially insufficient for mid-late stage lesions.

[0006] Traditional Chinese medicine treatment: Tongluo Mingmu Capsule: Composed of red peony root, astragalus membranaceus, etc., with a total effective rate of 61%, it can improve retinal microcirculation, but the action target is not clear, the curative effect still needs to be verified on a large scale, and it lacks dual regulation of glucose metabolism and retinal microvascular lesions. Tangning Tongluo Tablet: By inhibiting the ERS / NF-κB pathway to reduce inflammation, it is clinically shown to reverse fundus hemorrhage in non-proliferative DR, but long-term safety data is still needed. Summary of the Invention

[0007] Objective of the Invention: The present invention makes improvements to the problems existing in the above-mentioned prior art, that is, the present invention discloses the application of atractylenolide II in the preparation of a drug for treating diabetic retinopathy. Existing treatment regimens for diabetic retinopathy mostly target a single pathological link (such as inhibiting VEGF or improving microcirculation), and cannot simultaneously address the co-pathogenic factors such as hyperglycemia, oxidative stress, inflammation, and vascular occlusion. The present invention takes atractylenolide II as the core and combines its known anti-inflammatory and metabolic regulatory properties. For the first time, it is applied to the treatment of diabetic retinopathy, making up for the deficiencies of the single-action mechanism of existing regimens through multi-target intervention (lowering blood sugar, anti-inflammatory, and vascular protection), and having the advantages of the safety of natural drugs and comprehensive curative effects.

[0008] Application gap of natural drugs in retinal protection: Although atractylenolide II has been proven to have anti-inflammatory and metabolic regulatory effects, its specific efficacy and mechanism in diabetic retinopathy have not been explored, and the existing technology does not cover its potential for protecting the structure and function of the retina.

[0009] Technical Solution: The application of atractylenolide II as the only active ingredient in the preparation of a drug for treating diabetic retinopathy, wherein: the structural formula of the atractylenolide II is as follows: 。

[0010] Further, in the above application, the drug is composed of atractylenolide II and a pharmaceutically acceptable carrier.

[0011] Further, the drug exists in the form of tablets, capsules, oral liquids, or granules.

[0012] Even further, the tablet is one of ordinary compressed tablets, sugar-coated tablets, effervescent tablets, chewable tablets, multi-layer tablets, sustained-release tablets, or controlled-release tablets.

[0013] Even further, the oral liquid is one of solutions, syrups, emulsions, or suspensions.

[0014] Even further, the granule is one of soluble granules, suspension granules, or effervescent granules.

[0015] A drug for treating diabetic retinopathy, the drug contains atractylenolide II as the only active ingredient, and the structural formula of the atractylenolide II is as follows: 。

[0016] The dosage of the above drug for treating diabetic retinopathy is 30 - 60 mg / kg.

[0017] Beneficial effects: The application of atractylenolide II disclosed in the present invention in the preparation of a drug for treating diabetic retinopathy has the following beneficial effects: 1. Through the hypoglycemic, anti-inflammatory, antioxidant and vascular protection effects of atractylenolide II, a non-invasive, multi-target treatment strategy is provided, and at the same time, diabetic metabolic disorders and retinal microvascular lesions are improved, making up for the singularity and limitations of the prior art; 2. Atractylenolide II can effectively reduce the blood glucose of diabetic mice; 3. Atractylenolide II can effectively improve the glucose tolerance of diabetic mice; 4. Atractylenolide II can relieve the vascular occlusion of diabetic mice and make the blood vessel morphology of diabetic mice closer to that of control group mice; 5. Atractylenolide II can reduce the degree of pathological damage to the retinal tissue of diabetic mice. Description of the drawings

[0018] Figure 1 It is a schematic diagram of the blood glucose of mice in each group.

[0019] Figure 2 It is a schematic diagram of the fasting glucose tolerance of mice in each group.

[0020] Figure 3 It is a schematic diagram of the area under the curve of the fasting glucose tolerance of mice in each group.

[0021] Figure 4 It is a schematic diagram of the food intake of mice in each group.

[0022] Figure 5 It is a schematic diagram of the water intake of mice in each group.

[0023] Figure 6 It is a schematic diagram of the PAS staining of the retina of mice in each group.

[0024] Figure 7 It is a schematic diagram of the H&E staining of the retina of mice in each group. Detailed description of the specific implementation mode

[0025] The following is a detailed description of the specific implementation mode of the present invention.

[0026] The "scope" disclosed by the present invention is defined in the form of a lower limit and an upper limit. A given scope is defined by selecting a lower limit and an upper limit, and the selected lower limit and upper limit define the boundaries of a particular scope. The scope defined in this way can include the end values or not include the end values, and can be combined arbitrarily, that is, any lower limit can be combined with any upper limit to form a scope. For example, if a scope of 10 to 50 is listed for a specific parameter, it is understood that scopes of 10 to 40 and 20 to 50 are also contemplated. In addition, if the minimum range values 1 and 2 are listed, and if the maximum range values 3, 4, and 5 are listed, then the following ranges are all contemplated: 1 to 3, 1 to 4, 1 to 5, 2 to 3, 2 to 4, and 2 to 5. In this application, unless otherwise specified, the numerical range "a to b" represents an abbreviated representation of any real number combination between a and b, where a and b are both real numbers. For example, the numerical range "0 to 5" means that all real numbers between "0 to 5" have been fully listed herein, and "0 to 5" is only an abbreviated representation of these numerical combinations.

[0027] If there is no special instruction, all embodiments and optional embodiments of this application can be combined with each other to form a new technical solution.

[0028] If there is no special instruction, all technical features and optional technical features of this application can be combined with each other to form a new technical solution.

[0029] If there is no special instruction, all steps of this application can be carried out in sequence or randomly, preferably in sequence. For example, the method includes steps (a) and (b), which means that the method can include steps (a) and (b) carried out in sequence, or can also include steps (b) and (a) carried out in sequence. For example, it is mentioned that the method may further include step (c), which means that step (c) can be added to the method in any order. For example, the method can include steps (a), (b), and (c), or can also include steps (a), (c), and (b), or can also include steps (c), (a), and (b), etc.

[0030] If there is no special instruction, the "including" and "comprising" mentioned in this application mean open-ended or can also be closed-ended. For example, the "including" and "comprising" can mean that other components not listed can also be included or comprised, or can also mean only including or comprising the listed components.

[0031] If there is no special instruction, the reaction is carried out under normal temperature and normal pressure conditions.

[0032] If there is no special instruction, all parts or percentages are parts by weight or percentages by weight.

[0033] In the present invention, the substances used are all known substances and can be purchased or synthesized by known methods.

[0034] In the present invention, the devices or equipment used are all conventional devices or equipment known in the art and can all be purchased.

[0035] Use of atractylenolide II as the only active ingredient in the preparation of a medicament for treating diabetic retinopathy, wherein: the structural formula of the atractylenolide II is as follows: 。

[0036] Furthermore, in the above application, the medicament is composed of atractylenolide II and a pharmaceutically acceptable carrier.

[0037] In one embodiment, the medicament exists in the form of tablets, and the tablets are ordinary compressed tablets. In another embodiment, the medicament exists in the form of tablets, and the tablets are sugar-coated tablets. In another embodiment, the medicament exists in the form of tablets, and the tablets are effervescent tablets. In another embodiment, the medicament exists in the form of tablets, and the tablets are chewable tablets. In another embodiment, the medicament exists in the form of tablets, and the tablets are multilayer tablets. In another embodiment, the medicament exists in the form of tablets, and the tablets are sustained-release tablets. In another embodiment, the medicament exists in the form of tablets, and the tablets are controlled-release tablets.

[0038] In one embodiment, the medicament exists in the form of capsules.

[0039] In one embodiment, the medicament exists in the form of an oral liquid preparation, and the oral liquid preparation is a solution. In another embodiment, the medicament exists in the form of an oral liquid preparation, and the oral liquid preparation is a syrup. In another embodiment, the medicament exists in the form of an oral liquid preparation, and the oral liquid preparation is an emulsion. In another embodiment, the medicament exists in the form of an oral liquid preparation, and the oral liquid preparation is a suspension.

[0040] In one embodiment, the medicament exists in the form of granules, and the granules are soluble granules. In another embodiment, the medicament exists in the form of granules, and the granules are suspension-type granules. In yet another embodiment, the medicament exists in the form of granules, and the granules are effervescent-type granules.

[0041] A medicament for treating diabetic retinopathy, the medicament contains atractylenolide II as the only active ingredient, and the structural formula of the atractylenolide II is as follows: 。

[0042] In one embodiment, the dosage of the above-mentioned drug for treating diabetic retinopathy is 30 mg / kg. In another embodiment, the dosage of the above-mentioned drug for treating diabetic retinopathy is 45 mg / kg. In yet another embodiment, the dosage of the above-mentioned drug for treating diabetic retinopathy is 60 mg / kg.

[0043] Animals: SPF-grade C57 mice, male, weighing 18 - 22 g. After one week of adaptive feeding, the mice were used for the experiment.

[0044] Reagents: STZ (streptozotocin); Atractylenolide II.

[0045] Example 1 1.1. Grouping of experimental animals and model establishment: Grouping: The mice were randomly divided into a control group, a model group, a low-dose Atractylenolide II group (30 mg / kg), and a high-dose Atractylenolide II group (60 mg / kg), with 10 mice in each group.

[0046] 1.2. Model establishment: Except for the control group, the mice in the other groups were modeled by intraperitoneal injection of STZ (50 mg / kg), and the control group was injected with an equal volume of sodium citrate buffer solution.

[0047] STZ can selectively damage pancreatic islet β cells, induce hyperglycemia in mice, thus simulating the diabetic state and providing a basic pathological condition for the occurrence and development of diabetic retinopathy.

[0048] 1.3. Administration: After successful modeling, the mice in the low-dose Atractylenolide II group and the high-dose Atractylenolide II group were intragastrically administered the corresponding dose of Atractylenolide II, and the model group and the control group were given an equal volume of normal saline, and the administration was continued for 8 weeks.

[0049] Example 2: Observation indicators 2.1. Blood glucose detection: Blood was collected regularly every week to detect the random blood glucose levels of the mice in each group, and observe the regulatory effect of Atractylenolide II on blood glucose.

[0050] 2.2. Fasting glucose tolerance test: During the administration period, the fasting glucose tolerance test was regularly performed to understand whether the glucose tolerance of the mice in each group was improved.

[0051] 2.3. Behavioral observation: Record the food intake and water intake of the mice in each group, and observe the changes in polyphagia and polydipsia.

[0052] 2.4. Histopathological examination of retina: After the experiment, the retina tissues of the mice were taken out, stained with H&E and PAS, and observe the morphological changes of the retina tissues and the vascular occlusion conditions.

[0053] Example 3: Experimental Results 3.1 Blood Glucose Level: Compared with the model group, the random blood glucose levels of the mice in the low-dose atractylenolide II group and the high-dose atractylenolide II group were significantly decreased (P<0.05 or P<0.01), and the hypoglycemic effect of the high-dose group was more obvious (as Figure 1 shown).

[0054] 3.2 Fasting Glucose Tolerance Results: The fasting glucose tolerance curves of the mice in the low-dose atractylenolide II group and the high-dose atractylenolide II group showed that their glucose tolerance was significantly improved, the blood glucose peak value was decreased, and the speed of restoring the basal blood glucose level was accelerated (as Figure 2 and Figure 3 shown).

[0055] 3.3 Behavioral Performance: During the drug administration period, the phenomena of polyphagia and polydipsia in the mice in the low-dose atractylenolide II group and the high-dose atractylenolide II group were gradually alleviated. Compared with the model group, the food intake and water intake were significantly decreased (P<0.05 or P<0.01) (as Figure 4 and Figure 5 shown).

[0056] 3.4 Observation by PAS staining showed that the retinal vascular atresia in the model group mice was relatively severe, and the vascular atresia in the mice in the low-dose atractylenolide II group and the high-dose atractylenolide II group was alleviated, and the retinal vascular morphology was closer to that of the control group (as Figure 6 shown).

[0057] 3.5 Retinal Pathological Changes: The results of H&E staining showed that obvious pathological changes occurred in the retinal tissues of the model group mice, such as vascular dilation, exudation, hemorrhage, and disordered arrangement of ganglion cells, while the degree of pathological damage to the retinal tissues of the mice in the low-dose atractylenolide II group and the high-dose atractylenolide II group was alleviated (as Figure 7 shown).

[0058] The above has made a detailed description of the embodiments of the present invention. However, the present invention is not limited to the above embodiments, and various changes can be made without departing from the gist of the present invention within the knowledge scope of those of ordinary skill in the art to which the present invention pertains.

Claims

1. Use of atractylenolide II as the sole active ingredient in the preparation of a medicament for treating diabetic retinopathy, wherein: the structural formula of the atractylenolide II is as follows: 。 2. The application according to claim 1, characterized in that, The medicament consists of atractylenolide II and a pharmaceutically acceptable carrier.

3. The application according to claim 2, wherein The medicament exists in the form of tablets, capsules, oral liquid preparations, or granules.

4. The application according to claim 3, characterized in that, The tablets are one of ordinary compressed tablets, sugar-coated tablets, effervescent tablets, chewable tablets, multi-layer tablets, sustained-release tablets, or controlled-release tablets.

5. The application according to claim 3, characterized in that, The oral liquid preparations are one of solutions, syrups, emulsions, or suspensions.

6. The application according to claim 3, wherein The granules are one of soluble granules, suspension granules, or effervescent granules.

7. A drug for treating diabetic retinopathy, characterized in that, The medicament contains atractylenolide II as the sole active ingredient, and the structural formula of the atractylenolide II is as follows: 。

Images