Application of glutaric acid or pharmaceutical salt thereof in medicine, pharmaceutical composition and pharmaceutical preparation

Abstract

The invention discloses application of glutaric acid or medicinal salt thereof in medicine, a medicine composition and a medicine preparation, and belongs to the field of medicine application. According to the application of the glutaric acid or the medicinal salt thereof in preparing the medicine for inhibiting neurodegeneration, promoting lysosomal activity and treating the Alzheimer's disease, a new potential treatment medicine is provided for treatment of the Alzheimer's disease, and a more effective scheme for treating the Alzheimer's disease is provided.

Description

TECHNICAL FIELD

[0001] The application relates to the use of glutaric acid or a pharmaceutically acceptable salt thereof in medicine, a pharmaceutical composition and a pharmaceutical preparation, and belongs to the field of medical use. BACKGROUND

[0002] Glutaric acid, also known as gelatin acid, a, gamma-propane dicarboxylic acid, 1,3-propane dicarboxylic acid, and has the chemical formula: ; CAS: 110-94-1; molecular weight: 132.14; melting point: 97.5-98 DEG C; boiling point: 302 DEG C (760 mmHg); water solubility: 430 g / L (20 DEG C); appearance: monoclinic columnar crystal or needle-like crystal (in benzene); solubility: easily soluble in water, anhydrous ethanol, diethyl ether and chloroform, slightly soluble in petroleum ether.

[0003] Alzheimer's disease (AD) is the world's first neurodegenerative disease. In recent years, the incidence of Alzheimer's disease in people over 60 years old has shown a gradually increasing trend, and its high incidence has brought great burden to society and family. The main pathological features of the disease are neurofibrillary tangles and extracellular amyloid aggregates caused by intracellular Tau protein hyperphosphorylation. However, so far only a few drugs have been approved for the treatment of Alzheimer's disease, such as acetylcholinesterase inhibitors and N-methyl-D-aspartate receptor antagonists, and these drugs cannot completely cure Alzheimer's disease, but can only achieve partial relief of symptoms and cannot delay the progression of the disease, so it is imperative to screen new and efficient drugs. SUMMARY

[0004] In order to solve the above problems, the use of glutaric acid or a pharmaceutically acceptable salt thereof in the preparation of a drug for inhibiting neurodegeneration and treating Alzheimer's disease is provided, which provides a more effective treatment for patients with Alzheimer's disease.

[0005] According to a first aspect of the application, the use of glutaric acid or a pharmaceutically acceptable salt thereof in the preparation of a drug for inhibiting neurodegeneration is provided.

[0006] Inhibiting neurodegeneration is one of the core goals of Alzheimer's disease research and intervention, and the drug prepared from glutaric acid or a pharmaceutically acceptable salt thereof can inhibit neurodegeneration, thereby improving the cognitive function of the human body and improving the learning and memory ability related to aging, so as to be used as a drug for preventing and / or treating Alzheimer's disease, and to achieve the prevention and / or treatment of Alzheimer's disease.

[0007] According to a second aspect of the application, the use of glutaric acid or a pharmaceutically acceptable salt thereof in the preparation of a drug for promoting lysosomal activity is provided.

[0008] According to a third aspect of the present application, there is provided a use of glutaric acid or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing and / or treating Alzheimer's disease.

[0009] The present application finds that glutaric acid can effectively improve the paralysis phenotype of a nematode model of Alzheimer's disease, and glutaric acid achieves the effect of improving the symptoms of Alzheimer's disease by enhancing lysosomal activity and inhibiting neurodegeneration, thereby providing a new therapeutic drug for the treatment of Alzheimer's disease and a new treatment idea for the development of drugs for Alzheimer's disease.

[0010] Optionally, the glutaric acid or the pharmaceutically acceptable salt thereof includes glutaric acid hydrate, glutaric acid alcoholate, a pharmaceutically acceptable salt of glutaric acid hydrate, or a pharmaceutically acceptable salt of glutaric acid alcoholate.

[0011] Specifically, the glutaric acid hydrate includes glutaric acid monohydrate.

[0012] Optionally, the concentration of the glutaric acid or the pharmaceutically acceptable salt thereof is 10 μM.

[0013] According to a fourth aspect of the present application, there is provided a pharmaceutical composition for preventing and / or treating Alzheimer's disease, wherein the pharmaceutical composition takes glutaric acid or a pharmaceutically acceptable salt thereof as an active ingredient.

[0014] The pharmaceutical composition can reduce the paralysis rate of a C. elegans model of Alzheimer's disease, enhance lysosomal activity to inhibit neurodegeneration, and thus the pharmaceutical composition can be used not only for treating Alzheimer's disease, improving the memory of patients with Alzheimer's disease, but also for providing a new therapeutic drug for the treatment of Alzheimer's disease and a new treatment idea for the development of drugs for Alzheimer's disease. In addition, the pharmaceutical composition can also be used for preventing Alzheimer's disease and reducing the incidence of Alzheimer's disease, especially in people over 60 years old.

[0015] Optionally, the pharmaceutically acceptable salt of glutaric acid includes disodium glutarate, dilithium glutarate, etc.

[0016] Optionally, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient.

[0017] Specifically, the pharmaceutically acceptable excipient includes at least one of a filler, a diluent, a disintegrant, a binder, a lubricant, a preservative, a colorant, a flavoring agent, a coating material, a pH adjuster, a dispersant, a thickening agent, a plasticizer, an emulsifying agent, an isotonicity adjuster, a suspending agent, and an analgesic.

[0018] Optionally, the pharmaceutical composition further comprises a pharmaceutical excipient.

[0019] Specifically, for tablets, the pharmaceutical excipient includes at least one of a filler, a binder, a disintegrant, and a lubricant; for pills, the pharmaceutical excipient includes at least one of water, wine, vinegar, and medicinal juice. Preferably, the pharmaceutical excipient further includes a surfactant, a polymer, a fatty acid, and a solvent.

[0020] According to a fifth aspect of the present application, a pharmaceutical preparation is provided, which includes the pharmaceutical composition of any one of the above.

[0021] Specifically, the pharmaceutical composition can be prepared into any pharmaceutically acceptable dosage form, including but not limited to: decoction, powder, pill, wine, lozenge, gel, tea, koji, cake, lotion, stick, thread, strip, nail, moxibustion, paste, pill, liposome preparation, aerosol, injection, mixture, oral ampoule, tablet, capsule, dripping pill, emulsion, film or sponge.

[0022] Optionally, the pharmaceutical preparation includes a liquid dosage form or a solid dosage form. Optionally, the liquid dosage form includes a solution, an injection, an infusion or an oral liquid; the solid dosage form includes a tablet, a capsule, a powder or a granule.

[0023] According to a sixth aspect of the present application, the pharmaceutical composition of any one of the above or the pharmaceutical preparation of the above is used for preparing a medicament for inhibiting neurodegeneration, enhancing lysosome activity, preventing and / or treating Alzheimer's disease.

[0024] The beneficial effects of the present application include but are not limited to: 1. The present application finds that glutaric acid has the effect of improving the symptoms of Alzheimer's disease, providing a new treatment direction for the treatment of Alzheimer's disease, and providing a new treatment idea for the development of Alzheimer's disease drugs.

[0025] 2. The present application uses glutaric acid to effectively improve the paralysis phenotype of the C. elegans model of Alzheimer's disease, and glutaric acid inhibits neurodegeneration by enhancing lysosome activity, providing a more effective treatment for patients with Alzheimer's disease.

[0026] 3. The main pathological basis of Alzheimer's disease is neurodegeneration, and the present application finds a new small molecule drug glutaric acid for treating Alzheimer's disease, which stabilizes the intracellular environment of neurons and achieves the effect of preventing and treating Alzheimer's disease. BRIEF DESCRIPTION OF DRAWINGS

[0027] The accompanying drawings, which are included to provide a further understanding of the present application, form a part of the present application and illustrate the illustrative embodiments of the present application and its description, which are used to explain the present application and do not constitute improper limitations on the present application. In the drawings: Figure 1 The graph of the paralysis rate of the Alzheimer's disease C. elegans model involved in Example 1 of the present application.

[0028] Figure 2 The graph of the display of the nerve axon and the graph of the statistics involved in Example 2 of the present application.

[0029] Figure 3 The graph of the display of the fluorescence intensity and the graph of the statistics involved in Example 3 of the present application. DETAILED DESCRIPTION

[0030] The present application will be described in detail below with reference to examples, but the present application is not limited to these examples.

[0031] Unless otherwise specified, the raw materials in the examples of the present application are purchased through commercial channels.

[0032] Unless otherwise specified, the methods used in the examples of the present application are conventional methods in the prior art.

[0033] Glutaric acid working solution was prepared for use in the following examples: Take glutaric acid powder 10 mg, dissolve in 1513 μL ultrapure water to obtain 50 mM stock solution, and store the stock solution in a -20°C refrigerator. When used in the following examples, the stock solution is diluted with ultrapure water to 10 μM working solution, i.e. the glutaric acid working solution used in the following examples has a concentration of 10 μM.

[0034] Example 1 Reducing the paralysis rate of the Alzheimer's disease model The Alzheimer's disease C. elegans model was fed with glutaric acid working solution with a concentration of 10 μM, and after three days, L4 stage nematodes were picked for paralysis detection (heat shock treatment: 25°C, 24 hours). The Alzheimer's disease C. elegans model fed with E. coli (OP50) without glutaric acid was used as a control group, and the test results are shown in Figure 1 .

[0035] Figure 1 In <0.001, it can be seen that the paralysis rate of the group fed with 10 μM glutaric acid working solution is lower than 40%, the paralysis rate of the group fed with OP50 control is higher than 80%, and the paralysis rate of the group fed with 10 μM glutaric acid working solution is significantly lower than that of the group fed with OP50 control, thus it can be proved that glutaric acid can significantly improve the paralysis rate of the Alzheimer's disease model.

[0036] Example 2 Inhibiting nerve degeneration Since neurodegeneration is one of the core pathological features of AD patients, it is necessary to detect whether glutaric acid can alleviate the neurodegenerative changes of AD model nematodes. The Aβ transgenic AD model strain was selected, and it was combined with PGP-6.0, which can label D-type motor neurons of C. elegans, to detect whether glutaric acid can alleviate the neurodegenerative changes of AD model nematodes.unc-25 GFP strain were crossed. The AD model nematodes were fed with glutaric acid working solution at a concentration of 10 μM, and wild type nematodes and AD model nematodes were fed with E. coli OP50 without glutaric acid. After four days, day 1 (adult stage) was selected, and then the number of nerve axons of the three groups of nematodes was counted using ZEISS LSM.

[0037] The test results are shown in Figure 2 , and the number of axons of the AD model nematodes was significantly reduced. Figure 2 <0.0001, Figure 2 In Fig. (a), the axon fluorescence of the wild type nematodes fed with OP50 is shown, Figure 2 In Fig. (b), the axon fluorescence of the AD model nematodes fed with OP50 without glutaric acid is shown, Figure 2 In Fig. (c), the axon fluorescence of the AD model nematodes fed with 10 μM glutaric acid working solution is shown, Figure 2 In Fig. (d), the Figure 2 In Figs. (a), (b), and (c), the statistical graphs are shown. It can be seen from Figure 2 that the number of axons of the AD model nematodes fed with 10 μM glutaric acid working solution can be restored to the level of the number of axons of the wild type nematodes. Therefore, it can be proved that glutaric acid can effectively increase the number of axons and inhibit the nerve degeneration of the AD model.

[0038] Example 3 Promoting lysosome activity In order to detect lysosome activity, P hsp-16.2 NUC-1 pHTomato (abbreviated as pHTomato, which can detect lysosome acidity, and the lower the fluorescence intensity, the lower the acidity and the stronger the activity) was tested.

[0039] The pHTomato nematodes were fed with glutaric acid working solution at a concentration of 10 μM, and after three days, the L4 stage nematodes were incubated at 33°C for 30 minutes. Then, the nematodes were cultured at 20°C for 24 hours (day 1, i.e., adult stage), and then ZEISS LSM was used to take pictures of the pHTomato nematodes and count the relative fluorescence intensity values. The pHTomato nematodes fed with E. coli (OP50) without glutaric acid were used as a control group, and the test results are shown in Figure 3 .

[0040] Figure 3 In Fig. (a), the fluorescence intensity of the nematodes fed with OP50 is shown, <0.0001, Figure 3 In Fig. (a), the fluorescence intensity of the nematodes fed with OP50 is shown, Figure 3 ​Fig. 2 is a graph showing the fluorescence intensity of the nematodes fed with glutaric acid working solution at 10 μM, Figure 3 Fig. 3 is a graph showing the fluorescence intensity of the nematodes fed with OP50 and glutaric acid working solution at 10 μM, Figure 3 It can be seen that the average fluorescence intensity of the nematodes fed with glutaric acid working solution at 10 μM is lower than that of the nematodes fed with OP50, thus it can be proved that glutaric acid plays a role in enhancing lysosomal activity.

[0041] According to the operation and test results of the above-mentioned Examples 1-3, it can be known that the glutaric acid of the present application can reduce the paralysis rate of the Alzheimer's disease C. elegans model, enhance lysosomal activity, and reduce neural degeneration. Therefore, it is found by the present application that glutaric acid and its pharmaceutically acceptable salts can stabilize the intracellular environment of neurons from a mechanism, and can not only be used for treating Alzheimer's disease, but also provide a new treatment direction for the treatment of Alzheimer's disease, and provide a new treatment idea for the development of Alzheimer's disease drugs. Meanwhile, it can also be used for preventing Alzheimer's disease and reducing the incidence of Alzheimer's disease.

[0042] When the concentration of the glutaric acid working solution is 10 μM, it can reduce the paralysis rate of the Alzheimer's disease C. elegans model, enhance lysosomal activity, and reduce neural degeneration.

[0043] The above is only an embodiment of the present application, and the protection scope of the present application is not limited by these specific embodiments, but is determined by the claims of the present application. The present application can have various changes and variations for those skilled in the art. Any modification, equivalent replacement, improvement, etc. within the technical thought and principle of the present application shall be included in the protection scope of the present application.

Claims

1. Use of glutaric acid or its pharmaceutically acceptable salts in the preparation of drugs that inhibit neurodegeneration.

2. Use of glutaric acid or its pharmaceutically acceptable salts in the preparation of drugs that promote lysosomal activity.

3. Use of glutaric acid or its pharmaceutically acceptable salts in the preparation of medicines for the prevention and / or treatment of Alzheimer's disease.

4. The use according to any one of claims 1-3, characterized in that, The glutaric acid or its pharmaceutically usable salts include glutaric acid hydrate, glutaric acid alcohol, pharmaceutically usable glutaric acid salt hydrate, and pharmaceutically usable glutaric acid salt alcohol.

5. A pharmaceutical composition for the prevention and / or treatment of Alzheimer's disease, characterized in that, The pharmaceutical composition uses glutaric acid or its pharmaceutically acceptable salt as the active ingredient.

6. The pharmaceutical composition according to claim 5, characterized in that, It also includes pharmaceutically acceptable excipients.

7. The pharmaceutical composition according to claim 5, characterized in that, It also includes pharmaceutical excipients.

8. A pharmaceutical preparation, characterized in that, The pharmaceutical preparation comprises the pharmaceutical composition according to any one of claims 5-7.

9. The pharmaceutical preparation according to claim 8, characterized in that, The pharmaceutical preparations include liquid dosage forms and solid dosage forms; Preferably, the liquid dosage form includes solutions, injections, infusions, or oral solutions; the solid dosage form includes tablets, capsules, powders, or granules.

10. The use of the pharmaceutical composition of any one of claims 5-7 or the pharmaceutical preparation of any one of claims 8-9 in the preparation of a drug for inhibiting neurodegeneration, promoting lysosomal activity, and preventing and / or treating Alzheimer's disease.

Images