Application of 4MCSA in preparation of medicine for preventing and / or treating neurodegenerative diseases

Abstract

The invention belongs to the technical field of biological medicines, and particularly relates to an application of 4MCSA in preparation of a medicine for preventing and / or treating neurodegenerative diseases, and the 4MCSA is a compound shown as a formula (I). Research finds that the compound 4MCSA shown in the formula (I) has a remarkable effect of preventing and / or treating neurodegenerative diseases, meanwhile, the compound 4MCSA has high binding activity with extracellular cyclophilin and can be further combined with other position modifications of the extracellular cyclophilin, the binding capacity of the extracellular cyclophilin of the molecule is synergistically improved, and the compound 4MCSA can be used for preventing and / or treating neurodegenerative diseases. Therefore, the influence of the compound in neuron activity can be reduced, and the compound can be used for preparing medicines for preventing and / or treating neurodegenerative diseases. # imgabs0 # formula (I)

Description

Technical Field

[0001] The present application belongs to the field of biomedicine technology, and specifically relates to the use of 4MCSA in the preparation of a drug for preventing and / or treating neurodegenerative diseases, wherein 4MCSA is a compound represented by formula (I). Background Art

[0002] Alzheimer's disease (AD) is a common neurodegenerative disease and the leading form of dementia, accounting for 60-80% of all cases. β-amyloid (Aβ) plaques and neurofibrillary tau tangles are the two main pathological hallmarks of AD and serve as the basis for distinguishing AD from non-AD dementias. There is currently no effective treatment for AD. While existing marketed drugs can provide some relief, they cannot effectively slow or prevent AD progression, resulting in limited therapeutic efficacy.

[0003] To date, APOE4 is the strongest risk gene for late-onset AD, increasing the incidence of AD by 3-15 times. APOE is a 299-amino acid glycoprotein that exerts important physiological functions by binding to its receptors, including LRP1, LRP2, LDLR, and APOER2 / LRP8. Different APOE subtypes (APOE2, APOE3, and APOE4) have different binding capacities to their receptors.

[0004] Cyclophilins (CyPs) are a family of multifunctional proteins with a highly conserved PPIase domain, widely distributed in mammals, plants, insects, fungi, and bacteria. To date, the human cyclophilin family comprises 19 proteins, including hCypA, hCypB, hCypC, hCypD, hCypE, hCyp40, and hCypNK. Studies have shown that CyPs play important roles in a variety of pathological processes, including pathogen infection, inflammatory responses, cardiovascular diseases such as atherosclerosis and chronic heart failure, lipid metabolism disorders, endoplasmic reticulum stress-related diseases such as diabetes, and cancer.

[0005] 4MCSA is an avidin inhibitor prepared by a specific synthetic method. No studies have yet reported the application of 4MCSA in neurodegenerative diseases. Summary of the Invention

[0006] Based on this, one embodiment of the present application provides a use of 4MCSA in the preparation of a drug for preventing and / or treating neurodegenerative diseases.

[0007] On the one hand, the present application provides a use of a compound represented by formula (I) in the preparation of a medicament for preventing and / or treating neurodegenerative diseases;

[0008] Formula (I).

[0009] In some embodiments, the neurodegenerative disease prevented and / or treated by the drug includes Alzheimer's disease.

[0010] In some embodiments, the Alzheimer's disease includes APOE4 gene-mediated Alzheimer's disease.

[0011] In some embodiments, the drug can alleviate the onset of Alzheimer's disease.

[0012] In some embodiments, the drug is capable of inhibiting the decrease in mitochondrial membrane potential caused by CypA.

[0013] In some embodiments, the medicament is capable of reducing lactate secretion induced by eCypA.

[0014] In some embodiments, the drug shifts neurons from relying on glycolysis to relying on mitochondria to produce ATP.

[0015] In some embodiments, the drug comprises a compound represented by formula (I) and a pharmaceutically acceptable carrier.

[0016] In some embodiments, the dosage form of the drug includes solid preparations, semisolid preparations and liquid preparations.

[0017] In some embodiments, the compound represented by formula (I) is the only active ingredient in the pharmaceutical composition.

[0018] The present application study found that the compound 4MCSA represented by formula (I) has a significant effect in preventing and / or treating neurodegenerative diseases. At the same time, it has a high binding activity with extracellular cyclophilin A and can be further combined with other modifications of extracellular cyclophilin A (P1, P4, etc.) to synergistically improve the binding ability of this type of molecule to extracellular cyclophilin A, thereby reducing its impact on neuronal activity and having low cytotoxicity. It can be used to prepare drugs for preventing and / or treating neurodegenerative diseases. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] In order to more clearly illustrate the technical solutions in the embodiments of the present application and to more fully understand the present application and its beneficial effects, the following is a brief introduction to the drawings required for describing the embodiments. Obviously, the drawings described below are only some embodiments of the present application. Those skilled in the art can also derive other drawings based on these drawings without inventive effort.

[0020] Figure 1 This figure shows the changes in neuronal lactate and ATP during motor learning in humanized APOE4 mice after 4MCSA treatment;

[0021] Figure 2 This figure shows the changes in neuronal dendritic calcium activity during motor learning in humanized APOE4 mice after 4MCSA treatment;

[0022] Figure 3 Extracellular cyclophilin A (eCypA) reduces the mitochondrial membrane potential of glial cells BV2, while the eCypA inhibitor 4MCSA inhibits the decrease in mitochondrial membrane potential caused by CypA;

[0023] Figure 4 Extracellular cyclophilin A (eCypA) promoted glycolysis and lactate secretion in BV2 cells, while the eCypA inhibitor 4MCSA reduced lactate secretion induced by eCypA;

[0024] Figure 5 eCypA can synergistically promote neuroinflammation in BV2 microglia under Aβ stimulation. DETAILED DESCRIPTION

[0025] Below in conjunction with embodiment and example, the application is described in further detail.Should be understood that these embodiment and example are only used to illustrate the application and are not used to limit the scope of the application, and the purpose of providing these embodiment and example is to make the understanding of the disclosure of the application more thorough and comprehensive.It should also be understood that the application can be implemented in many different forms, is not limited to the embodiment and example described herein, and those skilled in the art can make various changes or modifications without violating the connotation of the application, and the equivalent form obtained also falls within the protection scope of the application.In addition, in the description hereinafter, a large amount of specific details are given in order to provide a more complete understanding of the application, and it should be understood that the application can be implemented without one or more of these details.

[0026] Unless otherwise defined, 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 application belongs.

[0027] the term

[0028] Unless otherwise specified or incompatible herewith, the terms and phrases used herein shall have the following meanings:

[0029] The terms "and / or", "or / and", and "and / or" used herein include any one of two or more related listed items, and also include any and all combinations of the related listed items, wherein the arbitrary and all combinations include any combination of two related listed items, any more related listed items, or all related listed items. It should be noted that when at least three items are connected by at least two conjunctions selected from "and / or", "or / and", and "and / or", it should be understood that in this application, the technical solution undoubtedly includes technical solutions connected by "logical and" and also undoubtedly includes technical solutions connected by "logical or". For example, "A and / or B" includes three parallel solutions of A, B and A+B. For example, the technical solution of "A, and / or, B, and / or, C, and / or, D" includes any one of A, B, C, and D (that is, the technical solution of all being connected by "logical OR"), and also includes any and all combinations of A, B, C, and D, that is, the combination of any two or any three of A, B, C, and D, and also includes the four-item combination of A, B, C, and D (that is, the technical solution of all being connected by "logical AND").

[0030] In this application, the terms "optionally," "optional," and "optional" mean optional or dispensable, i.e., they refer to either option being selected from two parallel options: "with" or "without." If a technical solution contains multiple "optional" clauses, each "optional" clause is independent unless otherwise specified and there are no contradictions or constraints.

[0031] In this application, the technical features described in an open manner include closed technical solutions composed of the listed features, and also include open technical solutions containing the listed features.

[0032] In this application, when referring to a numerical interval (i.e., a numerical range), unless otherwise specified, the distribution of the optional values ​​within the numerical interval is considered continuous and includes the two numerical endpoints of the numerical range (i.e., the minimum and maximum values), as well as every numerical value between these two numerical endpoints. Unless otherwise specified, when a numerical interval refers only to integers within the numerical interval, it includes the two numerical endpoints of the numerical range, as well as every integer between the two numerical endpoints. In this document, this is equivalent to directly listing each integer. For example, "t is an integer selected from 1 to 10" means that t is any integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10. In addition, when multiple ranges are provided to describe a feature or characteristic, these ranges may be combined. In other words, unless otherwise specified, ranges disclosed herein should be understood to include any and all subranges subsumed therein.

[0033] Unless otherwise specified, the temperature parameters in this application allow for both constant temperature treatment and temperature fluctuations within a certain temperature range. It should be understood that the constant temperature treatment allows for temperature fluctuations within the accuracy range of instrument control. Fluctuations within ranges such as ±5°C, ±4°C, ±3°C, ±2°C, and ±1°C are permitted.

[0034] In this application, % (w / w) and wt% both refer to weight percentage, % (v / v) refers to volume percentage, and % (w / v) refers to mass volume percentage.

[0035] All documents mentioned in this application are cited as references in this application, just as each document is cited as a reference individually. Unless they conflict with the invention purpose and / or technical solution of this application, the cited documents involved in this application are cited in their entirety and for all purposes. When cited documents are involved in this application, the definitions of relevant technical features, terms, nouns, phrases, etc. in the cited documents are also cited. When cited documents are involved in this application, the examples and preferred embodiments of the cited relevant technical features may also be incorporated into this application as references, but are limited to the ability to implement this application. It should be understood that when the cited content conflicts with the description in this application, the present application shall prevail or be adaptively amended according to the description in this application.

[0036] As used herein, "drug" includes any agent, compound, composition, or mixture that provides a physiological and / or pharmacological effect in vivo or in vitro, often with a beneficial effect. The scope of the physiological and / or pharmacological effect produced by the "drug" in vivo is not particularly limited and may have systemic or local effects. The activity of the "drug" is not particularly limited and may be an active substance that interacts with other substances or an inert substance that does not interact.

[0037] Herein, a "composition" may be a combination of multiple substances, and further, may be used in combination or may be a mixture of the combination.

[0038] As used herein, "pharmaceutically acceptable" refers to those ligands, materials, compositions, and / or dosage forms that are suitable for administration to a patient within the scope of sound medical judgment and commensurate with a reasonable benefit / risk ratio.

[0039] As used herein, "pharmaceutically acceptable carriers" include buffers, sterile water for injection, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, that are compatible with the administration of the drug. Each substance must be "pharmaceutically acceptable" in the sense of being compatible with the other ingredients of the formulation and not harmful to the patient. Suitable examples include, but are not limited to: (1) sugars such as lactose, glucose, and sucrose; (2) starches such as corn starch, potato starch, and substituted or unsubstituted β-cyclodextrins; (3) cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository waxes; (9) oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn starch, and maltose. Rice oil and soybean oil; (10) glycols such as propylene glycol; (11) polyols such as glycerol, sorbitol, mannitol and polyethylene glycol; (12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) phosphate buffer; and (21) other nontoxic compatible substances used in pharmaceutical formulations.

[0040] As used herein, "subject" and "patient" refer to animals, preferably mammals, more preferably humans. Subjects include, but are not limited to, patients with a disease, condition, and / or symptom. The term "mammal" primarily refers to warm-blooded vertebrate mammals, including, but not limited to, cats, dogs, rabbits, bears, foxes, wolves, monkeys, deer, mice (e.g., rats, mice), pigs, cattle, sheep, horses, humans, etc., preferably primates, and more preferably humans.

[0041] Preliminary research in this application utilized flow chemistry and Rh(I)-catalyzed asymmetric hydrogenation to achieve the asymmetric synthesis and large-scale preparation of a D-methyl (Me) modification at the P3 position, which plays a key regulatory role in the biological activity of the cyclophilin inhibitor cyclosporine (CsA). This not only enhances its binding activity with eCyPA, but also promotes its further combination with modifications at other positions (P1, P4, etc.), synergistically enhancing the binding ability of this type of molecule with eCyPA, thereby reducing its immunosuppressive activity.

[0042] On this basis, by optimizing the CsA ring-opening, followed by the Edman degradation reaction to selectively remove the P4-methylleucine, the entire process, without column chromatography purification, significantly reduced costs and improved synthesis efficiency. Finally, the maleimide group was selectively introduced and the ring was closed, resulting in the efficient synthesis of a new cell-impermeable CsA derivative, 4MCsA, with a yield of 62%. It was covalently coupled to the Cys34 binding site in endogenous albumin, increasing the specificity of 4MCsA's inhibitory effect on eCypA and reducing its immunosuppressive activity and cytotoxicity.

[0043] On the one hand, the present application provides the use of a compound represented by formula (I) in the preparation of a medicament for preventing and / or treating neurodegenerative diseases;

[0044] Formula (I).

[0045] In some embodiments, the neurodegenerative disease includes Alzheimer's disease.

[0046] In some embodiments, the Alzheimer's disease includes APOE4 gene-mediated Alzheimer's disease.

[0047] APOE4 is a high-risk AD-causing gene mutation. The presence of this mutation increases the risk of developing AD by 3-15 times.

[0048] On the other hand, the present application provides use of a pharmaceutical composition in preparing a medicament for preventing and / or treating a neurodegenerative disease, wherein the pharmaceutical composition comprises an active ingredient and a pharmaceutically acceptable carrier.

[0049] The active ingredient includes a compound represented by formula (I);

[0050] Formula (I).

[0051] In some embodiments, the neurodegenerative disease includes Alzheimer's disease.

[0052] In some embodiments, the Alzheimer's disease includes APOE4 gene-mediated Alzheimer's disease.

[0053] In some embodiments, the pharmaceutical composition and pharmaceutically acceptable excipients are prepared together as a preparation.

[0054] In some embodiments, the pharmaceutical composition and pharmaceutically acceptable excipients are prepared together to form a preparation. Herein, pharmaceutically acceptable excipients include but are not limited to diluents, wetting agents, adhesives, disintegrants, lubricants, color and flavor regulators, solvents, solubilizers, cosolvents, emulsifiers, antioxidants, metal complexing agents, inert gases, preservatives, local analgesics, pH regulators, isotonic or isotonic regulators, etc. Further: diluents, such as starch, sucrose, cellulose, inorganic salts, etc.; wetting agents, such as water, ethanol, etc.; adhesives, such as starch slurry, dextrin, sugar, cellulose derivatives, gelatin, povidone, polyethylene glycol, etc.; disintegrants, such as starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, sodium cross-linked methylcellulose, cross-linked polyvidone, surfactants, Paon disintegrants, etc.; lubricants, such as talc, calcium stearate, magnesium stearate, magnesium lauryl sulfate, micro powder silica gel, polyethylene glycol, etc.; color and flavor regulators, such as pigments, spices, sweeteners, Flavoring agents, adhesives, deodorants, etc., such as fuchsin and xylitol; solvents, such as water, oil, ethanol, glycerol, propylene glycol, polyethylene glycol, dimethyl sulfoxide, liquid paraffin, fatty oil, ethyl acetate, etc.; solubilizers, such as Tweens, sorbents, polyoxyethylene fatty alcohol ethers, soaps, sulfates, sulfonates, etc.; cosolvents, such as organic acids (such as citric acid) and their salts, amide and amine compounds, inorganic salts, polyethylene glycol, povidone, glycerol, etc.; emulsifiers, such as spans, Tweens, sorbents, benzyls, glycerol fatty acid esters, high fatty acid salts, sulfates, sulfonates, gum arabic, tragacanth gum, gelatin, pectin, phospholipids, agar, sodium alginate, hydroxide, silicon dioxide, bentonite, etc.; suspending agents, such as glycerol, syrup, gum arabic, tragacanth gum, agar, sodium alginate, cellulose derivatives, povidone, carbopol, polyvinyl alcohol, thixotropic glue, etc.; antioxidants, such as sulfites, metabisulfites, bisulfites, ascorbic acid, gallic acid and its esters, etc.; metal chelating agents, such as disodium edetate, polycarboxylic acid compounds, etc.; inert gases, such as Nitrogen, carbon dioxide, etc.; preservatives, such as parabens, organic acids and their salts (such as sodium benzoate), quaternary ammonium compounds, chlorhexidine acetate, alcohols, phenols and volatile oils; local analgesics, such as benzyl alcohol, chlorobutanol, lidocaine and procaine; pH adjusters, such as hydrochloric acid, sulfuric acid, phosphoric acid, tartaric acid, acetic acid, sodium hydroxide, sodium bicarbonate, ethylenediamine, meglumine, phosphates, acetates, citric acid, citrate, etc.; isotonic or isotonic adjusters, such as glucose, sodium chloride, sodium citrate, sorbitol and xylitol, etc.

[0055] It can be understood that the diluent described in the embodiments of the present application can also be called a filler, and plays the same role in the pharmaceutical preparation; the water described in the embodiments of the present application is water that meets the requirements of the pharmaceutical preparation, such as water for injection, purified water, etc., and the oil is oil for injection; the preservative described in the embodiments of the present application can also be called an antibacterial agent, which plays a role in inhibiting microbial growth and extending the shelf life in the preparation; the lubricant in the embodiments of the present application contains a flow aid, an anti-adhesive agent, etc.; the sugar described in the embodiments of the present application can be powdered sugar or syrup, and the type of sugar is not limited to glucose; the spices described in the embodiments of the present application include but are not limited to flavors.

[0056] In some embodiments, the dosage form of the preparation includes solid preparation, semisolid preparation and liquid preparation.

[0057] In some embodiments, the compound represented by formula (I) is the only active ingredient in the pharmaceutical composition.

[0058] In some embodiments, the prevention and / or treatment of neurodegenerative diseases comprises one or more of reducing neuronal calcium activity, inhibiting the decrease in mitochondrial membrane potential caused by CypA, and reducing lactate secretion induced by eCypA.

[0059] The pharmaceutical composition of the present application contains an effective amount of a compound represented by formula (I). As used herein, "effective amount" refers to a dosage of the component to which the term corresponds to achieve treatment, prevention, alleviation, and / or relief of a specific disease, condition, and / or symptom in a subject. As used herein, unless otherwise specified, it refers to a dosage that achieves treatment, prevention, alleviation, and / or relief of symptoms of neurodegenerative diseases. The subject herein can be a mammal. Furthermore, the subject can be a mouse or a human.

[0060] According to the above application, the present application also provides a method for preventing or treating a neurodegenerative disease, comprising administering a therapeutically effective amount of a compound represented by formula (I) to a patient in need thereof. That is, a therapeutically effective amount of a compound represented by formula (I) is administered to the patient. As used herein, "patient" refers to an animal, preferably a mammal, more preferably a human. The term "mammal" primarily refers to warm-blooded vertebrate mammals, including but not limited to cats, dogs, rabbits, bears, foxes, wolves, monkeys, deer, mice, pigs, cattle, sheep, horses, and humans, preferably primates, and more preferably humans.

[0061] Administration: There is no particular limitation on the dosage form and administration of the compound represented by formula (I) (4MCSA) or its pharmaceutical composition.

[0062] Representative routes of administration include, but are not limited to, oral, rectal, parenteral (intravenous, intramuscular or subcutaneous) injection, and topical administration.

[0063] Solid dosage forms for oral administration include tablets, capsules, granules, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets, and pills, the dosage form may also include a buffer. Solid dosage forms such as tablets, dragees, capsules, pills, and granules may be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may include opacifying agents, and the release of the active compound or compounds in such compositions may be delayed in a certain portion of the digestive tract. Examples of embedding components that may be used are polymeric substances and waxes. If desired, the active compound may also be microencapsulated with one or more of the above-mentioned excipients.

[0064] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers, and emulsifiers, specifically ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures thereof. In addition to these inert diluents, the composition may also contain adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and fragrances. For example, a suspension may contain a suspending agent, specifically ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide, and agar, or mixtures thereof.

[0065] Compositions for rectal or parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous or nonaqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0066] Dosage forms for topical administration include ointments, powders, patches, sprays and inhalants, which are prepared by mixing the active ingredient with a pharmaceutically acceptable carrier and any preservatives, buffers, or propellants as necessary under sterile conditions.

[0067] The embodiments of the present application will be described in detail below with reference to the examples. It should be understood that these examples are intended to illustrate the present application only and are not intended to limit the scope of the present application. The experimental methods for which specific conditions are not specified in the following examples are preferably referred to the guidance provided in the present application, and can also be based on the experimental manuals or conventional conditions in this area, or according to the conditions recommended by the manufacturer, or with reference to experimental methods known in the art.

[0068] In the following specific examples, the measured parameters of raw material components may have slight deviations within the range of weighing accuracy unless otherwise specified. For temperature and time parameters, acceptable deviations caused by instrument testing accuracy or operational accuracy are allowed.

[0069] It should be understood that in the various embodiments of the present application, the size of the serial numbers of the above-mentioned processes does not mean the order of execution. The execution order of each process should be determined by its function and internal logic, and should not constitute any limitation on the implementation process of the embodiments of the present application.

[0070] Example 1

[0071] 1. Construction of a humanized APOE4 mouse model

[0072] Humanized APOE4 mice were constructed and validated by Shanghai South Model Organisms Development Co., Ltd. The resulting APOE4 homozygous mice were co-housed and bred, and experiments were conducted using either 5-8 week-old female or male mice.

[0073] 2. Changes in neuronal lactate and ATP during motor learning in humanized APOE4 mice after treatment with the compound represented by Formula I (4MCSA) of the present application.

[0074] By injecting AAV viruses carrying lactate or ATP fluorescent indicator protein expression elements into the motor cortex area, lactate or ATP fluorescent indicator proteins are specifically expressed in motor cortical neurons. Then, the dynamic changes in the fluorescence intensity of lactate or ATP fluorescent indicator proteins in the neurons of exercising mice are observed in real time by in vivo two-photon microscopy, and the relative change in fluorescence intensity during exercise is calculated to reflect the changes in neuronal lactate or ATP levels. The experimental results showed that in the humanized APOE4 mouse model, the lactate produced by glycolysis in motor cortical neurons continued to increase and accumulate during motor learning, and the degree of accumulation was significantly higher than that of the humanized APOE3 mice in the control group. Targeted inhibition of eCypA by tail vein injection of 4MCSA significantly reduced the degree of lactate accumulation in motor cortical neurons during motor learning in humanized APOE4 mice (such as Figure 1 B in Figure 1 (shown in C). Statistical methods: GraphPad Prism software, parametric test: unpaired t-test, nonparametric test: Mann-Whitney test.

[0075] Although 4MCSA treatment had no direct effect on neuronal ATP levels during exercise, it altered the way neurons produce ATP (e.g. Figure 1 This is shown in Figure 1 (G), which indicates that neurons switch from relying on glycolysis to producing ATP to relying on mitochondria to produce ATP.

[0076] 3. Changes in neuronal dendritic calcium activity during motor learning in humanized APOE4 mice after treatment with the compound represented by Formula I (4MCSA) of the present application.

[0077] The level of dendritic calcium activity in the motor cortex of humanized APOE4 mice during motor learning was significantly higher than that of humanized APOE3 mice. After one week of treatment with 4MCSA injected into the tail vein, the excessive dendritic calcium activity in humanized APOE4 mice during motor learning was also significantly reduced, returning to a level comparable to that of humanized APOE3 mice (e.g. Figure 2 The above results indicate that 4MCSA treatment can improve the early symptoms of AD mouse model and alleviate the onset of AD.

[0078] 4. Extracellular cyclophilin A (eCypA) reduces the mitochondrial membrane potential of glial cells BV2, and the compound represented by the eCypA inhibitor formula I (4MCSA) inhibits the decrease in mitochondrial membrane potential caused by CypA.

[0079] To elucidate the cellular mechanism of CypA protein-mediated neurotoxicity, this example further verified in the BV2 microglial cell model that CypA protein treatment for 24 hours can significantly reduce the mitochondrial membrane potential of BV2 microglial cells, while intervention with the CypA inhibitor 4MCSA can reverse this pathological phenotype (e.g. Figure 3 This result suggests that eCypA protein participates in glial cell injury by interfering with mitochondrial function, and its inhibitor can maintain mitochondrial homeostasis by blocking the toxic effects of eCypA protein, providing a potential target for intervention in related neurodegenerative diseases.

[0080] 5. Extracellular cyclophilin A (eCypA) promotes glycolysis and lactate secretion in BV2 cells, while the eCypA inhibitor compound represented by formula I (4MCSA) reduces lactate secretion induced by eCypA.

[0081] Abnormal mitochondrial membrane potential is often accompanied by decreased oxidative phosphorylation capacity. To explore whether energy metabolism imbalance is accompanied by compensatory glycolysis activation, this example further tested lactate secretion levels. The results showed that 100 nM CypA treatment for 30 hours significantly promoted glycolysis and lactate secretion in BV2 microglia, while lactate levels returned to near baseline values ​​after treatment with the 4MCSA inhibitor (e.g., Figure 5 These results indicate that CypA drives metabolic abnormalities by activating the glycolytic pathway, and its inhibitors can reverse this pathological phenotype, providing a basis for intervention strategies targeting energy metabolism imbalance.

[0082] 6. eCypA synergistically promotes neuroinflammation in BV2 microglia stimulated by Aβ. Treatment with the 4MCSA inhibitor reduced inflammation in a concentration-dependent manner in BV2 cells. These results suggest that CypA may induce neurotoxicity by affecting glial metabolic homeostasis, promoting the AD phenotype.

[0083] The embodiments described above only express several implementation methods of the present application, which are convenient for understanding the technical solutions of the present application in a specific and detailed manner, but they cannot be understood as limiting the scope of protection of the patent application. It should be pointed out that for ordinary technicians in this field, without departing from the concept of the present application, several variations and improvements can be made, which all fall within the scope of protection of the present application. In addition, it should be understood that after reading the above-mentioned teaching content of the present application, those skilled in the art can make various changes or modifications to the present application, and the equivalent forms obtained also fall within the scope of protection of the present application. It should also be understood that the technical solutions obtained by those skilled in the art through logical analysis, reasoning or limited experiments on the basis of the technical solutions provided in the present application are all within the scope of protection of the claims attached to the present application. Therefore, the scope of protection of the patent application of this application shall be based on the content of the attached claims, and the description can be used to interpret the content of the claims.

Claims

1. Use of a compound represented by formula (I) in the preparation of a medicament for preventing and / or treating neurodegenerative diseases; Formula (I).

2. The use according to claim 1, characterized in that The neurodegenerative diseases prevented and / or treated by the drug include Alzheimer's disease.

3. The use according to claim 2, characterized in that The Alzheimer's disease includes Alzheimer's disease mediated by the APOE4 gene.

4. The use according to claim 2, characterized in that The drug can alleviate the onset of Alzheimer's disease.

5. The use according to claim 2, characterized in that The drug can inhibit the decrease of mitochondrial membrane potential caused by CypA.

6. The use according to claim 2, characterized in that The drug is capable of reducing lactate secretion induced by eCypA.

7. The use according to claim 2, characterized in that The drug shifts neurons from relying on glycolysis to generate ATP in mitochondria.

8. The use according to any one of claims 1 to 7, characterized in that The drug comprises a compound represented by formula (I) and a pharmaceutically acceptable carrier.

9. The use according to claim 8, characterized in that The pharmaceutical dosage forms include solid preparations, semisolid preparations and liquid preparations.

10. The use according to any one of claims 1 to 7, characterized in that The compound represented by formula (I) is the only active ingredient in the pharmaceutical composition.

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