WO2017078499A2 - Composition pour la prévention ou le traitement d'une maladie neuroinflammatoire, contenant un inhibiteur de la protéine tyrosine phosphatase - Google Patents
Composition pour la prévention ou le traitement d'une maladie neuroinflammatoire, contenant un inhibiteur de la protéine tyrosine phosphatase Download PDFInfo
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- WO2017078499A2 WO2017078499A2 PCT/KR2016/012746 KR2016012746W WO2017078499A2 WO 2017078499 A2 WO2017078499 A2 WO 2017078499A2 KR 2016012746 W KR2016012746 W KR 2016012746W WO 2017078499 A2 WO2017078499 A2 WO 2017078499A2
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- Prior art keywords
- ptp
- ptp1b
- inhibitor
- neuroinflammatory
- microglia
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- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
Definitions
- the present invention relates to a pharmaceutical composition for the prevention or treatment of neuroinflammatory diseases, including protein tyrosine phosphatas inhibitors.
- the central nervous system consists of neurons and glial cells. Glial cells make up about 90% of all brain cells, and by volume they make up about 50% of the entire brain. Glial cells can be further classified into three types: astrocytes, microglia, and oligodendrocytes. Among these, microglia are a kind of specialized macrophage and are widely distributed in the brain. Microglia serve as a phagocytic cell that swallows tissue debris and dead cells, as well as participates in the bioprotective activity of the brain.
- Neuroinflammation is a type of immune response in the nervous system that is closely associated with many degenerative neurological disorders, including Alzheimer's, Parkinson's disease, and multiple sclerosis, and is currently considered a typical feature of degenerative neurological disease.
- Neuroinflammatory responses include activation of innate immune cells (microglia), release of inflammatory mediators such as nitric oxide (NO), cytokines and chemokines, and macrophage infiltration, which induce neuronal cell death.
- Inflammatory activation of microglia and astrocytes is thought to be an important mechanism in the pathological marker and progression of degenerative neurological diseases. Strict regulation of microglia activity is essential for maintaining brain homeostasis and preventing infectious and inflammatory diseases.
- protein tyrosine phosphatase (hereinafter referred to as 'PTP') is a group of enzymes that remove phosphate groups from tyrosine residues of phosphorylated proteins.
- Protein tyrosine phosphorylation is a common post-translational modification that creates new recognition motifs for protein interactions, affects protein stability and modulates enzyme activity. Thus, maintaining adequate levels of protein tyrosine phosphorylation is essential for cellular function.
- proteins are known as protein tyrosine phosphatase.
- protein tyrosine phosphatase 1B (PTP1B) is one of protein tyrosine dephosphatase and is a major negative regulator of insulin and leptin signaling.
- PTP1B protein tyrosine phosphatase 1B
- Mouse studies with PTP1B removal confirmed that PTP1B senses insulin and that PTP1B inhibitors have a protective effect on diabetes.
- Many studies have shown that PTP1B is associated with cancer, but is currently associated with protein tyrosine dephosphatase and neuroinflammatory inflammation. Little is known about the relationship.
- the present inventors have continued to study substances that can fundamentally cure a wide range of neuroinflammatory diseases by inhibiting microglia activation and neuroinflammatory responses in various ways. As a result, the present inventors confirmed that PTP inhibitors have an effect of inhibiting neuroinflammatory inflammation.
- the present invention has been completed.
- a pharmaceutical composition for the prophylaxis or treatment of neuroinflammatory diseases comprising a PTP inhibitor.
- the present invention provides a pharmaceutical composition for the prevention or treatment of neuroinflammatory diseases comprising a protein tyrosine phosphatase (PTP) inhibitor.
- PTP protein tyrosine phosphatase
- the present invention provides a food composition for improving neuroinflammatory diseases comprising a PTP inhibitor.
- the present invention also provides a method for preventing or treating a neuroinflammatory disease comprising administering a PTP inhibitor to a subject.
- the protein tyrosine dephosphatase inhibitor of the present invention prevents neuroinflammatory diseases by inhibiting activated microglial cells through reduction of nitric oxide (NO) levels in microglial cells, and reduction of expression of proinflammatory factors TNF ⁇ , IL1 ⁇ , iNOS, etc. Or may be usefully used for treatment.
- NO nitric oxide
- 1 is a diagram showing the results confirmed by RT-PCR changes in the expression level of PTP mRNA by LPS in the mouse brain.
- Figure 2 shows the results confirmed by RT-PCR changes in the expression level of PTP mRNA by LPS in mouse primary microglia and primary astrocytic cells.
- Figure 3 is a diagram showing the results confirmed by the NO production level measurement and MTT analysis whether PTP inhibitors inhibit the activation of microglial cell line BV2.
- FIG. 4 is a diagram showing the results of confirming whether the PTP inhibitor inhibits microglial activation.
- 4A shows an experimental design
- FIG. 4B shows histological changes of morphological changes in the brain of the mouse.
- FIG. 4C shows Iba-1 positive cells as microglia markers in the hippocampus, cortex and thalamus of the mouse.
- a graph quantifying the results of identifying Iba-1 positive cells, microglia markers in the hippocampus, cortex and thalamus of mice.
- FIG. 5 is a diagram showing the results of confirming the expression level of PTP1B in the BV2 microglia (HA-PTP1B) overexpressing the prepared PTP1B.
- Figure 6 shows the results of measuring the NO production level in Lg-stimulated microglia cell line BV2 according to the dose of LPS.
- Figure 7 is a diagram showing the results of measuring the NO production level in Lg-stimulated microglia cell line BV2 over time.
- FIG. 8 is a diagram showing the results confirmed by real-time PCR the change in the expression level of inflammatory cytokine mRNA in BV2 microglial cell line overexpressing PTP1B.
- FIG. 9 is a diagram showing the results of confirming the change in the expression level of LPS-induced NO according to the treatment of the PTP1B inhibitor (iPTP1B) in the microglial cell line BV2.
- FIG. 10 is a diagram showing the results of confirming the change in the expression level of LPS-induced NO according to the treatment of PTP1B inhibitor (iPTP1B) in primary microglia.
- Figure 11 shows the results of confirming the change in the expression level of LPS-induced NO according to the treatment of PTP1B inhibitor (iPTP1B) in rat microglia.
- FIG. 12 is a diagram showing the results of confirming the change in the expression level of TNF ⁇ -induced NO according to the treatment of PTP1B inhibitor (iPTP1B) in rat microglia.
- Figure 13 is a diagram showing the results confirmed by RT-PCR change in the expression level of proinflammatory molecules according to the treatment of PTP1B inhibitor (iPTP1B) in microglial cell line BV2.
- PTP1B inhibitor iPTP1B
- Figure 14 is a diagram showing the numerical results of confirming the change in the expression level of pro-inflammatory molecules according to the treatment of PTP1B inhibitor (iPTP1B) in microglia cell line BV2 by RT-PCR.
- PTP1B inhibitor iPTP1B
- FIG. 15 is a diagram showing the results of confirming the change in the expression level of TNF ⁇ protein according to the treatment of the PTP1B inhibitor (iPTP1B) in microglia cell line BV2 by ELISA.
- iPTP1B PTP1B inhibitor
- 17 is a diagram confirming the increase of NO levels induced by LPS in microglial cell lines overexpressing PTP1B.
- 18 is a diagram confirming the decrease of NO levels induced by LPS by Src kinase inhibitors in microglia.
- 20 is a diagram showing the results confirming that the PTP1B inhibitor increases the phosphorylation of the Src Y527 position.
- Figure 21 is a simplified diagram illustrating the mechanism by which PTP1B is involved in neuroinflammatory.
- FIG. 22 is a diagram showing an experimental design for confirming the neuroinflammatory mitigation effect of the PTP1B inhibitor in vivo.
- Figure 23 shows the results confirmed by real-time PCR that PTP1B inhibitors inhibit the expression of TNF ⁇ and IL1 ⁇ in vivo.
- the present invention provides a pharmaceutical composition for the prophylaxis or treatment of neuroinflammatory diseases comprising a PTP inhibitor.
- PTP inhibitor protein tyrosine phosphatase inhibitor
- PTP1B protein tyrosine phosphatase type 1B
- TC-PTP T-cell phosphatase
- SHP2 Src homology domain2-containing PTP2
- MEG2 Megakaryocyte-PTP2
- LYP Lymphoid specific-tyrosine phosphatase
- RPTP ⁇ Receptor-type tyrosine protein phosphatase beta
- the PTP inhibitors include, but are not limited to, the compounds listed in the table below or pharmaceutically acceptable salts thereof.
- the "pharmaceutically acceptable salt” is not limited as long as it forms an addition salt with the compound, and includes salts derived from pharmaceutically acceptable inorganic acids, organic acids, or bases.
- suitable acid addition salts include inorganic acids such as sulfuric acid, hydrochloric acid, nitric acid, phosphoric acid, bromic acid, perchloric acid, hydroiodic acid and the like; Organic carbon acids such as oxalic acid, citric acid, succinic acid, tartaric acid, formic acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, glycolic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, salicylic acid, and the like; Acid addition salts formed by sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluene-p-sulfonic acid, naphthalene-2-sulf
- Suitable base addition salts include alkali metal or alkaline earth metal salts formed by lithium, sodium, potassium, calcium, magnesium, and the like; Amino acid salts such as lysine, arginine and guanidine; Base addition salts formed by organic salts such as dicyclohexylamine, N-methyl-D-glucamine, tris (hydroxymethyl) methylamine, diethanolamine, choline, triethylamine and the like.
- the PTP1B inhibitor and the compound of formula 1 according to the present invention can be converted to their salts by conventional methods, and the preparation of the salts can be easily carried out by those skilled in the art based on the structure of the compound without further explanation.
- the "neuroinflammatory disease” may include without limitation any disease caused by inflammation of the nervous system, for example, multiple sclerosis, neuroblastoma, stroke, Alzheimer's disease, Parkinson's disease, Lou Gehrig's disease, Huntington's disease, Creutzfeldt-Jakob disease , Post traumatic stress disorder, depression, schizophrenia, and amyotrophic lateral sclerosis.
- prevention means to inhibit the occurrence of a disease or a disease in an individual who has not been diagnosed as having a neuroinflammatory disease or a disease, but is prone to such a disease or a disease.
- treatment in the present invention also means the inhibition of the development of a neuroinflammatory disease or disease, the alleviation of the disease or disease, and the elimination of the disease or disease.
- PTP inhibitors reduce the activation of microglia under inflammatory conditions induced by LPS (lipopolysaccharide), reduce the secretion of inflammatory cytokines TNF ⁇ , IL1 ⁇ , iNOS, and reduce nitric oxide ( It was confirmed that the production of NO) was also reduced. Therefore, it was confirmed that the pharmaceutical composition including the PTP inhibitor as an active ingredient may be useful for the prevention or treatment of neuroinflammatory diseases by reducing the anti-inflammatory effect and the activation of microglia.
- LPS lipopolysaccharide
- the neuroinflammatory inhibitory effect of the PTP inhibitor was verified through in vitro and in vivo experiments.
- PTP1B promotes the production of proinflammatory cytokines, activates Src through dephosphorylation of the Y527 position of Src, and this activated Src also activates NF ⁇ B to increase the expression of proinflammatory factors. Confirmed. From these results, it was confirmed that the inhibitor of PTP1B can be usefully used as an active ingredient of a composition for preventing or treating neuroinflammatory diseases.
- the pharmaceutical composition of the present invention may further include a pharmaceutically acceptable carrier.
- a pharmaceutically acceptable carrier refers to a carrier or diluent that does not significantly irritate an organism and does not inhibit the biological activity and properties of the administered compound.
- Pharmaceutically acceptable carriers include, for example, oral carriers such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like for parenteral administration such as water, suitable oils, saline, aqueous glucose and glycols, and the like. Carrier and the like.
- Such pharmaceutically acceptable carriers may be used in combination with saline, sterile water, Ringer's solution, buffered saline, dextrose solution, maltodextrin solution, glycerol, ethanol and one or more of these components, as necessary.
- Other conventional additives such as stabilizers, preservatives, antioxidants, buffers and bacteriostatic agents can be added.
- compositions of the present invention may be prepared in various parenteral or oral administration forms according to known methods.
- Representative formulations for parenteral administration include isotonic aqueous solutions or suspensions, and can be prepared according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.
- each component may be formulated for injection by dissolving in saline or buffer.
- oral dosage forms include, but are not limited to, powders, granules, tablets, pills, emulsions, syrups and capsules.
- the present invention also provides a method for preventing or treating a neuroinflammatory disease comprising administering a PTP inhibitor to a subject.
- administration refers to the introduction of the pharmaceutical composition of the present invention to an individual in need of treatment of the disease in any suitable manner, and the route of administration of the composition of the present invention can reach the target tissue as long as it can Administration can be via oral or parenteral routes.
- the subject to be administered may be a mammal such as a mouse, mouse, livestock, human, etc., and may be administered through various routes including oral, transdermal, subcutaneous, intravenous, or intracranial injection.
- the prophylactic or therapeutic method of the present invention comprises administering a PTP inhibitor or a pharmaceutically acceptable salt thereof in a pharmaceutically effective amount.
- a suitable total daily dose may be determined by the practitioner within the correct medical judgment.
- the specific therapeutically effective amount for a particular patient is determined by the specific composition, including the type and extent of the reaction to be achieved and whether other agents are used, as appropriate, the age, body weight, general health status, sex of the patient. And various factors and similar factors well known in the medicinal art, including diet, time of administration, route of administration and rate of composition, duration of treatment, drugs used with or concurrent with the specific composition.
- the present invention provides a food composition for improving neuroinflammatory diseases comprising a PTP inhibitor.
- the term "food” means a natural product or processed product containing one or more nutrients, and preferably means a state in which it can be directly eaten through some processing process, It is used to mean all kinds of foods, health foods, beverages, food additives and beverage additives.
- the food composition of the present invention may be added to various foods, candy, chocolate, beverages, gums, teas, vitamin complexes, various health supplements, and the like, and may be used in the form of powders, granules, tablets, pills, capsules, or beverages.
- the food composition of the present invention may further include a food acceptable carrier.
- a food acceptable carrier There is no special limitation except for containing the PTP inhibitor of the present invention or a food-acceptable salt thereof, and for example, it may further contain various flavors or natural carbohydrates.
- the food composition of the present invention includes ingredients that are commonly added during food production, and may include, for example, proteins, carbohydrates, fats, nutrients and seasonings.
- various nutrients, vitamins, minerals, flavors such as synthetic and natural flavors, colorants, enhancers, fact acids and salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickeners, pH regulators, stabilizers, Preservatives, glycerin, alcohols, carbonation agents used in carbonated drinks, and the like.
- the amount of the PTP inhibitor or salt thereof may be included as 0.00001% to 50% by weight of the total weight of the food, if the food is a beverage based on the volume of 100 ml of the entire food 0.001 g to 50 g, preferably 0.01 g to 10 g, but is not limited thereto.
- mice injected with LPS were prepared as follows in an infected animal model.
- LPS Lipopolysaccharid
- mice All experiments were performed using 9-11 week-old male C57BL / 6 mice (25-30 g) supplied by Koatech (Pyeongtaek, Korea), and a mouse model was prepared by intraperitoneally injecting LPS at 5 mg / kg. .
- the control group was injected with a vehicle.
- PTP is correlated with inflammation of the brain because the expression of PTP is increased in the brain of mice induced by LPS.
- Microglial cells are immune cells present in the central nervous system and play a role in the initiation and progression of inflammatory responses resulting from inflammatory stimuli. The expression level change of was confirmed.
- mRNA levels of PTP1B, TC-PTP, SHP2, MEG2, LYP, and RPTP ⁇ in primary microglia and primary astrocytic cells were confirmed by RT-PCR. The confirmation result is shown in FIG.
- PTP is increased in glial cells under the inflammatory conditions induced by the injection of LPS, it can be seen that PTP is associated with brain inflammation.
- BV-2 microglia were treated with LPS (100 ng / ml) for 24 hours in the presence of 1, 2, 5, and 10 ⁇ M of each PTP inhibitor, and then the amount of NO was measured using a Greiss reaction. In addition, the cytotoxicity was confirmed using the MTT assay, and the results are shown in FIG. 3.
- the PTP inhibitor can safely inhibit the activation of microglial cells because it safely reduces the amount of NO induced by LPS without cytotoxicity.
- Encephalitis mouse models were prepared to determine whether PTP inhibitors inhibit microglial activation.
- C57BL / 6 mice were injected cerebral with vehicle (saline containing 0.5% DMSO and 5% propylene glycol) or PTP inhibitors (dilution in saline containing 5% propylene glycol) in Table 2 above.
- LPS (5 mg / kg) was injected intraperitoneally 30 minutes after infusion. Mice were sacrificed and brains were analyzed 48 hours after LPS injection.
- Mouse models were divided into a total of eight experimental groups; Group 1 treated with saline and 0.5% DMSO; Group 2 treated with LPS and 0.5% DMSO; Group 3 treated with LPS and PTP1B inhibitors; Group 4 treated with LPS and TC-PTP inhibitors; Group 5 treated with LPS and SHP2 inhibitors; Group 6 treated with LPS and MEG2 inhibitors; Group 7 treated with LPS and LYP inhibitors; Group 8 treated with LPS and RPTP ⁇ inhibitors.
- the experimental design as above is shown in Figure 4A.
- 4B shows the histologically confirmed result of staining of the brain of the sacrificed mouse with an antibody against Iba-1, a marker of microglia.
- the brain was removed and sectioned and stained with an antibody against Iba-1 for hippocampus, cortex and thalamus and histochemically confirmed.
- the results are shown in FIG. 4C and the graph shows the number of Iba-1 positive cells per mm 2 .
- the results are shown in FIG. 4D.
- the PTP inhibitor has an effect of reducing activation of microglia under inflammatory conditions in vitro and in vivo.
- PTP1B induces the expression of inflammatory cytokines in microglia, which indicates the overactivation of microglia, and thus, can be inferred that microglial cells are overactivated by PTP1B.
- PTP1B inhibitor ((S) -4-(((S) -1- (l2-azanyl) -3- (4- (difluoro (phosphono) methyl) phenyl) -1) -Oxopropan-2-yl) amino) -3-((S) -3- (4- (difluoro (phosphono) methyl) phenyl) -2-pentadecanamidopropaneamido) -4-oxo Butanoic acid) Obtained from Zhang group and used.
- the PTP1B inhibitor (hereinafter referred to as “iPTP1B”) used in the present invention has proved to be very specific for PTP1B.
- BV2 microglia were pretreated with different concentrations of iPTP1B indicated and stimulated with LPS (100 ng / ml) after 1 hour, and NO levels were measured according to the Griess method in the treated cells.
- LPS 100 ng / ml
- NO levels were measured according to the Griess method in the treated cells.
- MTT assay was performed 24 hours after iPTP1B treatment and the results are shown in FIG. 9.
- iPTP1B alone did not inhibit or increase NO production and significantly inhibited NO levels induced by LPS. Thus, iPTP1B itself does not change the basic level of NO production.
- iPTP1B the effect of iPTP1B on NO production was confirmed in mouse primary microglia. Specifically, primary microglia were pretreated with 5 ⁇ M of iPTP1B and then stimulated with LPS (50 ng / ml) for 24 hours. NO levels were confirmed in the stimulated primary microglia. In order to confirm the cytotoxicity of iPTP1B on primary microglia, MTT assay was performed 24 hours after iPTP1B treatment and the results are shown in FIG. 10.
- HAPI cells rat microglia
- LPS 100 ng / ml
- iPTP1B 10 ⁇ M
- NO levels were confirmed in HAPI cells, the stimulated rat microglia.
- MTT assay was performed 24 hours after iPTP1B treatment and the results are shown in FIG. 11.
- the rat microglia HAPI cells were stimulated with TNF ⁇ (100ng / ml) for 24 hours after pretreatment with 10 ⁇ M of iPTP1B for 1 hour. NO levels were confirmed in these stimulated cells.
- MTT assay was performed 24 hours after iPTP1B treatment and the results are shown in FIG. 12.
- BV2 microglia were treated with LPS (100 ng / ml) for 6 hours in the presence or absence of 10 ⁇ M of iPTP1B, and mRNA levels of iNOS, IL1 ⁇ , TNF ⁇ , Cox2, which are proinflammatory molecules, were RT in the treated cell samples. Confirmed by -PCR, the result is shown in FIG. In addition, the band strength obtained by RT-PCR is numerically shown in Figure 14 is shown in the graph.
- iPBP1B significantly inhibits the production of LPS-induced cytokine and proinflammatory molecules (iNOS, IL1 ⁇ , TNF ⁇ , Cox2).
- TNF ⁇ protein levels in BV2 microglia cultures treated with LPS as described above were confirmed by ELISA. Specifically, 24 hours after culturing BV2 cells in the presence or absence of iPTP1B with LPS, rat monoclonal anti-mouse TNF ⁇ antibodies as capture antibodies and goat biotinylated polyclonal anti-mouse TNF ⁇ antibodies as detection agents TNF ⁇ levels in the culture medium were measured. The results of the measured levels of TNF ⁇ protein are shown in FIG. 15.
- PTP1B increased the neuroinflammatory response and was performed as follows to determine how PTP1B increases the LPS-induced inflammatory response.
- Src kinases, tyrosine kinases were selected as targets of PTP1B among other known PTP1B substrates. The reason for this choice is that Src has a negative regulatory phosphorylation site (Y527). PTP1B can dephosphorylate the negative regulatory sites of Src, which induces Src kinase activity.
- BV2 microglia were prepared by transfecting BV2 microglia with HA-PTP1B to overexpress PTP1B.
- the band intensity was standardized and quantified by beta-actin, and the graph is shown in FIG. 16.
- LPS-induced NO production levels were determined after BV2 treatment with Src kinase inhibitor PP2 (5 ⁇ M) or PDTC (Ammonium pyrrolidinedithiocarbamate (NF ⁇ b inhibitor)). It was. This is shown in FIG. 18.
- BV2 microglia pretreated with Src inhibitor PP2 or iPTP1B for 1 hour were treated with LPS for 24 hours.
- the levels of NO in the treated BV2 microglia were shown in FIG. 19.
- the anti-inflammatory effect of iPTP1B was investigated.
- PTP1B promotes the production of proinflammatory cytokines and activates Src through dephosphorylation of Y527. This activated Src activates NF ⁇ B and increases the expression of proinflammatory factors.
- a schematic of this mechanism is briefly shown in FIG.
- inflammatory stimuli increase PTP1B expression, induce microglial hyperactivation in the brain, and blocking inflammatory cell PTP1B activity in inflammatory conditions prevents microglial hyperactivation in vitro and in vivo. It can be seen that it is possible to effectively prevent or treat an inflammatory disease in.
- the above ingredients are mixed and filled in an airtight cloth to prepare a powder.
- tablets are prepared by tableting according to a conventional method for preparing tablets.
- the above ingredients are mixed and filled into gelatin capsules to prepare tablets.
- the amount of the above ingredient is prepared per ampoule (2 ml).
- Purified water was added to adjust the total volume to 1,000 ml. According to the conventional method for preparing a liquid, the above components are mixed, and then filled into a brown bottle and sterilized to prepare a liquid.
- Vitamin B6 0.5 mg
- composition ratio of the above-mentioned vitamin and mineral mixtures is a composition that is relatively suitable for the health functional food
- the composition is mixed in a preferred embodiment, but the compounding ratio may be arbitrarily modified, and the above ingredients are mixed according to a conventional health functional food manufacturing method. Then, it can be used for the manufacture of the nutraceutical composition (eg, nutrition candy, etc.) according to a conventional method.
- the mixture was heated by stirring at 85 °C for about 1 hour, the resulting solution was filtered and obtained in a sterilized 2 L container, sealed and sterilized and then stored in a refrigerator. It is used for the manufacture of the health functional beverage composition of the invention.
- composition ratio is a composition suitable for a preferred beverage in a preferred embodiment
- the composition ratio may be arbitrarily modified according to regional and ethnic preferences such as demand hierarchy, demand country, use purpose.
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Abstract
La présente invention concerne une composition pharmaceutique pour la prévention ou le traitement d'une maladie neuroinflammatoire, ladite composition contenant un inhibiteur de la protéine tyrosine phosphatase. L'inhibiteur de la protéine tyrosine phosphatase de la présente invention inhibe les cellules microgliales activées en diminuant le taux d'oxyde nitrique (NO) dans les cellules microgliales et en réduisant l'expression de facteurs pro-inflammatoires TNFα, IL1ß, iNOS, et analogues, et peut ainsi être utilisée avantageusement dans la prévention ou le traitement d'une maladie neuroinflammatoire.
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US15/773,928 US20180325925A1 (en) | 2015-11-06 | 2016-11-07 | Composition for prevention or treatment of neuroinflammatory disease, containing protein tyrosine phosphatase inhibitor |
US16/998,867 US20200384001A1 (en) | 2015-11-06 | 2020-08-20 | Composition for prevention or treatment of neuroinflammatory disease, containing protein tyrosine phosphatase |
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US16/998,867 Division US20200384001A1 (en) | 2015-11-06 | 2020-08-20 | Composition for prevention or treatment of neuroinflammatory disease, containing protein tyrosine phosphatase |
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EP1062199A1 (fr) * | 1998-03-12 | 2000-12-27 | Novo Nordisk A/S | Modulateurs de proteine tyrosine phosphatases (ptpases) |
JP2006518738A (ja) * | 2003-02-12 | 2006-08-17 | トランス テック ファーマ,インコーポレイテッド | 治療薬としての置換アゾール誘導体 |
JP4018610B2 (ja) * | 2003-09-12 | 2007-12-05 | 株式会社サン・クロレラ | チロシンホスファターゼ阻害剤 |
UA94921C2 (en) * | 2005-12-08 | 2011-06-25 | Новартис Аг | 1-orthofluorophenyl substituted 1, 2, 5-thiazolidinedione derivatives as ptp-as inhibitors |
EA201000865A1 (ru) * | 2007-11-30 | 2010-12-30 | Новартис Аг | Комбинация ингибиторов протеинтирозинфосфатазы и гормона роста человека, предназначенная для лечения атрофии мышц и родственных нарушений |
KR101646725B1 (ko) * | 2012-09-24 | 2016-08-09 | 한양대학교 산학협력단 | PTPσ 매개성 질환 치료 또는 예방용 약학적 조성물 |
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