KR20240052657A - Pharmaceutical composition for the prevention or treatment of neuro-inflammation or neurodegenerative disorders comprising erdafitinib an active ingredient - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for the prevention or treatment of neuroinflammation or degenerative brain disease containing erdafitinib as an active ingredient. Specifically, the present invention relates to erdafitinib or a pharmaceutically acceptable composition thereof. Pharmaceutical composition for preventing or treating neuroinflammation or degenerative brain disease containing salt as an active ingredient, composition for protecting nerve cells damaged by excessive inflammatory response in nerve cells, A health functional food for preventing or improving neuroinflammation or degenerative brain disease, comprising a reagent composition for inhibiting activation, a reagent composition for inhibiting tau hyperphosphorylation, and erdafitinib or a foodologically acceptable salt thereof as active ingredients. It relates to composition.

Description

Pharmaceutical composition for the prevention or treatment of neuro-inflammation or neurodegenerative disorders comprising erdafitinib as an active ingredient}

The present invention relates to a pharmaceutical composition for the prevention or treatment of neuroinflammation or degenerative brain disease containing erdafitinib as an active ingredient.

Degenerative brain disease refers to a disease that occurs in the brain among degenerative diseases that occur with age. It can be classified based on the main symptoms and affected brain area. Representative examples include Alzheimer's disease and Parkinson's disease. . Degenerative brain diseases are known to be caused by neurodegeneration due to aging and the death of nerve cells due to protein aggregation due to genetic and environmental factors.

In addition, degenerative brain diseases include the death or deterioration of specific brain cells that occurs temporarily or over a long period of time. Since brain cells that die once cannot be regenerated, they are known to eventually lead to fatal loss of brain function, especially , Brain dysfunction accompanied by a progressive decline in cognitive, sensory, motor, and systemic functions eventually leads to changes in personality and behavior, reaching a point where patients are unable to take care of themselves. The main pathways of brain cell death include oxidative toxicity due to oxidative stress, excitatory toxicity, and apoptosis, and each causes cell death through a unique signaling process. Specifically, oxidative damage to proteins, nucleic acids, and lipids following accumulation of reactive oxygen species was suggested as the main cause of brain cell death in patients with stroke, brain damage, Alzheimer's disease (AD), and Parkinson's disease. , In particular, oxidative stress caused by free radicals has been reported as the main cause of cell death in each tissue in the body, and has also been suggested as one of the cell death cycles that occurs in brain and nerve diseases (Schapira, A.H., Curr. Opin. Neurol., 9(4):260-264, 1996).

In addition, it has been reported that the activity of microglia and astrocytes is related to the onset and progression of degenerative cranial nerve diseases, and microglia are immune cells residing in the central nervous system (CNS). It is known to be activated by stimulation and cause immune and inflammatory responses. In particular, when microglia are activated by substances such as bacterial endotoxin lipopolysaccharide (LPS), interferon-γ, beta-amyloid, or ganglioside, they actively engage in phagocytosis, unlike microglial cells in a normal state. and cell proliferation, and by expressing genes such as cytokines such as TNF-α, IL-1β, and IL-6, chemokines, iNOS (inducible nitric oxide synthase), and COX-2 (cyclooxygenase-2), inflammatory mediators are removed. Create. This activation of microglial cells removes damaged cells and protects nerve cells from invading bacteria or viruses, but also includes nitric oxide (NO) produced by iNOS, prostaglandins produced by COX-2, and TNF. Since -α and other substances are also toxic to nerve cells, the activation of microglial cells ultimately worsens the damage to nerve cells. Therefore, inhibiting the appropriate activation of microglia may be another way to treat degenerative brain diseases.

Additionally, astrocytes play an important role not only in the brain development process but also in maintaining normal brain activity. Astrocytes in the brain have been shown to play a role in supporting neuronal activity by appropriately removing neurotransmitters secreted by nerve cells or regulating ion concentration in the brain. In addition, neural stem cells differentiate into nerve cells. It has been found to play a decisive role.

However, when astrocytes are injured in the brain, their proliferation becomes active, swelling occurs, and they become activated into reactive astrocytes such as astrogliosis. These reactive astrocytes are observed in AIDS-related dementia, brain damage, ischemic brain disease, and Alzheimer's disease. Therefore, continuous activation of astrocytes eventually leads to neuronal death. Therefore, suppressing the appropriate activation of astrocytes can also be another way to treat degenerative brain diseases.

In addition, it has recently been revealed that inflammatory response is one of the main mechanisms causing neurodegeneration. Microglia, immune cells present in the central nervous system, can be activated by various exogenous and endogenous substances, and activated microglia can be activated by various exogenous and endogenous substances. Glial cells produce and release substances such as inflammatory cytokines TNF-α and IL-1β, nitric oxide, prostaglandins, and superoxide, and excessive or continuous production of these substances induces the death of nearby nerve cells, ultimately leading to nerve damage. That is, it causes regression. In addition, since substances released by dying nerve cells trigger the activity of microglial cells again, neurodegeneration falls into a continuous vicious cycle, and in fact, the activity of microglial cells causes Alzheimer's disease, Parkinson's disease, Huntington's disease, Lou Gehrig's disease, and Creutzfeldt disease. It has been reported to be related to various neurodegenerative diseases such as Creutzfelt-Jakob Disease (CJD) and multiple sclerosis.

Meanwhile, treatments used to treat degenerative brain diseases include drug therapy, surgery, and physical therapy. In the case of drug treatment, it generally replenishes the dopamine that is lacking in the brain and reduces the neurotransmitter due to the lack of dopamine. Drugs are being used to correct the imbalance, prevent or delay the destruction of nerve cells, and control other symptoms such as depression.

However, since these drugs cannot revive dead nerve cells, they have the limitation that they are aimed at controlling symptoms rather than a cure, so there is an urgent need to develop new treatments that can prevent or treat degenerative brain diseases more effectively. am.

Korean Patent Publication No. 10-2022-0070243

Accordingly, the present inventors found that erdafitinib, a drug used as an anticancer agent, has an excellent effect on improving microgliosis and astrogliosis induced by inflammation of nerve cells and inhibits the production of inflammatory cytokines. And as the modifiable activity was confirmed, the present invention was completed by confirming that erdafitinib can be used as a new treatment for neuroinflammation or degenerative brain diseases.

Therefore, the object of the present invention is to provide a pharmaceutical composition for preventing or treating neuroinflammation or degenerative brain disease, comprising erdafitinib or a pharmaceutically acceptable salt thereof as an active ingredient.

Another object of the present invention is to provide a composition for protecting nerve cells damaged by excessive inflammatory response in nerve cells, comprising erdafitinib or a pharmaceutically acceptable salt thereof as an active ingredient.

Another object of the present invention is to provide a reagent composition for inhibiting the activation of microglia or astrocytes, comprising erdafitinib or a pharmaceutically acceptable salt thereof as an active ingredient. will be.

Another object of the present invention is to provide a reagent composition for inhibiting tau phosphorylation, comprising erdafitinib or a pharmaceutically acceptable salt thereof as an active ingredient.

Another object of the present invention is to provide a health functional food composition for preventing or improving neuroinflammation or degenerative brain disease, comprising erdafitinib or a foodologically acceptable salt thereof as an active ingredient.

In order to achieve the above object, the present invention provides a pharmaceutical composition for preventing or treating neuroinflammatory or degenerative brain diseases, comprising erdafitinib or a pharmaceutically acceptable salt thereof as an active ingredient.

In one embodiment of the present invention, the composition inhibits the activity of microglia or astrocytes, thereby suppressing damage caused by activated microglia or activated astrocytes to nerve cells. It may be something to have.

In one embodiment of the present invention, the composition may inhibit the expression and production of inflammatory cytokines COX-2, IL-1β, IL-6, or TNF-a.

In one embodiment of the present invention, the composition may inhibit the activity of the JNK/c-JUN signaling pathway.

In one embodiment of the present invention, the composition may suppress excessive inflammatory response in nerve cells.

In one embodiment of the present invention, the composition may inhibit phosphorylation of tau protein.

In one embodiment of the present invention, the degenerative brain disease includes Alzheimer's disease, Parkinson's disease, progressive supranuclear palsy, multiple system atrophy, olivary nucleus-pontine-cerebellar atrophy (OPCA), Shay-Drager syndrome, and striatal-substantia nigra degeneration. , Huntington's disease, amyotrophic lateral sclerosis (ALS), essential tremor, cortico-basal gangrene, diffuse Lewy body disease, Parkinson-ALS-dementia complex, Niemann-Pick disease, Pick's disease, cerebral ischemia, and cerebral infarction. It could be.

The present invention also provides a composition for protecting nerve cells damaged by excessive inflammatory response in nerve cells, comprising erdafitinib or a pharmaceutically acceptable salt thereof as an active ingredient.

The present invention also provides a reagent composition for inhibiting the activation of microglia or astrocytes, comprising erdafitinib or a pharmaceutically acceptable salt thereof as an active ingredient.

The present invention also provides a reagent composition for inhibiting tau phosphorylation, comprising erdafitinib or a pharmaceutically acceptable salt thereof as an active ingredient.

In one embodiment of the present invention, the activation of the microglial cells or astrocytes may be due to an excessive inflammatory response of nerve cells.

In one embodiment of the present invention, the inflammatory response may be induced by LPS (Lipopolysaccharide).

In addition, the present invention provides a health functional food composition for preventing or improving neuroinflammation or degenerative brain disease, comprising erdafitinib or a foodologically acceptable salt thereof as an active ingredient.

In one embodiment of the present invention, the composition inhibits the activity of microglia or astrocytes, thereby suppressing damage caused by activated microglia or activated astrocytes to nerve cells. It can be something to have.

In one embodiment of the present invention, the composition may inhibit the expression and production of inflammatory cytokines COX-2, IL-1β, IL-6, or TNF-a.

In one embodiment of the present invention, the composition may inhibit the activity of the JNK/c-JUN signaling pathway.

In one embodiment of the present invention, the composition may suppress excessive inflammatory response in nerve cells.

In one embodiment of the present invention, the composition may inhibit phosphorylation of tau protein.

In one embodiment of the present invention, the degenerative brain disease includes Alzheimer's disease, Parkinson's disease, progressive supranuclear palsy, multiple system atrophy, olivary nucleus-pontine-cerebellar atrophy (OPCA), Shay-Drager syndrome, and striatal-substantia nigra degeneration. , Huntington's disease, amyotrophic lateral sclerosis (ALS), essential tremor, cortico-basal gangrene, diffuse Lewy body disease, Parkinson-ALS-dementia complex, Niemann-Pick disease, Pick's disease, cerebral ischemia, and cerebral infarction. It could be.

Erdafitinib of the present invention can inhibit the activity of microglia or astrocytes by LPS and inhibits inflammatory cytokines COX-2, IL-1β, IL-6, or TNF-a. It can suppress the expression and production of and has the inhibitory activity of JNK/c-JUN signaling related to inflammatory response. It also suppresses the activity of astrocytes in an animal model of Alzheimer's disease caused by overexpression of amyloid beta and inhibits the activation of tau protein. As it has been confirmed to have the activity of reducing phosphorylation, it can be used as a new therapeutic agent for the prevention or treatment of neuroinflammation or degenerative brain diseases.

Figure 1 shows the results confirming the improvement effect of microgliosis caused by LPS by erdafitinib treatment in wild-type mice. (A) shows erdafitinib (10 mg/kg, ip) or Vehicle (5% DMSO + 40% PEG + 5% Tween80 + 50% saline) was administered intraperitoneally daily for 7 days, then on day 7 of drug administration, LPS (10 mg/kg, ip) or PBS 30 min after drug administration. Shows the results of immunofluorescence staining for Iba-1 in the cerebral cortex and hippocampus (CA1 and DG) regions of wild type (WT) mice whose brains were removed 8 hours after intraperitoneal administration, and (B) shows the results of (A). is quantified and presented graphically (n = 20 brain slices from 5 mice/group).
Figure 2 shows the results confirming the effect of suppressing LPS-induced astrocyte activation by erdafitinib treatment in wild-type mice. (A) shows the effect of erdafitinib (10 mg/kg, ip) or vehicle (5% DMSO + 40 mg/kg, ip). % PEG + 5% Tween80 + 50% saline) was administered intraperitoneally every day for 7 days, then on the 7th day of drug administration, LPS (10 mg/kg, ip) or PBS was administered intraperitoneally 30 minutes after drug administration and 8 hours later. The results of immunofluorescence staining for GFAP are shown in the cortex and hippocampus (CA1 and DG) regions of wild type (WT) mice from which brains were removed, and (B) is a quantified graph showing the results in (A) (n = 20 brain slices from 5 mice/group).
Figure 3 shows the results confirming the effect of suppressing the production of LPS-induced pro-inflammatory cytokines IL-1β and IL-6 by treatment with erdafitinib in wild-type mice. (A) and (B) show erdafitinib (10 mg). /kg, ip) or vehicle (5% DMSO + 40% PEG + 5% Tween80 + 50% saline) daily for 7 days, then on the 7th day of drug administration, LPS (10 mg/kg) 30 min after drug administration. kg, ip) or PBS was administered intraperitoneally and the brain was removed 8 hours later, showing the results of immunofluorescence staining for IL-1β and IL-6 in the cortex and hippocampus (CA1 and DG) regions of wild-type (WT) mice, (C) is a graphical representation of the quantification of the results of (A) and (B) (n = 20 brain slices from 5 mice/group).
Figure 4 shows the results confirming the inhibitory effect of LPS-induced pro-inflammatory cytokine COX-2 by treatment with erdafitinib in wild-type mice. (A) shows erdafitinib (10 mg/kg, ip) or vehicle (5 % DMSO + 40% PEG + 5% Tween80 + 50% saline) was administered intraperitoneally every day for 7 days, and then on the 7th day of drug administration, LPS (10 mg/kg, ip) or PBS was administered intraperitoneally 30 minutes after drug administration. The immunofluorescence staining results for COX-2 are shown in the cortex and hippocampus (CA1 and DG) regions of wild type (WT) mice whose brains were removed 8 hours later, and (B) is a graph quantifying the results in (A). (n = 20 brain slices from 5 mice/group).
Figure 5 shows the results confirming the effect of erdafitinib treatment on suppressing the level of pro-inflammatory cytokines stimulated by LPS in BV2 microglial cells. (A) shows the chemical structural formula of erdafitinib, and (B) shows the results of MTT analysis of BV2 microglial cells, and (C) is treated with 1μM or 5μM erdafitinib or vehicle (1% DMSO) for 30 minutes, followed by sequential treatment with 1μg/ml LPS or PBS for 5.5 hours. This shows the results of confirming the mRNA levels of pro-inflammatory cytokines TNF-α, IL-1β, COX-2, and IL-6 in treated BV2 microglial cells through real-time PCR analysis (n = 8/group).
Figure 6 shows the results confirming the effect of erdafitinib on controlling LPS-mediated inflammatory response through downregulation of JNK/c-JUN signaling in BV2 microglial cells. (A) to (D) show the results of erdafitinib at 5 μM Er. After treatment with dafitinib or vehicle (1% DMSO) for 45 min, followed by 1 μg/ml LPS or PBS for 45 min, p-AKT/AKT, p-ERK/ERK, pJNK/JNK and The results of analyzing the expression level of pPLCγ1/PLCγ1 protein by Western blotting are shown (n = 9/group), and (E) to (F) show the results of 5 μM erdafitinib and 1 μg/ml LPS (n = 9/group). Group) shows the results of Western blotting analysis of the expression levels of pc-JUN and NF-κB proteins in nuclear fractions obtained from sequentially treated BV2 microglial cells.
Figure 7 shows that after treating Alzheimer's disease-induced 5xFAD mice with ertafitinib daily for 2 weeks, immunohistochemistry was performed on the brain cortex and hippocampus to determine astrocyte activity. This shows the analysis results using anti-GFAP antibody.
Figure 8 shows the results of measuring tau protein phosphorylation levels by performing immunohistochemistry on cortex and hippocampus tissue after treating Alzheimer's disease-induced 5xFAD mice with ertafitinib daily for 2 weeks, using anti-AT100 antibody This is the result of using .

The present invention identifies a new use of erdafitinib as a treatment for neuroinflammation or degenerative brain diseases. Specifically, the present invention uses erdafitinib or a pharmaceutically acceptable salt thereof as an active ingredient. It is characterized by providing a pharmaceutical composition for preventing or treating neuroinflammation or degenerative brain diseases, including:

Erdafitinib is a drug used as an anticancer agent and is a small molecule inhibitor of fibroblast growth factor receptor (FGFR) used in cancer treatment. FGFRs are known to be a subset of tyrosine kinases that are dysregulated in some tumors and affect tumor cell differentiation, proliferation, angiogenesis, and cell survival. Erdafitinib was approved as an anticancer drug by the U.S. Food and Drug Administration (FDA) in 2018 as a treatment for urothelial cancer, and in 2019, it was approved by the FDA for the treatment of metastatic or locally advanced bladder cancer with FGFR3 or FGFR2 alterations. I have received it.

Meanwhile, no study has yet been conducted on the possibility of using the drug erdafitinib as a treatment for neuroinflammation or degenerative brain diseases.

Accordingly, the present inventors conducted an experiment to confirm the possibility of using erdafitinib, which was used as an anticancer agent, as a new medicinal use as a treatment for neuroinflammation or degenerative brain diseases. According to one embodiment of the present invention, erdafitinib was administered to wild-type mice. After administering erdafitinib, neuroinflammation was induced by LPS treatment, and the mouse brain tissue was analyzed for improvement in microgliosis. As a result, in the erdafitinib-treated mouse brain tissue, It was confirmed that LPS-mediated microgliosis was significantly suppressed, with microglial hypertrophy and the number of Iba-1 positive cells decreased. In addition, erdafitinib was shown to effectively inhibit astrogliosis, and it was confirmed that the fluorescence intensity of LPS-induced GFAP, the area fraction labeled with GFAP, and the number of GFAP-positive astrocytes were all suppressed.

Therefore, through these results, the present inventors showed that erdafitinib can effectively inhibit the activation of microglia and astrocytes in brain tissue or brain cells, which causes excessive activation of microglia or astrocytes. It was found that neuroinflammation or degenerative brain diseases caused by it can be prevented, improved, and treated.

Microglial cells, which play the role of macrophages in the brain, are important effector cells that regulate immune responses in the central nervous system (CNS). Their activation plays an important role in maintaining CNS homeostasis by removing foreign substances caused by drugs or toxins and secreting nerve growth factors. However, when exposed to harmful stress such as signals generated from damaged neurons, accumulation of abnormal proteins modified by external stimuli, or invasion of pathogens, the activity of microglial cells increases excessively, causing damage to nerve cells, leading to Alzheimer's disease. It can cause degenerative neurological diseases such as Parkinson's disease, multiple sclerosis, and cerebral infarction. Additionally, recent research results have revealed that excessive inflammatory responses in microglia or astrocytes are the cause of neurodegenerative diseases.

Specifically, hyperactivated microglia, unlike normal microglia, actively engage in phagocytosis, proliferate, and produce cytokines such as TNF-α, IL-1β, and IL-6, chemokines, and iNOS. Genes such as (inducible nitric oxide synthase) and COX-2 (cyclooxygenase-2) are expressed to produce inflammatory mediators. Activation of microglial cells removes damaged cells and protects nerve cells from invading bacteria or viruses. However, nitric oxide (NO) produced by iNOS, prostaglandins produced by COX-2, and TNF- Since α and the like are also toxic to nerve cells, the resulting activation of microglial cells worsens damage to nerve cells and acts as a cause of degenerative brain disease or neurodegenerative disease.

In addition, astrocytes are also known to play an important role in maintaining normal brain activity. In particular, they are known to play a role in the formation of neuronal synapses, regulation of synapse number, synaptic function, and differentiation of neural stem cells into neurons. . However, when these astrocytes become excessively reactive, that is, when they remain in an excessively activated state, they cause death of nerve cells and induce death of neighboring nerve cells, thereby acting as a cause of degenerative brain disease. Therefore, suppressing excessive astrocyte activation can also be a new treatment method for degenerative brain diseases.

Causes of excessive activation of microglia and astrocytes include lipopolysaccharide (LPS), interferon-γ, beta-amyloid, and ganglioside, which are bacterial endotoxins that can induce inflammatory responses.

According to another embodiment of the present invention, in order to determine whether erdafitinib can suppress the inflammatory response, wild-type mice were treated with erdafitinib, then treated with LPS, and brain tissue was treated with erdafitinib. The expression levels of inflammatory cytokines were analyzed.

As a result, it was confirmed that the expression of COX-2, IL-1β, IL-6, and TNF-a was effectively suppressed in the group treated with erdafitinib compared to the group not treated with erdafitinib.

These results mean that the erdafitinib drug of the present invention can effectively suppress excessive inflammatory responses in nerve cells caused by LPS.

Among various inflammatory factors, LPS (lipopolysaccharide), one of the endotoxins, enhances the secretion of pro-inflammatory cytokines, which leads to the secretion of inflammatory mediators such as nitric oxide and prostaglandins, and causes neuroinflammation and degeneration due to excessive inflammatory responses. Brain disease develops.

Furthermore, the present inventors analyzed the effect of erdafitinib on JNK/c-JUN, an intracellular signaling pathway related to inflammatory response, and were able to confirm that it inhibits the activation of JNK/c-JUN signaling activated by LPS. .

In addition, when erdafitinib was administered to mice suffering from Alzheimer's disease, a degenerative brain disease, it was confirmed that it had the activity of inhibiting astrocyte activity and phosphorylation of Tau protein.

Tau proteins are a family of microtubule-binding proteins with a molecular weight of 50,000 to 70,000 Da and are involved in the tangle of nerve fibers. Tau protein is one of the microtubule-associated proteins present in axons of normal nerve cells. When these tau proteins accumulate excessively, microtubules collapse and the network of normal nerve cells disintegrates. It is known that the cause of tau protein accumulation is that phosphorus is excessively attached to tau protein, forming a heavy body due to phosphorylation, and the accumulation of these tau proteins and aggregation of nerve cells are known to cause various degenerative brain diseases. .

In this regard, erdafitinib of the present invention has the activity of inhibiting phosphorylation of Tau protein, and can be used as a treatment for degenerative brain diseases caused by phosphorylation of Tau protein in nerve cells or brain cells. Could know.

Therefore, the present invention provides a pharmaceutical composition for the prevention or treatment of neuroinflammatory or degenerative brain disease, comprising erdafitinib or a pharmaceutically acceptable salt thereof as an active ingredient.

The pharmaceutical composition of the present invention may include a pharmaceutically acceptable carrier. The composition containing a pharmaceutically acceptable carrier may be in various oral or parenteral dosage forms. When formulated, it is prepared using diluents or excipients such as commonly used fillers, extenders, binders, wetting agents, disintegrants, and surfactants.

Solid preparations for oral administration include tablets, powders, granules, capsules, etc. These solid preparations contain one or more compounds and at least one excipient, such as starch, calcium carbonate, sucrose, or lactose. ), gelatin, etc. Additionally, in addition to simple excipients, lubricants such as magnesium stearate, talc, etc. are also used. Liquid preparations for oral administration include suspensions, oral solutions, emulsions, and syrups. In addition to the commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, fragrances, and preservatives may be included. there is.

Preparations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. Non-aqueous solvents and suspensions may include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, and injectable esters such as ethyl oleate. As a base for suppositories, witepsol, macrogol, tween 61, cacao, laurel, glycerogelatin, etc. can be used.

The pharmaceutical composition may be any selected from the group consisting of tablets, pills, powders, granules, capsules, suspensions, oral solutions, emulsions, syrups, sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. It can have one dosage form.

Additionally, as described above, the pharmaceutical compositions of the present invention can be administered to treat various diseases, including symptoms associated with inflammatory responses.

The composition of the present invention is administered in a pharmaceutically effective amount. The term "pharmaceutically effective amount" means an amount sufficient to treat a disease with a reasonable benefit/risk ratio applicable to medical treatment, and the effective dose level is determined by the type and severity of the subject, age, sex, activity of the drug, and It can be determined based on factors including sensitivity, time of administration, route of administration and excretion rate, duration of treatment, concurrently used drugs, and other factors well known in the medical field.

The composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered singly or multiple times. It is important to consider all of the above factors and administer the amount that will achieve the maximum effect with the minimum amount without side effects. The general dosage of the pharmaceutical composition of the present invention is within the range of 0.001-100 mg/kg for adults.

The pharmaceutical composition may be administered through any general route as long as it can reach the target tissue. The composition of the present invention may be administered intraperitoneally, intravenously, intramuscularly, subcutaneously, intradermally, orally, intranasally, intrapulmonaryly, or rectally, depending on the purpose, but is not limited thereto. Additionally, the composition can be administered by any device capable of transporting the active agent to target cells.

The composition of the present invention can be used alone or in combination with methods using surgery, hormone therapy, drug therapy, and biological response regulators to prevent and treat neuroinflammation or degenerative brain diseases.

In the present invention, the neuroinflammation refers to inflammatory diseases in the central nervous system mediated by glial cells, and preferably refers to 'cranial nerve inflammatory disease'.

The neuroglia include, but are not limited to, oligodendrocytes, astrocytes, ependymal cells, microglia in the central nervous system, and Schwann in the peripheral nervous system. It may include Schwann cells and satellite cells.

The degenerative brain diseases that the composition containing erdafitinib is intended to treat in the present invention are not limited thereto, but include Alzheimer's disease, Parkinson's disease, progressive supranuclear palsy, multiple system atrophy, and olive nucleus-pontine-cerebellar atrophy (OPCA). , Shay-Drager syndrome, striato-substantia nigra degeneration, Huntington's disease, amyotrophic lateral sclerosis (ALS), essential tremor, cortico-basal degeneration, diffuse Lewy body disease, Parkinson-ALS-dementia complex, Niemann-Pick disease. , Pick's disease, cerebral ischemia, and cerebral infarction.

Furthermore, the present invention provides a health functional food composition for preventing or improving neuroinflammation or degenerative brain disease, comprising erdafitinib or a foodologically acceptable salt thereof as an active ingredient.

The health functional food of the present invention may additionally contain a foodologically acceptable carrier.

The health functional food may have a function that helps improve neuroinflammation or degenerative brain disease, and the food may be in the form of pills, powders, granules, needles, tablets, capsules, or liquids, and may be effective in the present invention. There are no particular restrictions on the types of foods to which ingredients can be added, for example, various beverages, gum, tea, vitamin complexes, health supplements, etc.

In addition to the active ingredients of the present invention, other ingredients that do not interfere with the inhibitory activity of neuroinflammation or degenerative brain disease can be added to the health functional food, and the types are not particularly limited. For example, like regular foods, it may contain various herbal extracts, foodologically acceptable food supplements, or natural carbohydrates as additional ingredients.

The term “health functional food” used in the present invention refers to food manufactured and processed in the form of tablets, capsules, powders, granules, liquids, and pills using raw materials or ingredients with functional properties useful to the human body. Here, functionality means controlling nutrients for the structure and function of the human body or obtaining useful effects for health purposes such as physiological effects. The health functional food of the present invention can be manufactured by a method commonly used in the art, and can be manufactured by adding raw materials and ingredients commonly added in the art. In addition, unlike general drugs, it is made from food, so it has the advantage of not having any side effects that may occur when taking the drug for a long time, and it can be highly portable.

There is no particular limitation on the type of health functional food of the present invention, and specific examples include meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gum, dairy products including ice cream, various soups, There are beverages, tea, drinks, alcoholic beverages, and vitamin complexes, and can include all health functional foods in the conventional sense.

Additionally, in the present invention, “pharmacologically or foodologically acceptable” means that the composition is not toxic to cells or humans exposed to it.

The salt may be used in the form of either a pharmaceutically or foodologically acceptable basic salt or an acid salt. Basic salts can be used in the form of either organic base salts or inorganic base salts, including sodium salts, potassium salts, calcium salts, lithium salts, magnesium salts, cesium salts, amidium salts, ammonium salts, triethylaminium salts, and pyrilicate salts. It may be selected from the group consisting of dinium salts. A useful acid salt is an acid addition salt formed by free acid. Inorganic acids and organic acids can be used as free acids. Hydrochloric acid, hydrobromic acid, sulfuric acid, sulfurous acid, phosphoric acid, double phosphoric acid, and nitric acid can be used as inorganic acids, and citric acid, acetic acid, maleic acid, malic acid, and fumaric acid can be used as organic acids. , glucolic acid, methanesulfonic acid, benzenesulfonic acid, camphorsulfonic acid, oxalic acid, malonic acid, glutaric acid, acetic acid, glycolic acid, succinic acid, tartaric acid, 4-toluenesulfonic acid, galacturonic acid, embonic acid, Glutamic acid, citric acid, aspartic acid, stearic acid, etc. may be used, but are not limited thereto and may include all salts formed using various inorganic acids and organic acids commonly used in the art.

In addition, the erdafitinib compound or its salt of the present invention may include not only pharmaceutically or foodologically acceptable salts, but also all salts, hydrates, solvates, derivatives, etc. that can be prepared by conventional methods. there is. Addition salts can be prepared by conventional methods, by dissolving them in a water-miscible organic solvent, such as acetone, methanol, ethanol, or acetonitrile, adding an excess amount of organic base, or adding an aqueous base solution of an inorganic base and then precipitating or crystallizing. It can be manufactured by ordering. Alternatively, an addition salt can be obtained by evaporating the solvent or excess base from this mixture and drying it, or it can be prepared by suction filtration of the precipitated salt.

Furthermore, the present invention can provide a method of inhibiting inflammatory activity of cells in vitro, comprising the step of treating cells in which inflammatory activity is induced with erdafitinib or a salt thereof, and the inflammatory activity may be induced by LPS (Lipopolysaccharide) treatment.

Additionally, the present invention can provide a composition for protecting nerve cells damaged by excessive inflammatory response in nerve cells, comprising erdafitinib or a pharmaceutically acceptable salt thereof as an active ingredient.

As described above, erdafitinib can suppress excessive inflammatory responses in nerve cells or brain tissue, thereby suppressing damage to nerve cells caused by the inflammatory response.

Furthermore, the present invention can provide a reagent composition for inhibiting the activation of microglia or astrocytes, comprising erdafitinib or a pharmaceutically acceptable salt thereof as an active ingredient, Additionally, the present invention can provide a reagent composition for inhibiting tau phosphorylation, comprising erdafitinib or a pharmaceutically acceptable salt thereof as an active ingredient.

Hereinafter, the present invention will be described in more detail through examples. These examples are merely for illustrating the present invention in more detail, and it will be apparent to those skilled in the art that the scope of the present invention is not limited to these examples.

<Preparation example and experiment method>

Preparation of erdafitinib compound

Erdafitinib was purchased and used from InvivoChem (V2672, Libertyville, IL, USA). The dose used was 1 to 5 μM (dissolved in DMSO) for in vitro analysis, and 10 mg/kg (i.p., 5% DMSO + 40% PEG + 5% Tween80) for in vivo analysis. + It was used in an amount of sequentially dissolved in 50% saline solution.

Wild-type mouse preparation

Male C57BL6/N mice (3 months old, 24-26g; Gyeonggi-do Coretech) were used in the in vivo experiment, and experimental groups were randomly assigned. Mice were raised in groups of 3-4 each in pathogen-free cages with a 12-hour photoperiod, and were allowed to consume food and water freely. All experimental procedures were approved by the Institutional Biological Safety Committee (IBC) and performed in accordance with the approved animal protocols and guidelines of the Korea Brain Research Institute (KBRI, approval number IACUC-19-00049).

Production of Alzheimer's disease-induced mouse animal model (5x FAD mice)

Male C57BL6/N (wild type) mice were purchased from Orient-Bio Company (Gyeonggi-do, Korea), and 5x FAD mice (stock # 34848-JAX, B6Cg-Tg APPSwFlLon, PSEN1 * M146L * L286V6799Vas/Mmjax) were purchased from Jackson Laboratory. used. 5x FAD mice (4 months old) were housed in a germ-free facility with 12 hours of light/dark control per day at an ambient temperature of 22°C.

Immunofluorescence staining (IF)

To determine the effect of erdafitinib on LPS-induced neuroinflammation, 10 mg/kg erdafitinib (i.p.) or vehicle (5% DMSO + 40% PEG + 5% Tween80 + 50% saline) was administered. The analysis was performed using wild-type mice injected intraperitoneally for 7 consecutive days. On day 7, wild-type mice were injected with erdafitinib, 30 minutes later administered LPS (Sigma Aldrich, St. Louis, MO, Escherichia coli, 10 mg/kg, i.p.) or PBS, and 8 hours later 2,2 ; Anesthetized with 2-tribromoethanol (Sigma Aldrich, St. Louis, MO, USA, 2.5% v/v, 150 mg/kg, i.p.). Anesthetized mice were perfused transcardially with PBS followed by 4% PFA (Cembio, Seoul, Korea). Afterwards, the mouse brain was removed, the tissue was fixed overnight in 4% paraformaldehyde at 4°C, and then dehydrated in 30% sucrose solution for 2 days. Then, coronal sections were sectioned at a thickness of 35 μm using a cryostat (Leica CM1850, Wetzlar, Germany).

For another immunohistochemical experiment, 4-month-old Alzheimer's disease-induced mice (5x FAD mice) were treated with erdafitinib (10 mg/kg, i.p.) or vehicle (% DMSO + 40% PEG + 5% Tween80 + 50% saline). was administered intraperitoneally daily for 2 weeks, and 14 days later, brain tissue was sectioned in the same manner as above.

The sectioned brain tissue was permeabilized with PBS (PBST) containing 0.2% Triton X-100 and 10% normal goat serum for 1 hour at room temperature. Then, mouse brain sections were incubated at 4°C for 48 hours with anti-Iba-1, anti-GFAP, anti-IL-1β, anti-IL-6, anti-COX-2, or anti-AT100 antibodies diluted in PBST. Immunostaining was performed for ~72 hours. After reaction with the primary antibody, the brain sections were washed three times with PBST, and then the reaction was performed with an appropriate secondary antibody at room temperature for 2 hours. Finally, the brain sections were washed three times with PBS and mounted using anti-fade medium containing DAPI (Vector Laboratories, Burlingame, CA, USA). Section images were acquired with a fluorescence microscope (DMi8, Leica Microsystems, Wetzlar, Germany) and analyzed with the software ImageJ (version 1.53a, National Institutes of Health, Bethesda, MD, USA). Information on the primary and secondary antibodies used in the experiments of the present invention is shown in Table 1 below.

BV2 microglial preparation

BV2 microglia (obtained from Dr. Kyung-Ho Seok) were cultured in high-glucose DMEM (Invitrogen, Carlsbad, CA, USA) medium was used and cultured in a 5% CO2 incubator.

MTT assay

MTT analysis was performed to confirm the effect of erdafitinib on the survival rate of BV2 microglia. For this purpose, cells in a 96-well plate (4x10 ⁴ cells/well) were cultured in FBS-free medium for 1 hour and then incubated with erdafitinib (0.1, 1, 5, 10 or 20 μM) or vehicle (0.0005, 0.005, 0.025 μM). , 0.05 or 0.1% DMSO) for 24 hours. Then, the cells were reacted with MTT solution for 3 h, and the formazan product was dissolved in DMSO for 20 min at room temperature. Afterwards, the absorbance of formazan was measured at 570 nm using a microplate reader (SPECTROstar Nano, BMG Labtech, Germany).

Real-time quantitative PCR (q-PCR)

To determine whether erdafitinib can modulate the LPS-induced inflammatory response, BV2 microglial cells were treated with 1 μM or 5 μM erdafitinib or vehicle (1% DMSO) for 30 minutes, then 1 μg /ml LPS or PBS was treated for 5.5 hours. Afterwards, total RNA was extracted from cells or brain tissues (cortex and hippocampus) using TRIzol (Invitrogen, Waltham, MA, USA) according to the manufacturer's protocol. Then, total RNA (1 μg) was reverse transcribed into cDNA using the Superscript cDNA Premix Kit II containing oligo(dT) primers (GeNetBio, Chungman, Korea), and the synthesized cDNA was then purified using the QuantStudio 5 Real-Time PCR System ( Applied Biosystems, Thermo Fisher Scientific, Waltham, MA, USA) was used as a template for real-time qPCR using Fast SYBR Green Master Mix (Thermo Fisher Scientific, Waltham, MA, USA). Additionally, the primers used for real-time qPCR reaction are listed in Table 2 below. Cycle threshold (Ct) values were normalized to gapdh values and fold changes were calculated relative to the control group.

Western blotting

To investigate whether erdafitinib can inhibit the production of inflammatory cytokines induced by LPS in vitro, BV2 microglia were treated with 5 μM erdafitinib or vehicle (1% DMSO) for 45 min. After that, the cells were treated with 1μg/ml LPS or PBS for 45 minutes. Western blotting was then performed on the total cell lysates using anti-pAKT/AKT, anti-pERK/ERK, anti-pJNK/JNK, anti-pPLCγ1/PLCγ1, and β-actin antibodies. Specifically, lysis buffer containing protease inhibitors (50mM Tris, pH 7.4, 1% Triton After centrifugation at 12000 rpm for 15 minutes, the protein concentration of the supernatant was measured using protein analysis reagent (Bio-Rad Laboratories, Hercules, CA, USA), and then 15 μg of protein was heated at 100°C for 5 minutes. Electrophoresis was performed on 8% SDS-polyacrylamide gels, and proteins were electrotransferred to polyvinylidene difluoride (PVDF) membranes (Millipore, Bedford, MA, USA). The membrane was then blocked with 5% skim milk dissolved in TBST, reacted with primary antibody overnight at 4°C, and then reacted with horseradish peroxidase-conjugated secondary antibody for 1 hour. Then, ECL solution (ATTO, Tokyo, Japan) was added, and detection images were collected and analyzed using Fusion Capt Advance software (Vilber Lourmat, Eberhardzell, Germany).

Additionally, for analysis of signaling pathways involved in AKT or JNK activation, Western blotting was performed using anti-p-c-JUN, anti-NFkB, and anti-PCNA antibodies. Specifically, BV2 microglia were treated with 5 μM erdafitinib or vehicle (1% DMSO) for 30 min, followed by 1 μg/ml LPS or PBS for 5.5 h, followed by cytoplasm supplemented with protease and phosphatase inhibitors. Cells were lysed for 5 minutes on ice using fractionation buffer (10mM HEPES, pH 8.0, 1.5mM MgCl2, 10mM KCl, 0.5mM DTT, 300mM Sucrose, 0.1% NP-40, and 0.5mM PMSF). After centrifugation at 10,000 rpm for 1 min at 4°C, the pellet was incubated in buffer for nuclear fractionation containing protease and phosphatase inhibitors (10mM HEPES pH 8.0, 20% glycerol, 100mM KCl, 100mM NaCl, 0.2mM EDTA). , 0.5mM DTT and 0.5mM PMSF) for 15 minutes on ice. Finally, the cell lysate was centrifuged at 10,000 rpm for 5 minutes at 4°C, and Western blotting was performed using the supernatant as previously described. Table 3 below lists information on the primary and secondary antibodies used for Western blotting.

Statistical processing

GraphPad Prism 7 software (GraphPad Software, San Diego, CA, USA) was used for graph generation and statistical analysis. Data were expressed as individual data points and mean ± SEM. Student's t test was used for pairwise comparisons, and one-way analysis of variance (ANOVA) with Tukey's multiple comparison test was used for multiple comparisons. * (asterisk) indicates significance. *p<0.05, **p<0.01, ***p<0.001.

<Example 1>

Confirmation of the inhibitory activity of Erdafitinib on LPS-induced microgliosis and astrogliosis

To determine whether erdafitinib can modulate LPS-mediated neuroinflammation in the central nervous system, the present inventors administered 10 mg/kg erdafitinib (i.p.) or vehicle (5% DMSO + 40% PEG + 5% tween80 + 50% saline) was injected for 7 consecutive days. PBS or LPS (10 mg/kg, i.p.) was injected at 30-minute intervals on the 7th day after erdafitinib administration. The brain was removed 8 hours after LPS injection, and the mice were sacrificed for analysis of gliosis and expression of proinflammatory cytokines.

As a result of the analysis, as shown in Figure 1, erdafitinib was found to significantly downregulate LPS-mediated microgliosis in the cortex and hippocampus of wild-type mice (Figures 1A and 1B). Specifically, erdafitinib-treated mice showed reduced Iba-1-labeled areas in the cortex and hippocampus (CA1 and DG) regions compared to the LPS-only treated group, and these results suggest that erdafitinib is active in the brain. This means that it can significantly suppress LPS-induced hypertrophy of microglial cells (Figure 1B). Additionally, the LPS-induced increased number of Iba-1 positive cells was found to be significantly downregulated in the cortex and hippocampal CA1 of erdafitinib-treated mice, while no significant downregulation was seen in the hippocampal DG region (Figure 1B ). However, erdafitinib appeared to have some effect in controlling the LPS-induced increase in the fluorescence intensity of Iba-1 (Figure 1B).

In addition, as a result of examining the effect of erdafitinib on LPS-induced astrogliosis in wild-type mice, astrogliosis was found to be significantly reduced in the group treated with erdafitinib (Figures 2A and 2B). Erdafitinib was shown to inhibit LPS-induced fluorescence intensity of GFAP, GFAP-labeled area fraction, and number of GFAP-positive astrocytes in the cortex ( Fig. 2B ). However, in the hippocampus, erdafitinib appeared to downregulate LPS-induced astrocyte hypertrophy and GFAP fluorescence intensity without altering the number of GFAP-positive cells (Figure 2B).

Therefore, through these results, the present inventors showed that erdafitinib of the present invention can effectively inhibit the activation of microglia and astrocytes induced by LPS in the brain of wild-type mice, which ultimately results in erdafitinib This means that Fitinib can be used as a treatment for degenerative brain diseases.

<Example 2>

Confirmation of proinflammatory cytokine and COX-2 inhibitory activity of erdafitinib

Considering that gliosis can produce pro-inflammatory cytokines upon immune stimulation, the present inventors analyzed whether erdafitinib treatment could regulate the production of LPS-induced inflammatory cytokines. For this purpose, wild-type mice were treated with erdafitinib, then LPS, and immunofluorescence staining was performed on mouse brain tissue with anti-IL-1β, anti-IL-6, and anti-COX2 antibodies. carried out.

As a result, as shown in Figure 3, the fluorescence intensity of pro-inflammatory cytokines IL-1β and IL-6 in the cortex and hippocampus (CA1 and DG) regions of the brain of wild-type mice injected with erdafitinib was erdafitinib. It was found to be significantly reduced compared to the control group that did not inject nip (Figure 3). In addition, erdafitinib also appeared to down-regulate the fluorescence intensity of COX-2 in the cortex and hippocampus (CA1 and DG) compared to LPS treatment alone (Figure 4).

Through these results, the present inventors can see that the erdafitinib drug of the present invention can prevent and treat gliosis by effectively suppressing and controlling LPS-mediated brain inflammation (neuroinflammation) in the wild-type mouse brain. there was.

<Example 3>

Confirmation of the regulatory effect of erdafitinib on LPS-induced pro-inflammatory cytokines in BV2 microglial cells

Before analyzing whether erdafitinib affects the LPS-mediated inflammatory response in vitro, whether erdafitinib affects cell viability was analyzed through MTT analysis.

As a result, erdafitinib appeared to have no particular cytotoxicity on BV2 microglia at a treatment concentration of 20 μM (Figure 5B).

Accordingly, based on the results of this MTT analysis, the present inventors determined erdafitinib treatment concentrations of 1 μM and 5 μM for analysis of pro-inflammatory cytokines, and treated BV2 microglial cells at each concentration for 30 minutes. . At this time, the vehicle (1% DMSO) treated group was used as the control group. After the above treatment, treatment was performed with 1 μg/ml LPS or PBS for 5.5 hours. Afterwards, the production level of pro-inflammatory cytokines was analyzed through real-time qPCR.

As a result, the 5μM erdafitinib treatment group showed a significant decrease in LPS-induced mRNA levels of TNF-α, Il-1β, Cox-2, and Il-6, whereas the 1μM erdafitinib treatment group showed a significant decrease in LPS-induced mRNA levels of TNF-α, Il-1β, Cox-2, and Il-6. This significant reduction effect was not observed (Figure 5C).

Through these results, the present inventors found that treatment with 5 μM erdafitinib was appropriate for suppressing the production of pro-inflammatory cytokines in brain cells induced by LPS.

<Example 4>

Confirmation of JNK/c-JUN signaling pathway inhibition effect following erdafitinib treatment in BV2 microglial cells

Furthermore, the present inventors performed an analysis to determine whether erdafitinib affects the regulatory mechanism of the LPS-induced neuroinflammatory response. For this purpose, BV2 microglial cells were treated with 5 μM erdafitinib or vehicle (1% DMSO) for 45 minutes, then treated with 1 μg/ml LPS or PBS, and the JNK/c-JUN signaling pathway was treated with 1 μg/ml LPS or PBS. Changes in the expression levels of the involved molecules were confirmed through Western blot.

As a result, as shown in Figure 6, when pretreated with erdafitinib, the expression level of p-AKT, which was increased by stimulation with LPS, was found to be significantly reduced, but the expression level of total AKT protein was not affected. was found to be absent (Figure 6A). However, in BV2 microglial cells pretreated with erdafitinib compared to the LPS-treated group, the level of pERK was not reduced by pretreatment of erdafitinib (Figure 6B). In addition, treatment with erdafitinib was shown to significantly reduce the level of pJNK increased by LPS in BV2 microglia (Figure 6C), and pPLCγ1 level was also significantly reduced by treatment with erdafitinib. (Figure 6D).

In addition, the present inventors investigated the effect of erdafitinib on the downstream signaling pathways of AKT and JNK. For this purpose, BV2 microglial cells were treated with 5 μM erdafitinib or vehicle (1% DMSO) for 30 minutes. Afterwards, it was treated with 1μg/ml LPS or PBS for 5.5 hours. Western blotting was then performed on the nuclear fraction using anti-p-c-JUN or anti-NF-κB antibodies.

As a result, it was confirmed that the level of p-c-JUN in the nuclear fraction was significantly reduced in the group treated with erdafitinib compared to the group treated with LPS alone (Figure 6E). However, the level of NF-κB in the nuclear fraction did not appear to be significantly altered by erdafitinib pretreatment (Figure 6F).

Through these results, the present inventors confirmed that erdafitinib of the present invention can suppress the inflammatory response caused by LPS by reducing the activation of the JNK/c-JUN signaling pathway.

<Example 5>

Analysis of astrocyte activity in brain tissue of mice with degenerative brain disease induced by erdafitinib

To determine the effect of erdafitinib on amyloid beta-mediated astrocyte activation, 3-month-old 5x FAD mice induced with Alzheimer's disease were administered 10 mg/kg erdafitinib (i.p.) or vehicle (5% DMSO + 40 mg/kg). % PEG + 5% tween80 + 50% saline) was administered daily for 2 weeks, and then immunohistochemistry was performed using an anti-GFAP antibody that can detect astrocyte activity.

As a result, as shown in Figures 7A to 7E, the positive cell number of GFAP, an indicator of astrocyte activity, in the hippocampal DG region of the erdafitinib-treated group was significantly decreased compared to the control group. On the other hand, there was no decrease in GFAP activity in the hippocampus CA1 and cortex due to erdafitinib treatment.

<Example 6>

Analysis of tau phosphorylation inhibition activity of erdafitinib

To determine the effect of erdafitinib on tau phosphorylation, 3-month-old 5x FAD mice induced with Alzheimer's disease were treated with 0 mg/kg erdafitinib (i.p.) or vehicle (5% DMSO + 40% PEG + 5% tween80 + 50% saline) was administered daily for 2 weeks, and then immunohistochemistry was performed using an anti-AT100 antibody that can detect phosphorylated tau protein.

As a result, it was confirmed that the fluorescence intensity of AT100, which can detect phosphorylated tau protein, was significantly reduced in the cerebral cortex of 5x FAD mice with degenerative brain disease (Alzheimer's disease) injected with erdafitinib compared to the control group. . (See Figures 8A-8F).

Overall, according to the results confirmed above, erdafitinib of the present invention has the activity of effectively suppressing inflammatory reactions occurring in brain cells or nerve cells, and effectively inhibits tau phosphorylation, which is known to be the cause of degenerative brain diseases. , it was confirmed that it can be used as a new treatment that can prevent or treat brain inflammation-related diseases and degenerative brain diseases.

So far, the present invention has been examined focusing on its preferred embodiments. A person skilled in the art to which the present invention pertains will understand that the present invention may be implemented in a modified form without departing from the essential characteristics of the present invention. Therefore, the disclosed embodiments should be considered from an illustrative rather than a restrictive perspective. The scope of the present invention is indicated in the claims rather than the foregoing description, and all differences within the equivalent scope should be construed as being included in the present invention.

Claims (19)

A pharmaceutical composition for the prevention or treatment of neuroinflammatory or degenerative brain disease, comprising erdafitinib or a pharmaceutically acceptable salt thereof as an active ingredient. According to paragraph 1,
The composition is characterized in that it has the effect of suppressing the damage caused to nerve cells by activated microglia or activated astrocytes by inhibiting the activity of microglia or astrocytes, neuroinflammation or Pharmaceutical composition for preventing or treating degenerative brain diseases. According to paragraph 1,
The composition is a pharmaceutical composition for preventing or treating neuroinflammatory or degenerative brain diseases, characterized in that it inhibits the expression and production of inflammatory cytokines COX-2, IL-1β, IL-6 or TNF-a. According to paragraph 1,
The composition is a pharmaceutical composition for preventing or treating neuroinflammatory or degenerative brain diseases, characterized in that it inhibits the activity of the JNK/c-JUN signaling pathway. According to paragraph 1,
The composition is a pharmaceutical composition for preventing or treating neuroinflammation or degenerative brain disease, characterized in that it suppresses excessive inflammatory response in nerve cells. According to paragraph 1,
The composition is a pharmaceutical composition for preventing or treating neuroinflammatory or degenerative brain diseases, characterized in that it inhibits phosphorylation of tau protein. According to paragraph 1,
The degenerative brain diseases include Alzheimer's disease, Parkinson's disease, progressive supranuclear palsy, multiple system atrophy, olivary nucleus-pontine-cerebellar atrophy (OPCA), Shay-Drager syndrome, striatal-substantia nigra degeneration, Huntington's disease, and amyotrophic lateral sclerosis ( ALS), essential tremor, cortico-basal degeneration, diffuse Lewy body disease, Parkinson-ALS-dementia complex, Niemann Pick disease, Pick disease, cerebral ischemia, and cerebral infarction. Pharmaceutical composition for preventing or treating brain diseases. A composition for protecting nerve cells damaged by excessive inflammatory response in nerve cells, comprising erdafitinib or a pharmaceutically acceptable salt thereof as an active ingredient. A reagent composition for inhibiting the activation of microglia or astrocytes, comprising erdafitinib or a pharmaceutically acceptable salt thereof as an active ingredient. According to clause 9,
A reagent composition for inhibiting the activation of microglia or astrocytes, wherein the activation of the microglia or astrocytes is caused by an excessive inflammatory response of nerve cells. According to clause 10,
A reagent composition for inhibiting the activation of microglia or astrocytes, wherein the inflammatory response is induced by LPS (Lipopolysaccharide). A reagent composition for inhibiting tau phosphorylation, comprising erdafitinib or a pharmaceutically acceptable salt thereof as an active ingredient. A health functional food composition for preventing or improving neuroinflammation or degenerative brain disease, comprising erdafitinib or a foodologically acceptable salt thereof as an active ingredient. According to clause 13,
The composition is characterized in that it has the effect of suppressing the damage caused to nerve cells by activated microglia or activated astrocytes by inhibiting the activity of microglia or astrocytes, neuroinflammation or Health functional food composition for preventing or improving degenerative brain diseases. According to clause 13,
The composition is a health functional food composition for preventing or improving neuroinflammation or degenerative brain disease, characterized in that it inhibits the expression and production of inflammatory cytokines COX-2, IL-1β, IL-6, or TNF-a. According to clause 13,
The composition is a health functional food composition for preventing or improving neuroinflammation or degenerative brain disease, characterized in that it inhibits the activity of the JNK/c-JUN signaling pathway. According to clause 13,
The composition is a health functional food composition for preventing or improving neuroinflammation or degenerative brain disease, characterized in that it suppresses excessive inflammatory response in nerve cells. According to clause 13,
The composition is a health functional food composition for preventing or improving neuroinflammation or degenerative brain disease, characterized in that it inhibits phosphorylation of tau protein. According to clause 13,
The degenerative brain diseases include Alzheimer's disease, Parkinson's disease, progressive supranuclear palsy, multiple system atrophy, olivary nucleus-pontine-cerebellar atrophy (OPCA), Shay-Drager syndrome, striatal-substantia nigra degeneration, Huntington's disease, and amyotrophic lateral sclerosis ( ALS), essential tremor, cortico-basal degeneration, diffuse Lewy body disease, Parkinson-ALS-dementia complex, Niemann Pick disease, Pick disease, cerebral ischemia, and cerebral infarction. Health functional food composition for preventing or improving brain disease.