Use of novel PPAR activity modulators for the prevention, amelioration or treatment of degenerative brain diseases

Abstract

The present invention relates to the use of novel PPAR activity modulators for the prevention, amelioration, or treatment of degenerative brain diseases. More specifically, the present invention provides compositions for preventing, ameliorating, or treating degenerative brain diseases and compositions for improving learning ability, memory, or ameliorating cognitive decline using PPAR activator preparations that bind to and activate all PPAR subtypes. The present invention also provides methods for preventing, ameliorating, or treating degenerative brain diseases and methods for improving learning ability, memory, or ameliorating cognitive decline using the novel PPAR activator preparations.

Description

[Technical Field]

[0001] The present invention relates to the use of novel PPAR activity modulators for the prevention, amelioration, or treatment of degenerative brain diseases. More specifically, the present invention provides compositions for preventing, ameliorating, or treating degenerative brain diseases and compositions for improving learning ability, memory, or ameliorating cognitive decline using PPAR activator preparations that bind to and activate all PPAR subtypes. The present invention also provides methods for preventing, ameliorating, or treating degenerative brain diseases and methods for improving learning ability, memory, or ameliorating cognitive decline using the novel PPAR activator preparations. [Background technology]

[0002] Rapid modernization has led to the development of people's income levels and social medical and healthcare environments, and as a result, the proportion of the elderly population is gradually increasing worldwide. The increase in the elderly population has resulted in an increase in the prevalence of geriatric diseases, and among these, the incidence of senile dementia, a degenerative brain disease, is rising every year, and the socioeconomic costs incurred by the increase in the number of dementia patients are also increasing.

[0003] Many patients with senile dementia suffer from Alzheimer's disease, but there are currently no effective treatments for the cause of Alzheimer's disease, nor are there any methods for prevention.Recently, the antibody drugs aducadumab and lecanemab, which target amyloid beta aggregates to treat Alzheimer's disease, were approved by the US Food and Drug Administration (FDA), but the effectiveness of these treatments has yet to be proven.There are also five other drugs prescribed for Alzheimer's patients, including acetylcholinesterase inhibitors and glutamate receptor inhibitors, but all of these only serve to alleviate symptoms.

[0004] Degenerative brain diseases, including Alzheimer's disease, share a common characteristic: the formation of abnormal protein aggregates in brain tissue, which leads to chronic inflammation. In Alzheimer's disease, Aβ peptides entangle and form extracellular plaques, which generate reactive oxygen species and trigger an inflammatory response by microglia. In this case, overactivated microglia secrete cytokines (IL-6, TNFα) and reactive oxygen species (ROS), promoting the death of surrounding neurons. The effects of microglia have been reported in numerous studies to not only cause neuronal death but also the formation of protein aggregates and serious pathological phenomena. Therefore, active research is being conducted into the development of therapeutic agents that not only reduce protein aggregates but also reduce chronic inflammation in brain tissue.

[0005] In this regard, Korean Patent Publication No. 10-2022-0060494 discloses that chlorpromazine regulates the activity of microglial cells and alleviates neuroinflammation, thereby showing therapeutic effects on degenerative neurological diseases, and Korean Patent Publication No. 10-2022-0039607 discloses that N-palmitoyl serinol protects the brain by reducing the amount of inflammatory cytokines in brain tissue, and is effective in improving cognitive ability and memory.

[0006] Peroxisome proliferator-activated receptors (PPARs) are ligand-mediated transcription factors known to be major regulators of metabolic processes. PPARs exist in three subtypes: PPARα, PPARβ / δ, and PPARγ. Antagonists targeting these subtypes are used to treat conditions such as dyslipidemia, diabetes, and obesity. Previous research has shown that PPARs not only regulate metabolic processes but also the quantitative and activity levels of NF-κB, a key regulator of inflammatory responses. PPARs are also closely related to inflammatory responses. According to a 2021 clinical trial report on Alzheimer's disease treatments, losartan, a PPARγ antagonist, is currently undergoing phase 3 clinical trials. Various papers have also shown that pan-agonists, which can activate all three PPAR subtypes, have memory-enhancing effects in animal models of Alzheimer's disease.

[0007] Against this background, the present inventors screened for novel synthetic small molecule substances that can regulate PPAR activity, and confirmed that the screened compounds regulate inflammatory responses in microglial cells and exhibit memory-improving effects when administered to an animal model of Alzheimer's dementia. This led to the discovery of potential applications of the compounds as drugs that not only have preventive, ameliorative, and therapeutic effects on the pathological phenomena of Alzheimer's dementia, but also exhibit enhancing effects on learning ability, memory, and cognitive ability, and led to the completion of the present invention. Summary of the Invention [Problem to be solved by the invention]

[0008] Therefore, the present invention aims to provide a composition for preventing, ameliorating, or treating degenerative brain diseases using a novel PPAR activator that exhibits the effect of inhibiting excessive inflammatory responses through activation of PPAR transcription factors in microglial cells.

[0009] Another object of the present invention is to provide a composition for improving learning ability, memory, or ameliorating cognitive decline, using the novel PPAR activator preparation described above.

[0010] A further object of the present invention is to provide a method for preventing, ameliorating or treating degenerative brain diseases using the novel PPAR activating preparation described above.

[0011] Another object of the present invention is to provide a method for improving learning ability, memory, or ameliorating cognitive decline using the novel PPAR activator preparation described above.

[0012] A further object of the present invention is to provide use of the novel PPAR activating preparation described above for the manufacture of a medicament for preventing, ameliorating or treating degenerative brain diseases.

[0013] It is still another object of the present invention to provide use of the novel PPAR activating preparation described above for the manufacture of a medicament for improving learning ability, memory, or ameliorating cognitive decline.

[0014] However, the technical problems that the present invention aims to achieve are not limited to those mentioned above, and other problems not mentioned will be clearly understood by those skilled in the art from the following description. [Means for solving the problem]

[0015] In order to solve the above problems, the present invention provides a pharmaceutical composition for preventing or treating degenerative brain diseases, comprising, as an active ingredient, a compound represented by the following chemical formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: JPEG2025527284000002.jpg96156The present invention also provides a health functional food composition for preventing or improving degenerative brain diseases, comprising the compound represented by the above-mentioned chemical formula 1, its stereoisomer or a nutritively acceptable salt thereof as an active ingredient.

[0016] The present invention also provides a composition for improving learning ability, memory, or ameliorating cognitive decline, comprising the compound represented by Chemical Formula 1, a stereoisomer thereof, or a pharmaceutically or food-based acceptable salt thereof as an active ingredient.

[0017] Furthermore, the present invention provides a method for preventing, ameliorating, or treating a degenerative brain disease, which comprises administering the compound represented by Chemical Formula 1, a stereoisomer thereof, or a pharmaceutically or food-based acceptable salt thereof to an individual in need thereof.

[0018] The present invention also provides a method for improving learning ability, memory, or ameliorating cognitive decline, comprising administering the compound represented by Chemical Formula 1, a stereoisomer thereof, or a pharmaceutically or food-based acceptable salt thereof to an individual in need thereof.

[0019] Furthermore, the present invention provides use of the compound represented by the aforementioned Chemical Formula 1, its stereoisomer, or a pharmaceutically or food-based acceptable salt thereof for the manufacture of a medicament for preventing, ameliorating, or treating a degenerative brain disease.

[0020] The present invention also provides a use of the compound represented by Chemical Formula 1, its stereoisomer, or a pharmaceutically or food-based acceptable salt thereof for the manufacture of a medicament for improving learning ability, memory, or cognitive decline.

[0021] Additionally, the stereoisomers may include racemates, enantiomers, partial stereoisomers, mixtures of enantiomers or mixtures of partial stereoisomers.

[0022] Furthermore, the degenerative brain disease may include any one or more selected from the group consisting of dementia, autism, Alzheimer's disease, Huntington's diseases, vascular dementia, stroke, ischemic stroke, traumatic brain injury, amnesia, Parkinson's disease, Pick's disease, Creutzfeldt-Jakob disease, peripheral neuropathy, amyotrophic lateral sclerosis, multiple sclerosis, and mild cognitive impairment.

[0023] Furthermore, the compound, its stereoisomer, or a pharmaceutically or food-based acceptable salt thereof can activate all of PPARα, PPARβ / δ, and PPARγ.

[0024] Furthermore, the compound, its stereoisomer, or a pharmaceutically or food-based acceptable salt thereof can exhibit any one or more of the following effects (i) to (iii): (i) Activation of PPAR transcription factors in microglial cells inhibits inflammatory responses; (ii) the effect of inhibiting the formation of Aβ aggregates in brain tissue; and (iii) the inhibitory effect of gliosis caused by the excessive activity of microglial cells and astrocytes.

[0025] Furthermore, the composition for improving learning ability, memory or cognitive decline may be a pharmaceutical or health food composition. [Effects of the Invention]

[0026] The compound of the present invention represented by Chemical Formula 1 is a PPAR activator that activates PPAR transcription factors in microglial cells and inhibits excessive inflammatory responses that increase in Alzheimer's disease, thereby inhibiting the formation of Aβ aggregates, which are known to be the cause of Alzheimer's disease. Furthermore, the compound inhibits gliosis caused by microglial cells and astrocytes in the brain tissue of 5xFAD-induced dementia mice, and shows an improving effect on learning ability, memory, and cognitive function decline. Therefore, the compound can be used as a medicine and health functional food for preventing, ameliorating, or treating degenerative brain diseases, as well as for improving learning ability, memory, and cognitive function decline. [Brief explanation of the drawings]

[0027] [Figure 1a-d] Figures 1a to 1d show the results of comparing the degree of PPAR transcription factor activity due to DTMB treatment, Figure 1a is a schematic diagram showing a screening method for PPAR active agents, Figure 1b is a diagram showing the results of PPAR activity analysis using a GAL4 reporter vector, Figure 1c is a diagram showing the results of molecular docking analysis, and Figure 1d is a diagram showing the results of a binding experiment between CNBr, drugs, and proteins. [Figure 2a] FIG. 2a shows the results of MTT analysis in which DTMB cytotoxicity was tested in a concentration-dependent manner using HMO6, BV2, and RAW264.7 cell lines. [Figure 2b] FIG. 2b is a graph showing the anti-inflammatory effect of DTMB treatment in a macrophage cell line in which an inflammatory response was induced by lipopolysaccharide (LPS) treatment, as measured by NO production. [Figure 2c-d]Figures 2c and 2d show the anti-inflammatory effect of DTMB treatment on the BV2 cell line, as measured by cytokine production, after inflammatory responses were induced by LPS and Aβ aggregate treatment, respectively. Data are shown as mean ± standard error of the mean (SEM) of three independent experiments. *p<0.05; **p<0.01; ***p<0.001 by one-way ANOVA. [Figure 2e-f] Figures 2e and 2f show the anti-inflammatory effect of DTMB treatment, as measured by cytokine production, in primary microglia isolated from mice in which an inflammatory response was induced by treatment with LPS and Aβ aggregates, respectively. Blot intensity was quantified using ImageJ. Data represent the mean ± standard error of the mean (SEM) of three independent experiments. *p<0.05; **p<0.01; ***p<0.001 by one-way ANOVA. [Figure 2g] Figure 2g shows quantitative PCR analysis of mRNA expression of proinflammatory cytokines (Il-6 and Il-1β), related enzymes (iNOS), and an M2 phenotype microglial cell marker (Arg-1). Data represent the mean ± standard error of the mean (SEM) of three independent experiments. *p<0.05; **p<0.01; ***p<0.001 by one-way ANOVA. [Figure 2h] Figure 2h shows the results of Western blotting to confirm the effect of DTMB treatment on reducing NF-κB and inflammation-related factors (NLRP-3 and ASC) in microglial cells (primary microglia) isolated from mice. [Figure 2i]Figure 2i shows the results of DTMB treatment in isolated mouse primary microglia to determine the changes in protein expression levels of NF-κB and inflammation-related factors (NLRP-3 and ASC). Data are shown as mean ± standard error of the mean (SEM) from three independent experiments. p values from one-way ANOVA are indicated as follows: *p<0.05; **p<0.01; ***p<0.001. [Figure 2j-k] Figures 2j and 2k show representative Western blot data for NF-κB, NLRP3, and ASC in primary microglial cells treated with DMSO (0.1%) or DTMB (25 μM) for 4 hours. Inflammatory responses were induced using LPS (1 μg / mL). Data represent the mean ± standard error of the mean (SEM) of three independent experiments. p values from one-way ANOVA were expressed as follows: *p<0.05; **p<0.01; ***p<0.001. [Figure 2l-m] Figures 2l and 2m show the results of treating cells with MG132 (20 μM) for 6 hours to inhibit proteasomal degradation, followed by DTMB (25 μM) for 24 hours, and then examining NF-κB gene expression levels. Data represent the mean ± standard error of the mean (SEM) of three independent experiments. p values from one-way ANOVA are indicated as follows: *p<0.05; **p<0.01; ***p<0.001. [Figure 3a-c]Figure 3a is a schematic diagram showing the experimental design for evaluating the effects of DTMB in a 5xFAD animal model of Alzheimer's disease. Figure 3b shows changes in body weight and relative organ weights after DTMB treatment in a 5xFAD mouse model. Figure 3c shows the results of a Y-maze test to confirm the effects of DTMB administration on short-term memory and cognitive function in a 5xFAD animal model of Alzheimer's disease. The left graph in Figure 3c shows the alternation activity of mice in each group, and the right graph shows the total number of arm entries, which indicates the total number of times each group entered each arm. All data are means ± standard error of the mean (SEM) (n = 25 per group). p values from two-way ANOVA are indicated as follows: **p < 0.01, ***p < 0.001. [Figure 4a-c] Figures 4a-4c show the results of a water maze test to confirm the effects of DTMB administration on long-term memory and cognitive function in the 5xFAD Alzheimer's disease animal model. Figure 4a shows the time it took mice in each group to reach the platform (escape latency), Figure 4b shows the time mice in each group spent at the platform (target quadrant occupancy) and swimming distance (total path), and Figure 4c shows the movement trajectories of mice in each group. All data are means ± standard error of the mean (SEM) (n = 25 per group). p values from two-way ANOVA are indicated as follows: **p < 0.01, ***p < 0.001. [Figure 5a-b] Figure 5a shows photographs of the immunochemical staining of brain tissue (hippocampus and cerebral cortex) in a 5xFAD Alzheimer's disease animal model, demonstrating the inhibitory effect of DTMB administration on amyloid aggregate formation. Figure 5b shows a graph quantifying the results of Figure 5a. All data are means ± standard error of the mean (SEM) (n = 25 per group). p values from t tests are indicated as follows: **p < 0.01, ***p < 0.001. [Figure 5c]Figure 5c shows the results of Western blotting analysis of total APP levels in hippocampal tissue following DTMB administration in the 5xFAD Alzheimer's disease animal model. All data are means ± standard error of the mean (SEM) (n = 25 per group). p values from t tests are indicated as follows: **p < 0.01, ***p < 0.001. [Figure 5d-e] Figures 5d and 5e show the results of Western blotting of the protein levels of enzymes associated with APP processing (Bace-1 for β-secretase, Aph1 for γ-secretase, Nicastrin, and Pen2) in hippocampal tissue following DTMB administration in the 5xFAD Alzheimer's disease animal model. All data are means ± standard error of the mean (SEM) (n = 25 per group). p values from t tests are indicated as follows: **p < 0.01, ***p < 0.001. [Figure 5f] Figure 5f shows the results of quantitative PCR analysis of the gene expression of β-secretase (Bace-1) and γ-secretase (Aph1, nicastrin, and Pen2) in hippocampal tissue following DTMB administration in the 5xFAD Alzheimer's disease animal model. All data are means ± standard error of the mean (SEM). p values from t tests are indicated as follows: **p<0.01, ***p<0.001. [Figure 5g-h] Figures 5g and 5h show the results of Western blotting of protein levels of enzymes involved in APP processing (Bace-1 for β-secretase, Aph1 for γ-secretase, nicastrin, and Pen2) in lysates of cortical tissues from DTMB-treated 5xFAD Alzheimer's disease animal models. All data are means ± standard error of the mean (SEM). p values from t tests are indicated as follows: **p<0.01, ***p<0.001. [Figure 5i] FIG. 5i shows the results of Western blotting of brain tissue lysates from DTMB-administered 5xFAD Alzheimer's disease animal models, in which the Aβ monomer levels were confirmed using the 6e10 antibody. [Figure 5j] FIG. 5j shows dot blot data of Aβ plaque levels in the insoluble fraction of brain tissue lysates following DTMB administration in the 5xFAD animal model of Alzheimer's dementia. [Figure 6a-f] Figures 6a-6f show the reduction in microglial and astrocyte gliosis in brain tissue following DTMB administration in a 5xFAD Alzheimer's disease animal model. Figures 6a and 6c show the results in the cerebral cortex, and Figures 6b and 6d show the results in the hippocampus. Figure 6e is a graph quantifying the suppression of microglial hyperactivity in the hippocampus and cerebral cortex. Figure 6f is a graph quantifying the suppression of astrocyte hyperactivity in the hippocampus and cerebral cortex. All data are means ± standard error of the mean (SEM). p values from one-way ANOVA and t-tests are indicated as follows: **p<0.01, ***p<0.001. [Figure 6g] Figure 6g shows quantitative PCR data of pro-inflammatory cytokines and related enzymes in brain tissue following DTMB administration in the 5xFAD Alzheimer's dementia animal model. All data are means ± standard error of the mean (SEM). p values from one-way ANOVA and t-tests are indicated as follows: **p<0.01, ***p<0.001. [Figure 6h-i] Figures 6h and 6i show the results of Western blotting to examine the levels of inflammasome-related proteins in hippocampal tissue lysates from DTMB-treated 5xFAD Alzheimer's disease animal models. All data are means ± standard error of the mean (SEM). p values from one-way ANOVA and t-tests are indicated as follows: **p<0.01, ***p<0.001. [Figure 7]Figure 7 shows the expression patterns of inflammatory response-related genes (TNF-α, IL-6, IL-1β, Cxcl10, and clec7a) and microglial activation-related genes (Iba-1, Trem2, and Itgax2) in microglial cells in brain tissue following DTMB administration in the 5xFAD Alzheimer's disease animal model. Data are shown as mean ± standard error of mean (SEM) from three independent experiments. p values from one-way ANOVA are indicated as follows: *p<0.05; **p<0.01; ***p<0.001. DETAILED DESCRIPTION OF THE INVENTION

[0028] As mentioned above, the therapeutic effects of currently known therapeutic agents for Alzheimer's disease have not been clearly proven, or they are only effective in alleviating symptoms, so there is a continuing need for the development of therapeutic agents that can treat the underlying cause. Based on previous reports that pan-agonists that can activate all three PPAR subtypes can exhibit therapeutic effects for Alzheimer's disease, the present inventors screened for novel synthetic small molecule substances that can regulate PPAR activity and experimentally verified that the screened compounds not only exhibit preventive, ameliorative, and therapeutic effects for degenerative brain diseases, but also enhance learning ability, memory, and cognitive function, thereby seeking a solution to the above-mentioned problem.

[0029] Therefore, a first aspect of the present invention relates to a pharmaceutical composition for preventing or treating degenerative brain diseases, which contains, as an active ingredient, a compound represented by the following chemical formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a health functional food composition for preventing or ameliorating degenerative brain diseases, which contains the same active ingredient: JPEG2025527284000003.jpg96136 In relation to the first aspect, the present invention also provides a method for preventing, ameliorating, or treating a degenerative brain disease, comprising administering the compound represented by Chemical Formula 1, a stereoisomer thereof, or a pharmaceutically or food-based acceptable salt thereof to an individual in need thereof.

[0030] Furthermore, the first aspect of the present invention provides use of the compound represented by Chemical Formula 1, its stereoisomer, or a pharmaceutically or food-based acceptable salt thereof for the manufacture of a medicament for preventing, ameliorating, or treating a degenerative brain disease.

[0031] The compound represented by Chemical Formula 1 is [4-(4-methoxyphenyl)-8-methyl-2-oxochromen-7-yl](2S)-3-(1H-indol-3-yl)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoate (DTMB) with CAS No. 956044-42-1, and was discovered as a novel regulator of PPAR transcription factors that can activate all three PPAR subtypes (PPARα, PPARβ / δ, and PPARγ) through computer molecular prediction program analysis and GAL4 translocation activity analysis.

[0032] Additionally, the stereoisomers may include racemates, enantiomers, partial stereoisomers, mixtures of enantiomers or mixtures of partial stereoisomers.

[0033] The degenerative brain disease may include, but is not limited to, any one or more selected from the group consisting of dementia, autism, Alzheimer's disease, Huntington's disease, vascular dementia, stroke, ischemic stroke, traumatic brain injury, amnesia, Parkinson's disease, Pick's disease, Creutzfeldt-Jakob disease, peripheral neuropathy, amyotrophic lateral sclerosis, multiple sclerosis, and mild cognitive impairment.

[0034] It has been reported that all three subtypes of PPAR inhibit inflammatory responses through the inhibition of the activity and quantitative changes of NF-κB transcription factors, which are the main regulators of inflammatory responses. Therefore, in a specific embodiment of the present invention, to confirm whether DTMB, which was discovered as a novel regulator of PPAR transcription factors, exhibits anti-inflammatory effects, RAW264.8 macrophage cell line was treated with LPS to induce an inflammatory response, and then DTMB or known PPAR regulators (WY14643, rosiglitazone, and GW501516) were treated to confirm the inhibitory effect on NO production. As a result, as can be seen from Figure 2b, DTMB inhibited NO production in a concentration-dependent manner, and IC 50 The value was very low at 1.23 μM. In particular, DTMB was confirmed to inhibit NO production more effectively than WY14643 and rosiglitazone at the same concentration, demonstrating superior anti-inflammatory effects.

[0035] Degenerative brain diseases, including Alzheimer's disease, characteristically exhibit chronic inflammation of brain tissue.

[0036] Beta amyloid (Aβ) is derived from amyloid precursor protein (APP), which is degraded by beta-secretase and gamma-secretase to generate Aβ. It is the main component of amyloid plaques found primarily in the brains of patients with brain diseases such as Alzheimer's disease. Abnormal accumulation can cause various brain diseases. In addition, excessive accumulation of beta amyloid causes an inflammatory response in the hippocampus, cerebral cortex, and surrounding cells, which can damage neurons and even disrupt the neural circuitry that maintains normal brain function.

[0037] Therefore, in another specific embodiment of the present invention, to confirm the anti-inflammatory effect of DTMB in neurons, the BV2 microglial cell line and microglial cells isolated from mice (primary microglia) were treated with LPS or Aβ aggregates to induce an inflammatory response, and then DTMB was administered and the levels of cytokines (TNF-α and IL-6) were measured. As confirmed by the results in Figures 2c to 2f, treatment of the BV2 microglial cell line and microglial cells isolated from mice treated with LPS or Aβ aggregates with DTMB statistically significantly reduced the levels of TNF-α and IL-6, thereby inhibiting the inflammatory response.

[0038] In yet another specific embodiment of the present invention, to confirm the mechanism by which DTMB exerts its anti-inflammatory effect, we treated isolated mouse microglial cells with Aβ aggregates to induce an inflammatory response, and then treated them with DTMB to measure the levels of NF-κB and NLRP3, a component of the inflammasome, and its adaptor, ASC (Apoptosis-associated speck-like protein containing a caspase recruitment domain). As shown in Figures 2h and 2i, NF-κB and NLRP3, which were increased by Aβ aggregate treatment, were statistically significantly reduced by DTMB treatment, indicating that DTMB inhibits the inflammatory response of microglial cells.

[0039] In yet another specific embodiment of the present invention, to confirm whether DTMB actually alleviates the pathological phenomena of Alzheimer's dementia, changes in learning ability, memory, and cognitive function following DTMB administration were analyzed using the Y-maze test and Morris water maze test in 5xFAD mice, which are Alzheimer's dementia-induced mice, as shown in Figure 3a. As a result, as confirmed by the results in Figures 3c and 4a-4c, 5xFAD mice showed reduced short-term and long-term memory and cognitive function compared to normal mice, but DTMB administration improved short-term and long-term memory and cognitive function to levels comparable to those of normal mice.

[0040] In yet another specific embodiment of the present invention, to confirm the inhibitory effect of DTMB administration on Aβ aggregate formation, the amount of Aβ aggregates in the hippocampus and cerebral cortex of brain tissue from DTMB-administered 5xFAD mice was measured by immunochemical staining. As a result, as can be seen from Figures 5a and 5b, the increased Aβ aggregates in the hippocampus and cerebral cortex of brain tissue from 5xFAD mice not administered DTMB were significantly reduced by DTMB administration.

[0041] The activity of microglia and astrocytes has been reported to be related to the onset and progression of degenerative neurological diseases. Microglia are immune cells resident in the central nervous system (CNS) that are activated by external stimuli and are known to induce immune and inflammatory responses. Microglia are the primary immune cells in the CNS. They maintain a thin cell body with long, thin branches. In the presence of external or internal toxins, they transform into an activated form with thick, short branches and a mast cell body to protect neurons from these toxins.

[0042] However, when microglial cells are stimulated by substances such as bacterial endotoxins (LPS), interferon-γ, beta-amyloid, or gangliosides, they exhibit distinct behaviors compared to normal microglial cells: increased phagocytosis, increased cell proliferation, and the expression of cytokines such as TNF-α, IL-1β, and IL-6, chemokines, and inflammatory mediators such as inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). While this activation of microglial cells serves to remove damaged cells and protect neurons from invading bacteria and viruses, nitric oxide (NO) produced by iNOS, prostaglandins produced by COX-2, and TNF-α are toxic to neurons, resulting in excessive microglial activation exacerbating neuronal damage. Therefore, appropriate inhibition of microglial activation may be an additional method for treating degenerative brain diseases.

[0043] Astrocytes also play an important role in maintaining normal brain activity, as well as in the developmental process of the brain. It has been revealed that astrocytes in the brain properly remove neurotransmitters secreted by neurons, regulate ion concentrations in the brain, and support the activity of neurons. They also play a crucial role in the differentiation of neural stem cells into neurons.

[0044] However, when the brain is injured, astrocytes actively proliferate, causing swelling and activation into reactive astrocytes, such as those found in astrogliosis. Such reactive astrocytes have been observed in AIDS-related dementia, brain injury, ischemic brain disease, and Alzheimer's disease. Therefore, because sustained activation of astrocytes ultimately leads to the death of neurons, appropriate inhibition of astrocyte activation may be another method for treating degenerative brain diseases.

[0045] Therefore, in yet another specific embodiment of the present invention, to confirm whether administration of DTMB inhibits inflammatory responses in brain tissue, brain tissue from DTMB-administered 5xFAD mice was treated with antibodies against IBA-1, a microglial cell-specific protein, and GFAP, an astrocyte-specific protein, and the level of gliosis was analyzed. As shown in Figures 6a-6f, compared to control mice, 5xFAD mice not administered DTMB showed a rapid increase in gliosis due to excessive activity of microglial cells and astrocytes in the cerebral cortex (Figures 6a, 6c, 6e, and 6f) and hippocampus (Figures 6b, 6d, 6e, and 6f) of 5xFAD mice, whereas gliosis was significantly reduced in the cerebral cortex (Figures 6a, 6c, 6e, and 6f) and hippocampus (Figures 6b, 6d, 6e, and 6f) of DTMB-administered 5xFAD mice.

[0046] In yet another specific embodiment of the present invention, to determine whether the reduction in gliosis by DTMB administration was due to alterations in microglial cell function, microglial cells were isolated from the brain tissue of DTMB-administered 5xFAD mice and analyzed for the expression levels of inflammatory response-related cytokine genes (TNF-α, IL-6, and IL-1β), chemokine genes (Cxcl10 and clec7a), and genes related to microglial cell activity (Iba-1, Trem2, and Itgax2). As shown in Figure 10, the expression levels of cytokine genes (TNF-α, IL-6, and IL-1β), chemokine genes (Cxcl10 and clec7a), and genes related to microglial cell activity (Iba-1, Trem2, and Itgax2) were all increased in microglial cells from 5xFAD mice compared to control mice, whereas the expression levels of these genes were decreased in microglial cells from DTMB-administered 5xFAD mice. This confirmed that DTMB can suppress the excessive activity of microglial cells.

[0047] Therefore, the compound represented by Chemical Formula 1 according to the present invention, its stereoisomer, or a pharmaceutically or food-based acceptable salt thereof can exhibit any one or more of the following effects (i) to (iii): (i) Activation of PPAR transcription factors in microglial cells inhibits inflammatory responses; (ii) the effect of inhibiting the formation of Aβ aggregates in brain tissue; and (iii) the inhibitory effect of gliosis caused by the excessive activity of microglial cells and astrocytes.

[0048] The effects of DTMB as described above can have a positive impact on improving degenerative brain diseases, learning ability decline, memory impairment, or cognitive decline caused by Aβ aggregate deposition and / or neuroinflammatory responses. Therefore, the compound represented by Chemical Formula 1 according to the present invention, its stereoisomer, or a pharmaceutically or food-based acceptable salt thereof can be used not only as a medicine or health functional food for preventing, improving, or treating degenerative brain diseases, but also as a medicine or health functional food for improving learning ability, memory, or improving cognitive decline.

[0049] Therefore, a second aspect of the present invention relates to a composition for improving learning ability, memory, or cognitive function, comprising, as an active ingredient, a compound represented by the following chemical formula 1, a stereoisomer thereof, or a pharmaceutically or food-related acceptable salt thereof: JPEG2025527284000004.jpg96143In relation to the second aspect, the present invention also provides a method for improving learning ability, memory, or ameliorating cognitive decline, comprising administering a compound represented by Chemical Formula 1, a stereoisomer thereof, or a pharmaceutically or food-based acceptable salt thereof to an individual in need thereof.

[0050] Furthermore, a second aspect of the present invention provides use of the compound represented by Chemical Formula 1, its stereoisomer, or a pharmaceutically or food-based acceptable salt thereof for the manufacture of a medicament for improving learning ability, memory, or cognitive decline.

[0051] The composition and effects of the compound represented by Chemical Formula 1, its stereoisomer or its pharmaceutically or food-based acceptable salt, which are contained as active ingredients in the composition according to the second aspect of the present invention, are the same as those described in the pharmaceutical composition and health functional food composition according to the first aspect, and therefore detailed description thereof will be omitted.

[0052] The composition for improving learning ability, memory or cognitive function according to the present invention may be a pharmaceutical composition or a health food composition.

[0053] In the present invention, the terms "memory improvement" and "cognitive function improvement" refer to the effects of maintaining cognitive ability by regulating toxic substances that damage brain cells, or improving impaired cognitive ability by regulating neurotransmitters in the brain, which can cause memory loss, memory impairment, or decreased cognitive ability caused by brain atrophy and destruction of brain neurons due to physical fatigue, lack of sleep, excessive alcohol intake, dementia, etc. Memory is the ability to receive necessary information, store it in the brain, and then retrieve and use it when needed, while cognitive ability is the ability to distinguish and recognize things.

[0054] The term "prevention" as used herein refers to any action that inhibits or delays the onset of a disease or symptom. In this invention, it refers to delaying or inhibiting the onset of a degenerative brain disease. Alternatively, it refers to delaying or inhibiting the onset of symptoms such as impaired learning ability, impaired memory, or impaired cognitive function.

[0055] The term "improvement" as used in the present invention means any action that improves or beneficially alters a disease or pathological condition, and in the present invention means improving the symptoms of degenerative brain diseases, or enhancing learning ability, memory, and cognitive function.

[0056] The term "treatment" as used herein means any action that delays, halts, or reverses the progression of a disease or condition, and in this invention means reducing, alleviating, eliminating, or reversing the symptoms of a degenerative brain disease, or reducing, alleviating, eliminating, or reversing the symptoms of learning ability decline, memory decline, or cognitive decline.

[0057] The term "pharmaceutically or food-grade acceptable salt" as used herein refers to any organic or inorganic addition salt of the compound of Formula 1 or its stereoisomers that is relatively non-toxic and harmless to patients at effective concentrations, and the side effects attributable to the salt do not diminish the beneficial effects of the compound of Formula 1 or its stereoisomers. These salts can be made with inorganic or organic acids as free acids, such as hydrochloric acid, bromic acid, nitric acid, sulfuric acid, perchloric acid, and phosphoric acid. Organic acids that can be used include citric acid, acetic acid, lactic acid, maleic acid, fumaric acid, gluconic acid, methanesulfonic acid, succinic acid, tartaric acid, galacturonic acid, embonic acid, glutamic acid, aspartic acid, oxalic acid, (D) or (L) malic acid, maleic acid, methanesulfonic acid, ethanesulfonic acid, 4-toluenesulfonic acid, salicylic acid, citric acid, benzoic acid, and malonic acid. These salts also include alkali metal salts (sodium salt, potassium salt, etc.) and alkaline earth metal salts (calcium salt, magnesium salt, etc.), etc. For example, acid addition salts include acetate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hyphenate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, May also include methyl sulfate, naphthylate, 2-nafcylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, saccharate, stearate, succinate, tartrate, tosylate, trifluoroacetate, aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine, zinc salts and the like.

[0058] The pharmaceutical composition of the present invention may further comprise a pharmaceutically acceptable carrier. The pharmaceutical composition containing a pharmaceutically acceptable carrier may be in various oral or parenteral dosage forms. When formulating, it can be prepared using commonly used diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, and surfactants. Solid formulations for oral administration include tablets, pills, powders, granules, capsules, lozenges, and the like. These solid formulations can be prepared by mixing one or more compounds of the present invention with at least one or more excipients, such as starch, calcium carbonate, sucrose, lactose, or gelatin. In addition to simple excipients, lubricants such as magnesium, stearate, and talc can also be used. Liquid formulations for oral administration include suspensions, oral solutions, emulsions, and syrups. In addition to commonly used simple diluents such as water and liquid paraffin, various excipients, such as wetting agents, sweeteners, flavoring agents, and preservatives, can be included.

[0059] Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried preparations, suppositories, etc. Non-aqueous solvents and suspensions that can be used include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. Suppository bases that can be used include Witepsol (registered trademark), macrogol, Tween 61, cocoa butter, laurin butter, glycerol, gelatin, etc.

[0060] The pharmaceutical composition of the present invention, when containing an effective amount of the compound represented by Chemical Formula 1, its stereoisomer, or a pharmaceutically or food-based acceptable salt thereof, can provide desirable effects in preventing, ameliorating, or treating degenerative brain diseases, improving learning ability, memory, or improving cognitive decline. In this application, the term "effective amount" refers to an amount that shows a response greater than or equal to that of a negative control group, preferably an amount sufficient to prevent, ameliorate, or treat degenerative brain diseases, or an amount sufficient to improve learning ability, memory, or improve cognitive decline. The pharmaceutical composition of the present invention may contain 0.01 to 99.9% of the compound represented by Chemical Formula 1, its stereoisomer, or a pharmaceutically or food-based acceptable salt thereof, with the remainder being a pharmaceutically acceptable carrier. The effective amount of the compound represented by Chemical Formula 1, its stereoisomer, or a pharmaceutically or food-based acceptable salt thereof in the pharmaceutical composition of the present invention varies depending on the form in which the composition is manufactured.

[0061] The total effective amount of the pharmaceutical composition of the present invention can be administered to a patient in a single dose or in multiple doses over a long period of time (fractionated treatment protocol). The pharmaceutical composition of the present invention may vary the content of the active ingredient depending on the severity of the disease. The effective dose of the compound represented by Formula 1, its stereoisomer, or its pharmaceutically or alimentarily acceptable salt is determined by taking into account various factors, such as the patient's age, weight, health condition, sex, severity of the disease, diet, and excretion rate, as well as the route of administration and frequency of the pharmaceutical composition. Taking these factors into consideration, a person skilled in the art can determine an appropriate effective dose of the compound represented by Formula 1, its stereoisomer, or its pharmaceutically or alimentarily acceptable salt for a specific purpose, such as the prevention, amelioration, or treatment of degenerative brain diseases, the enhancement of learning ability, the enhancement of memory, or the improvement of cognitive decline. The pharmaceutical composition of the present invention is not particularly limited in its dosage form, route of administration, or method of administration, as long as it exhibits the effects of the present invention.

[0062] The pharmaceutical composition of the present invention can be administered via any common route that can reach the target tissue or cells in an individual or sample. The administration may include systemic or local administration, including, but not limited to, intraperitoneal administration, intravenous administration, intramuscular administration, subcutaneous administration, intradermal administration, oral administration, intranasal administration, intrapulmonary administration, and intrarectal administration. The dosage of the pharmaceutical composition may vary depending on the patient's age, weight, sex, administration form, health condition, and disease severity.

[0063] The term "patient" refers to any single individual for whom treatment is sought, including humans, cows, dogs, guinea pigs, rabbits, chickens, insects, etc. Also included is any subject participating in a clinical research trial who does not show any clinical signs of disease, or a subject participating in a dynamic study or used as a control group.

[0064] In the present invention, the term "health food" includes both the meanings of "functional food" and "health food."

[0065] In the present invention, the term "functional food" is the same as "Food for special health use (FoSHU)" and refers to food with high medical and therapeutic effects that is processed to efficiently exhibit bioregulatory functions in addition to providing nutrients.

[0066] In the present invention, the term "health food" refers to a food that has a more active effect in maintaining or improving health than general foods, and "health supplement food" refers to a food intended for health supplementation. In some cases, the terms "functional food," "health food," and "health supplement" are used interchangeably. The food can be prepared in various forms, such as tablets, capsules, powders, granules, liquids, and pills, to achieve useful effects in preventing or ameliorating degenerative brain diseases, and improving learning ability, memory, or cognitive function.

[0067] As a specific example of such functional foods, processed foods that utilize and modify the properties of agricultural products, livestock products, or marine products and have improved shelf life can be produced using the compound represented by Chemical Formula 1 of the present invention, its stereoisomer, or a food-science-acceptable salt thereof.

[0068] The health functional food composition of the present invention can also be prepared in the form of a nutritional supplement, food additive, feed, etc., and is intended for consumption by humans or animals, including livestock.

[0069] The food compositions of the above types can be prepared in various forms by conventional methods known in the art. Common foods include, but are not limited to, beverages (including alcoholic beverages), fruits and processed foods (e.g., canned fruits, bottled fruits, jams, marmalades, etc.), fish, meat and processed foods (e.g., ham, sausage, corned beef, etc.), breads and noodles (e.g., udon, buckwheat, ramen, spaghetti, macaroni, etc.), fruit juices, various drinks, cookies, candies, dairy products (e.g., butter, cheese, etc.), edible vegetable oils and fats, margarine, vegetable proteins, retort foods, frozen foods, and various seasonings (e.g., miso paste, soy sauce, sauces, etc.), and can be prepared by adding the compound represented by Formula 1 of the present invention, its stereoisomer, or a food-safe salt thereof.

[0070] Furthermore, nutritional supplements can be prepared by adding the compound represented by Chemical Formula 1 of the present invention, its stereoisomer, or a food-grade acceptable salt thereof to, but not limited to, capsules, tablets, pills, etc.

[0071] In addition, health functional foods include, but are not limited to, the compound represented by Chemical Formula 1 of the present invention, its stereoisomer, or a nutritively acceptable salt thereof, which can be liquefied, granulated, encapsulated, or powdered to be prepared in the form of tea, juice, or drink and consumed (health drinks). Furthermore, the compound represented by Chemical Formula 1 of the present invention, its stereoisomer, or a nutritively acceptable salt thereof can be prepared in the form of a powder or concentrate to be used as a food additive. Furthermore, the compound represented by Chemical Formula 1 of the present invention, its stereoisomer, or a nutritively acceptable salt thereof can be mixed with a known active ingredient known to be effective in preventing or ameliorating degenerative brain diseases or to improve learning ability, memory, or cognitive function, to prepare a composition.

[0072] When the food composition of the present invention is used as a health drink composition, the health drink composition may contain various flavoring agents or natural carbohydrates as additional ingredients, as in conventional beverages. The natural carbohydrates may be monosaccharides such as glucose and fructose; disaccharides such as maltose and sucrose; polysaccharides such as dextrin and cyclodextrin; or sugar alcohols such as xylitol, sorbitol, and erythritol. Examples of sweeteners that can be used include natural sweeteners such as thaumatin and stevia extract; and synthetic sweeteners such as saccharin and aspartame. The proportion of the natural carbohydrates per 100 mL of the composition of the present invention is generally about 0.01 to 0.04 g, preferably about 0.02 to 0.03 g.

[0073] The compound represented by Chemical Formula 1, its stereoisomer, or a nutrient-acceptable salt thereof of the present invention may be contained as an active ingredient in a health functional food composition for preventing or improving degenerative brain diseases or for improving learning ability, memory, or cognitive function, in an amount effective for achieving the preventive or improving effect, for example, preferably 0.01 to 100 wt% based on the total weight of the entire composition, but is not particularly limited thereto. The health functional food composition of the present invention may be prepared in the form of a composition by mixing the compound represented by Chemical Formula 1, its stereoisomer, or a nutrient-acceptable salt thereof with a known active ingredient known to be effective in preventing or improving degenerative brain diseases or to improve learning ability, memory, or cognitive function.

[0074] In addition to the above, the health functional food of the present invention may contain various nutrients, vitamins, electrolytes, flavoring agents, colorants, pectic acid, pectic acid salts, alginic acid, alginic acid salts, organic acids, protective colloid thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohol, or carbonation agents. The health food of the present invention may also contain fruit pulp for the production of natural fruit juice, fruit juice drinks, or vegetable drinks. These ingredients may be used independently or in combination. The proportion of these additives is not critical, but is typically selected in the range of 0.01 to 0.1 parts by weight per 100 parts by weight of the composition of the present invention.

[0075] In the methods of the present invention, the term "individual" includes, but is not limited to, any animal (e.g., human, horse, pig, rabbit, dog, sheep, goat, non-human primate, cow, cat, guinea pig, or rodent). Such term does not denote a particular age or sex. Thus, it is intended to include female, male, adult, and newborn subjects, as well as fetuses. A patient refers to a subject with a disease or disorder. The term patient includes human and veterinary subjects.

[0076] In the method of the present invention, the effects of the compound represented by Chemical Formula 1, its stereoisomer or its nutrient-acceptable salt, and the configuration including the administration route, administration frequency, dosage, etc. are the same as those described above, so further description will be omitted.

[0077] The present invention will be described in more detail below based on examples. However, since the present invention can be modified in various ways and can have various forms, the specific examples and explanations described below are merely intended to aid in understanding the present invention and are not intended to limit the present invention to the specific disclosed forms. The scope of the present invention should be understood to include all modifications, equivalents, and alternatives that fall within the spirit and technical scope of the present invention.

[0078] [Example 1] Discovery and efficacy analysis of DTMB as a novel PPAR transcription factor activator To develop novel active compounds for PPARs, we simultaneously performed computer molecular binding prediction program analysis and GAL4-transactivation assay to discover DTMB compounds, as shown in Figure 1a.

[0079] 1-1.Preparation of DTMB compound DTMB was synthesized by Oi Kakin Co., Ltd. (Korea) and dissolved in dimethyl sulfoxide (Sigma Aldrich, St. Louis, MO, USA) for cell-based experiments.

[0080] 1-2.GAL4 transposition activity analysis To examine the binding of drugs to the PPAR ligand binding site, a GAL4 transfection assay was performed. HEK293A cells were electroporated using the Neon Transfection System (Invitrogen, Carlsbad, CA, USA) and transfected with the GAL4 reporter plasmid and pGL4.74 (Promega, Madison, WI, USA) as an internal control. All vectors were provided by Professor Yuichiro Kanno of Toho University, Japan. After overnight incubation, the cells were treated with DTMB and each positive control compound for 24 hours. The cells were then harvested, resuspended in luciferase lysis buffer (Promega), and incubated on ice for 10 minutes. Cell debris was removed by centrifugation at 20,000 x g for 10 minutes at 4°C, and the supernatant was used for luciferase assays. Luciferase activity was measured using the Luciferase Reporter Assay System (Promega) according to the manufacturer's instructions. In the measurement experiments, the firefly luciferase activity was normalized to the Renilla luciferase activity. To examine the concentration-dependent effect of DTMB, various concentrations of DTMB were applied and the EC 50 The values were measured.

[0081] As a result, as can be seen in Figure 1b, when compared with previously reported preparations that activate each PPAR subtype, the DTMB compound was found to increase the degree of binding to PPAR in a concentration-dependent manner, activating PPARα at a lower concentration than WY14643, and PPARβ / δ and PPARγ at slightly higher concentrations than GW501516 and rosiglitazone, respectively.

[0082] 1-3. CNBr-drug-protein binding analysis To screen for PPAR-active compounds, we used the Autodock Vina and Phymol programs to predict the binding of DTMB to PPAR transcription factors. The 3D structures of PPARs were provided by the RCSB Protein Data Bank and used to predict binding (PPARα: 4BCR, 3VI8, 5HYK; PPARδ: 5U3Q, 5U46; PPARγ: 3U9Q, 5YCP, 5JI0). The energy of DTMB or other PPAR agonists (WY14643, GW501516, and rosiglitazone) was minimized using Open Babel in PyRx software for further docking analysis. AutoDock Vina in PyRx software was used to perform molecular docking and predicted binding energy calculations to identify the docking positions of the ligands to PPARs. The grid map for docking was generated relative to the overall macromolecule structure. The docking results were visualized using the PyMol visualization system. Hydrogen bonds were predicted by PyMol software. Similar to the luciferase analysis, the molecular docking analysis results (Fig. 1c and Table 1) confirmed that the binding energy between DTMB and the PPARα ligand-binding domain (LBD) was predicted to be higher than that of WY14643, and DTMB was predicted to form hydrogen bonds with Ser280 of the PPARα LBD, Arg248 and Ala306 of PPARδ, and Ser289 of PPARγ.

[0083] [Table 1] Since computer prediction programs predicted that DTMB binds to PPAR transcription factors, we conducted CNBr-drug and protein binding experiments to confirm whether DTMB actually binds to PPAR. To examine the actual degree of binding between the drug and protein, we reacted proteins in the PPAR-α, β / δ, and γ ligand binding domains with CNBr beads conjugated with the DTMB drug, followed by Western blotting.

[0084] Specifically, CNBr Sepharose 4B beads were prepared and activated according to the manufacturer's instructions. 100 mg of CNBr-activated Sepharose 4B beads were incubated with drug or DMSO for 18 hours at 4°C. The drug-bound beads reacted with HIS-tagged recombinant PPARα, β / δ, and γ proteins. After 24 hours of incubation, Western blotting experiments were performed to confirm whether the recombinant proteins bound to the drug-bound beads.

[0085] As a result, as shown in Figure 1d, it was found that DTMB binds well to the PPAR ligand-binding protein, confirming that DTMB binds to all PPAR subtypes. Based on these results, DTMB was proposed as a novel regulator of PPAR transcription factors.

[0086] [Example 2] Confirmation of the anti-inflammatory effect of DTMB 2-1. Cell viability assay (MTT assay) Cell viability was measured using a chromogenic assay based on the biological reduction of 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) with formazan in live cells. Briefly, cells were cultured in 96-well plates in a final volume of 100 μL. After 24 h, the culture medium was replaced with fresh medium containing DTMB compound, and the cells were further cultured for 48 h. Next, MTT (dissolved in PBS at 5 mg / mL) was added to the culture medium. After culturing the cells in the dark at 37°C for 1 h, the supernatant was removed from the wells. Total MTT solvent (4 mM HCl and 0.1% Nonidet P-40, both dissolved in isopropanol) was added to dissolve the formazan crystals, and the absorbance was measured at 570 nm using an Infinite 200 Pro NanoQuant microplate reader (TECAN, Switzerland).

[0087] As a result, as can be seen from FIG. 2a, when immune cells such as RAW264.7, BV2, and HMO6 cell lines were treated with DTMB, there was no cytotoxicity even at higher concentrations.

[0088] 2-2. Confirmation of the NO production inhibitory effect of DTMB Previous research has shown that all three PPAR subtypes inhibit inflammatory responses by inhibiting the activity and changing the quantity of NF-κB transcription factor, a key regulator of inflammatory responses. To confirm whether DTMB treatment would have an anti-inflammatory effect, RAW264.8 macrophage cell lines were treated with DTMB and the previously known PPAR regulators WY14643 (PPAR-α regulator), rosiglitazone (PPAR-γ regulator), and GW501516 (PPARβ / δ), and the amount of NO produced, a product of inflammatory responses, was measured using Griess reagent.

[0089] First, RAW264.7 macrophages were cultured in DMEM containing 10% FBS and 1% penicillin / streptomycin in a humidified 5% CO2 incubator at 37°C. After inducing an inflammatory response in RAW264.7 macrophages by LPS treatment, nitrite levels were measured using a Griess assay (Promega) according to the manufacturer's instructions. Known PPAR-selective agonists, such as WY14643 (PPARα), GW501516 (PPARβ / δ), and rosiglitazone (PPARγ), were used as positive controls.

[0090] As a result, as shown in Figure 2b, DTMB inhibited NO production in a concentration-dependent manner, with an IC 50 The value was very low at 1.23 μM, and it was confirmed that it inhibited NO production more effectively than the PPAR-α regulator WY14643 and the PPAR-γ regulator rosiglitazone at the same concentration.

[0091] 2-3. Confirmation of the cytokine reduction effect in microglial cells by DTMB treatment To confirm a clearer anti-inflammatory effect, a microglial cell line (BV2) and microglial cells isolated from mice were treated with lipopolysaccharide (LPS) and Aβ aggregates, respectively, to induce an inflammatory response, and then DTMB was administered. The reduction in cytokine levels in microglial cells following DTMB treatment was measured by ELISA.

[0092] The BV2 mouse microglial cell line was provided by Professor Seok Kyung-ho of Kyungpook National University, Korea. BV2 cells were cultured in Dulbecco's Modified Eagle Medium (DMEM) (Hyclone, Logan, UT, USA) containing 5% fetal bovine serum (FBS) and 50 μg / mL gentamicin (Lonza, Switzerland) in a 5% CO2 incubator at 37°C in a humidified atmosphere.

[0093] Primary microglial cell culture was performed as described previously [Lian H, Roy E, Zheng H. Protocol for primary microglial culture preparation. Bio-protocol. 2016;6(21)]. Three-day-old mice were used for primary microglial cell preparation. Newborn pups were anesthetized with ice and then sacrificed. Isolated cortices and hippocampi were collected after removing the meninges. Brain tissue was dissociated by incubation with trypsin (2.5%) in HBSS (Gibco, Gaithersburg, MD, USA) for 15 minutes. The cell homogenate was then cultured in DMEM-F12 medium supplemented with M-CSF (20 ng / mL, R&D Systems) containing 10% fetal bovine serum, 10% horse serum, 1% GlutaMAX (Gibco, MD, USA), and 1% penicillin / streptomycin (Welgene, Korea). After 10 days, microglial cells were purified by shaking at 260 rpm for 2 hours.

[0094] Cytokine levels (TNF-α, IL-1β, and IL-6) were measured in the culture medium of BV2 microglial cells and primary microglial cells treated with LPS (1 μg / mL) and human Aβ1-42 (5 μg / mL). Human Aβ1-42 (AnaSpec, Fremont, CA, USA) was pre-aggregated in an incubator for 24 hours before cell treatment. BV2 cells and primary microglial cells were cultured at 1 x 10 in 1 mL of complete medium. 5 The cells were plated into 12-well plates (SPL) at a density of 100 cells / well. After 12 hours, the cells were treated with LPS or human Aβ1-42 and further cultured with DTMB for 24 hours. ELISA experiments were performed using a mouse TNF-α ELISA kit (Invitrogen, BMS607-3TEN), a mouse IL-1β ELISA kit (Invitrogen, BMS6002), and a mouse IL-6 ELISA kit (Invitrogen, BMS603-2) according to the manufacturer's instructions.

[0095] As a result, as shown in the results of Figures 2c to 2f, it can be confirmed that DTMB treatment inhibits inflammatory responses in a statistically significant manner.

[0096] Furthermore, the gene expression levels of chronic inflammation-related NF-κB target genes Il-6, Il-1β, and iNOS, as well as the anti-inflammatory marker Arg-1, were confirmed by quantitative PCR (qPCR) analysis in primary microglial cells.

[0097] Total RNA was isolated using TRI Reagent (Molecular Research Center, Cincinnati, OH, USA). RNA was reverse transcribed using the ImProm-II Reverse Transcription System (Promega) according to the manufacturer's instructions. For detection and quantification, the StepOnePlus Real-Time PCR System (Applied Biosystems, Foster City, CA, USA) was used with FastStart Universal SYBR Green Master (Roche, Basel, Switzerland). Real-time qPCR data were analyzed using the comparative CT method.

[0098] As shown in Figure 2g, the expression of NF-κB target genes Il-6, Il-1β, and iNOS, which are associated with chronic inflammation, was decreased in primary microglial cells. In contrast, the anti-inflammatory marker Arg-1 was induced by DTMB treatment.

[0099] 2-4. Confirmation of the mechanism of anti-inflammatory activity of DTMB To confirm the mechanism by which DTMB exerts its anti-inflammatory effect, microglial cells isolated from mice were treated with Aβ aggregates or LPS to induce an inflammatory response, and then treated with DTMB. NF-κB, NLRP-3, and ASC protein levels were examined by Western blotting.

[0100] Cells were lysed in lysis buffer containing 50 mM Tris (pH 7.4), 140 mM NaCl, 5 mM EDTA, and a protease inhibitor tablet, followed by sonication. Lysate protein concentration was determined using Bradford reagent (Amersco, MA, USA). Proteins were separated by SDS (sodium dodecyl sulfate) polyacrylamide gel electrophoresis, transferred to nitrocellulose membranes (Pall Corporation, New York, NY, USA), and incubated with blocking buffer (5% nonfat dry milk and 0.1% Tween 20 in TBS) for 30 minutes. Western blot analysis was performed using primary antibodies against NF-κB, NLRP3, and ASC (Cell Signaling Technology, Danvers, MA, USA). Rabbit (Promega), rat, and goat (Bethyl Laboratories) secondary antibodies were used, and detection was performed using SUPEX ECL reagent (Neuronex, Korea) and ImageQuant LAS-4000 (GE Healthcare, MA, USA) according to the manufacturer's instructions. Integrated blot density was quantified using ImageJ.

[0101] As a result, as shown in Figures 2h to 2k, we confirmed that the anti-inflammatory activity of DTMB occurs by reducing NF-κB, a major regulator of intracellular inflammatory responses, and that NLRP3, a component of the inflammasome, is also reduced, thereby confirming that DTMB regulates the inflammatory response of microglial cells.

[0102] To inhibit proteasomal degradation, cells were treated with MG132 (20 μM) for 6 hours and then with DTMB (25 μM) for 24 hours, after which NF-κB gene expression levels were confirmed by qPCR analysis. As shown in Figures 2l and 2m, this response was mediated by proteasomal degradation, not transcriptional repression, since there was no change in NF-κB mRNA levels.

[0103] [Example 3] DTMB administration improves memory and cognitive function in 5xFAD Alzheimer's disease-induced mice through Y-maze analysis 3-1. Preparation of experimental animals 5xFAD (Tg6799) mice were purchased from Jackson Laboratory (Bar Harbor, ME, USA), and male transgenic mice were mated with B6 / SJL hybrid female mice. Genotyping was performed by PCR analysis of tail snip samples. In this experiment, 8-week-old female mice were used for drug administration, and wild-type littermates served as controls. All procedures related to animal behavior experiments were approved by the Pohang University of Science and Technology Animal Care and Use Committee (POSTECH IACUC), Korea. All animal experiments were conducted in accordance with the Animal Welfare Act, the PHS Animal Welfare Policy, and the principles of the NIH Guide for the Care and Use of Laboratory Animals. All mice were maintained under standard conditions in the POSTECH animal facility in accordance with institutional guidelines.

[0104] 3-2. Drug Treatment To evaluate the effects of DTMB on 5xFAD mice, DTMB (10 mg / kg) and vehicle (1% carboxymethylcellulose and 10% DMSO) were orally administered to four groups (wild-type, wild-type + DTMB, 5xFAD, and 5xFAD + DTMB) 6 days per week for 3 months.

[0105] 3-3.Y-maze test To confirm whether DTMB actually alleviates the pathology of Alzheimer's disease, 5xFAD mice (also known as Alzheimer's disease-induced mice) were orally administered DTMB at 10 mg / kg for 12 weeks, starting at 8 weeks of age (Figure 3a). At the end of the treatment period, mice were tested in a Y-Rice laboratory to assess short-term memory improvement and cognitive function. The measurement apparatus consisted of three arms, each 42 cm long, 3 cm wide, and 12 cm high, with the arms bending at a 120° angle. The apparatus was made of black polyvinyl plastic, and the three arms were designated A, B, and C before the experiment. The experimental animals were placed in each arm for 8 minutes, and a score of 1 was awarded based on the number of times the animals entered each arm with their tail and whether they entered each arm sequentially. Alternation behavior was defined as entering all three arms without overlapping and was calculated using the following formula:

[0106] Formula Alternative action power (%) = actual alternation / maximum alternation x 100 (Maximum number of substitutions: Total number of positions - 2) First, we examined the physical changes in the mice after the behavioral tests. As shown in Figure 3b, when DTMB was treated for 12 weeks (3 months), there was no change in body weight or tissue weight between vehicle-treated and DTMB-treated mice.

[0107] As shown in Figure 3c, the behavioral test results showed that the alternation ability of the 5xFAD mice was reduced compared to the control mice. However, DTMB administration statistically significantly increased the alternation ability, confirming the improvement of short-term memory and cognitive function. On the other hand, there was no change in total arm entries, which indicates the total number of entries into each area, confirming that the spontaneous alternation was not due to a change in the mice's activity.

[0108] [Example 4] DTMB administration improves memory and cognitive function in Morris water maze tests in 5xFAD Alzheimer's disease-induced mice As shown in Figure 3a, after oral administration of DTMB at 10 mg / kg, a water maze experiment was performed to examine memory improvement and cognitive function.

[0109] A 9cm diameter, 25cm high platform was placed in one of the quadrants of a circular aquarium, 90cm in diameter and 45cm in height. Clean water (20±2°C) was filled approximately 1cm above the platform, and the time it took the experimental animals to reach the platform was measured. Four signposts were placed in the circular aquarium, and the water entry positions were varied across the quadrants. The experiment was repeated four times a day for 60 seconds. The experiment ended if the experimental animals reached the platform within 60 seconds; if they did not, they were manually guided to the platform and asked to remain there for 10 seconds. After five days of training to reach the platform, which was placed under the water in the aquarium, the platform was removed and the time the animals spent in the platform area for 60 seconds was measured to assess their learning ability.

[0110] As can be seen in Figure 4a, the escape latency of the 5xFAD mice increased over the five-day training experiment compared to the control group, indicating impaired long-term memory. Furthermore, as can be seen in Figures 4b and 4c, on the final day of the experiment, the time spent at the platform in the 5xFAD mice decreased significantly compared to the control group, indicating impaired spatial perception.

[0111] In contrast, the DTMB-treated 5xFAD mice showed similar improvements in long-term memory and spatial perception as compared to normal mice, as shown in Figures 4a-4c. Furthermore, as shown in Figure 4b, there was no difference in the total swimming distance (total path) between the normal mice treated with a drug-free vehicle, the normal mice treated with DTMB, the 5xFAD mice treated with a drug-free vehicle, and the 5xFAD mice treated with DTMB, indicating that there was no difference in the motor abilities of the mice in each group.

[0112] Therefore, the results of this example confirmed the ability of DTMB to improve long-term memory and cognitive function.

[0113] [Example 5] Confirmation of the pathological improvement effect of DTMB administration through brain tissue analysis of Alzheimer's dementia mice 5-1. Immunohistochemistry Increased formation of Aβ aggregates in brain tissue is a common pathological phenomenon observed in Alzheimer's disease. Therefore, to investigate whether DTMB administration inhibited Aβ aggregate formation, we measured the amount of Aβ aggregates in the hippocampus and cerebral cortex, which are closely related to memory ability, using immunochemical staining in 5xFAD Alzheimer's disease-induced mice.

[0114] Mice were perfused with ice-cold phosphate-buffered saline (PBS). Brain tissue was used separately for molecular analysis or immunohistochemistry. The right hemisphere was fixed in 4% PFA and transferred to sucrose solution (30%) for 24 hours. The right hemisphere was frozen by placing it in optimal cutting temperature compound on dry ice. Coronal sections (18 μm thick) containing the hippocampus were cut and prepared on glass slides. The tissue sections were then permeabilized and blocked with blocking solution (5% goat serum and 0.2% Triton X-100 in PBS) for 1 hour at room temperature. Primary antibody incubation was performed overnight at 4°C using anti-6e10 antibody (Biolegend, Japan, 1:100). After washing, sections were incubated with the appropriate secondary antibody (1:500) for 1 hour at room temperature. Slides were counterstained with Hoechst and then mounted in fluorescent mounting medium (Dako, Denmark). All images were taken through an Axioplan2 microscope (Zeiss, Germany). Fluorescence was measured by calculating the % area and analyzed using ImageJ. Sample sizes were 10–15 animals per group.

[0115] As shown in Figures 5a and 5b, in the 5xFAD mouse group without DTMB administration (control in Figure 5a; 5xFAD in Figure 5b), the amount of Aβ aggregates was significantly increased in the hippocampus and cerebral cortex, whereas in the 5xFAD mouse group with DTMB administration (DTMB in Figure 5a; 5xFAD+DTMB in Figure 5b), the amount of Aβ aggregates was significantly reduced.

[0116] 5-2. Western blot analysis Aβ peptides are generated from the amyloid precursor protein (APP) by the action of β- and γ-secretase. DTMB may affect APP processing and inhibit the formation of Aβ aggregates. To investigate this possibility, we measured the protein levels of total APP and components of β- and γ-secretase in the hippocampus and cortex by Western blot and qPCR.

[0117] To investigate soluble and insoluble Aβ components, two extraction steps were performed. Left hemisphere samples were homogenized at a concentration of 100 mg / mL in cold Tris-buffered saline (TBS, composed of 50 mM Tris, pH 7.5, and 150 mM NaCl) with a protease inhibitor cocktail (Thermo Fisher Scientific, Waltham, MO, USA). After centrifugation at 15,000 rpm for 1 h at 4°C, the sample supernatant was used for Western blotting. Insoluble proteins were extracted from the pellet by dissolving in 5 M guanidine buffer (5 M guanidine HCl and 150 mM NaCl, pH 7.5). Soluble and insoluble protein samples were stored at -80°C.

[0118] Western blot analysis was performed using primary antibodies against nicastrin, pen2 (Cell Signaling Technology, Danvers, MA, USA), Aph1 (Invitrogen), amyloid C-terminal fragment (Santa Cruz Biotechnology, Dallas, TX, USA), and GAPDH (Bethyl Laboratories, Mongolia, TX, USA) in the same manner as in Examples 2-4. Secondary antibodies were rabbit (Promega), rat, and goat (Bethyl Laboratories). Detection was performed using SUPEX ECL reagent (Neuronex, Korea) and an ImageQuant LAS-4000 (GE Healthcare, MA, USA) according to the manufacturer's instructions. Integrated blot density was quantified using ImageJ.

[0119] As can be seen from Figures 5c–5h, there were no changes in APP protein and mRNA levels or in the protein levels of β- and γ-secretase in the hippocampus, and the protein level of β-secretase was slightly decreased in the cortex of DTMB-treated mice.

[0120] 5-3. Filter trap assay The insoluble fraction of protein lysates from 5xFAD mice was diluted in 1% SDS-PBS and boiled at 95°C for 5 min. The membrane was pre-equilibrated with 1X TBS. A dot blotter apparatus (Bio-Rad Laboratories, Hercules, CA, USA) was used for sample application. The 6e10 antibody was used to detect Aβ content in brain lysates from DTMB-treated 5xFAD mice. The sample size was three mice per group.

[0121] As shown in Figures 5i and 5j, amyloid-β monomers were not reduced by DTMB treatment, but Aβ aggregates in the insoluble fraction were. These data indicate that DTMB reduces Aβ aggregates in the brain, regardless of the Aβ generation process from APP.

[0122] [Example 6] Analysis of the degree of gliosis due to hyperactivation of microglial cells and astrocytes in the brain tissue of DTMB-treated mice with Alzheimer's disease 6-1. Immunohistochemistry Since the anti-inflammatory effects of DTMB were observed at the cellular level, to confirm whether drug administration also inhibited inflammatory responses in brain tissue, brains from DTMB-treated and untreated 5xFAD Alzheimer's-induced mice were excised and sectioned, and the degree of gliosis was assessed using immunohistochemistry with antibodies against IBA-1, a protein specific to microglia, and GFAP, a protein specific to astrocytes. Specifically, immunohistochemistry was performed using anti-Iba1 antibody (Wako, Japan, 1:200) and anti-GFAP antibody (Abcam, Cambridge, UK, 1:200) as primary antibodies, following the same procedure as in Example 6-1.

[0123] As can be seen from Figures 6a to 6f, when observing the cerebral cortex (Figures 6a, 6c, 6e, and 6f) and hippocampus (Figures 6b, 6d, 6e, and 6f) tissues, the 5xFAD mouse group showed a significant increase in the hyperactivity of microglia and astrocytes compared to the normal mouse group, whereas the DTMB-administered mouse group showed a significant decrease in the hyperactivity of microglia and astrocytes, i.e., gliosis.

[0124] 6-2. Real-time quantitative PCR (qPCR) We examined the gene expression levels of proinflammatory cytokines and related enzymes (Il-1β, Il-6, and iNOS) in the brain tissue of 5xFAD Alzheimer's disease-induced mice treated with and without DTMB using qPCR. As shown in Figure 8g, the expression levels of proinflammatory cytokines and related enzymes (Il-1β, Il-6, and iNOS) were also reduced in DTMB-treated transgenic mice.

[0125] Western Blot NLRP3, NF-κB, and ASC protein levels were examined by Western blot analysis in hippocampal tissue isolated from 5xFAD mice and DTMB-treated 5xFAD mice. Western blot analysis was performed using primary antibodies against NLRP3, NF-κB, and ASC (Cell Signaling Technology, Danvers, MA, USA) in the same manner as in Examples 2-4.

[0126] As shown in Figures 6h and 6i, NLRP3 and NF-κB protein levels were decreased in hippocampal brain lysates, whereas ASC levels were not significantly altered. These results suggest that DTMB reduces chronic inflammatory pathology in a mouse model of Alzheimer's disease.

[0127] [Example 7] Functional changes in microglial cells isolated from DTMB-treated mice To clarify whether the gliosis-reducing effect of DTMB administration confirmed in Example 6 was due to functional changes in microglial cells, brain tissue was removed from DTMB-administered mice, microglial cells were isolated, and the extent of changes in the expression of inflammatory responses and activation-related genes within microglial cells was analyzed.

[0128] We used a magnetic-activated cell sorting (MACs) system to isolate adult microglial cells from DTMB- or vehicle-treated 5xFAD mouse brains. Whole brain tissue was dissociated at the single-cell level using the gentleMACs dissociation kit (Miltenyi Biotech, Bergisch Gladbach, Germany) according to the manufacturer's instructions. To isolate the immune cell fraction, a 47% Percoll gradient was applied to the single-cell mixture and centrifuged at 2,000 rpm for 10 minutes. Adult microglial cells were cultured with anti-CD11b MicroBeads (Miltenyi Biotech) and then separated using an LS column. RT-PCR was performed on the isolated adult microglial cells to analyze the expression of microglial activation and inflammation-related genes. The sample size was three mice per group.

[0129] As shown in Figure 7, compared to the normal mice, the microglial cells of the 5xFAD mice showed increased expression of the cytokine genes TNF-α, IL-6, and IL-1β, the chemokine genes Cxcl10 and clec7a, and the microglial cell activation-related genes Iba-1, Trem2, and Itgax2. However, the expression levels of all of these genes were decreased in the microglial cells of the DTMB-treated 5xFAD mice, confirming that DTMB can suppress excessive microglial cell activation.

[0130] statistical analysis All statistical analyses were performed using GraphPad Prism version 9.2. Normality tests were performed using the GraphPad system before statistical analysis. Comparisons between two groups were analyzed using a two-tailed unpaired Student's t test. For comparisons between more than two groups, one-way or two-way analysis of variance (ANOVA) with Tukey's test was used. A p value of less than 0.05 was considered statistically significant. All quantitative data are expressed as mean ± standard error of the mean (SEM).

Claims

1. A pharmaceutical composition for preventing or treating a degenerative brain disease, comprising, as an active ingredient, a compound represented by the following chemical formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

2. 2. The pharmaceutical composition for preventing or treating a degenerative brain disease according to claim 1, wherein the stereoisomer comprises a racemate, an enantiomer, a partial stereoisomer, a mixture of enantiomers, or a mixture of partial stereoisomers.

3. The degenerative brain diseases include dementia, autism, Alzheimer's disease, Huntington's disease, vascular dementia, stroke, ischemic stroke, traumatic brain injury, amnesia, Parkinson's disease, Pick's disease, Creutzfeldt-Jakob disease, and peripheral neuropathy.

2. The pharmaceutical composition for preventing or treating degenerative brain diseases according to claim 1, comprising any one or more selected from the group consisting of atherosclerosis, amyotrophic lateral sclerosis, multiple sclerosis, and mild cognitive impairment.

4. The pharmaceutical composition for preventing or treating a degenerative brain disease according to claim 1, wherein the compound, its stereoisomer or a pharmaceutically acceptable salt thereof activates all of PPARα, PPARβ / δ and PPARγ.

5. The pharmaceutical composition for preventing or treating a degenerative brain disease according to claim 1, wherein the compound, its stereoisomer, or a pharmaceutically acceptable salt thereof exhibits any one or more of the following effects (i) to (iii): (i) The effect of activating PPAR transcription factors in microglial cells and inhibiting inflammatory responses; (ii) the effect of inhibiting the formation of Aβ aggregates in brain tissue; and (iii) Inhibitory effect on gliosis caused by excessive activity of microglial cells and astrocytes.

6. A health functional food composition for preventing or ameliorating degenerative brain diseases, comprising as an active ingredient a compound represented by the following chemical formula 1, a stereoisomer thereof, or a nutritively acceptable salt thereof:

7. The health functional food composition for preventing or improving degenerative brain diseases according to claim 6, wherein the stereoisomer comprises a racemate, an enantiomer, a partial stereoisomer, a mixture of enantiomers or a mixture of partial stereoisomers.

8. The degenerative brain diseases include dementia, autism, Alzheimer's disease, Huntington's disease, vascular dementia, stroke, ischemic stroke, traumatic brain injury, amnesia, Parkinson's disease, Pick's disease, Creutzfeldt-Jakob disease, and peripheral neuropathy.

7. The health functional food composition for preventing or improving degenerative brain diseases according to claim 6, comprising any one or more selected from the group consisting of: amylotrophic lateral sclerosis, multiple sclerosis, and mild cognitive impairment.

9. The health functional food composition for preventing or improving degenerative brain diseases according to claim 6, wherein the compound, its stereoisomer or a nutrient-acceptable salt thereof activates all of PPARα, PPARβ / δ and PPARγ.

10. The health functional food composition for preventing or ameliorating degenerative brain diseases according to claim 6, wherein the compound, its stereoisomer, or a nutritively acceptable salt thereof exhibits any one or more of the following effects (i) to (iii): (i) The effect of activating PPAR transcription factors in microglial cells and inhibiting inflammatory responses; (ii) the effect of inhibiting the formation of Aβ aggregates in brain tissue; and (iii) Inhibitory effect on gliosis caused by excessive activity of microglial cells and astrocytes.

11. A composition for improving learning ability, memory or cognitive function, comprising, as an active ingredient, a compound represented by the following chemical formula 1, a stereoisomer thereof or a pharmaceutically or food-based acceptable salt thereof:

12. The composition for improving learning ability, memory or cognitive function according to claim 11, wherein the stereoisomer comprises a racemate, an enantiomer, a partial stereoisomer, a mixture of enantiomers or a mixture of partial stereoisomers.

13. The composition for improving learning ability, memory or cognitive function according to claim 11, wherein the compound, its stereoisomer or a pharmaceutically or food-based acceptable salt thereof activates all of PPARα, PPARβ / δ and PPARγ.

14. The composition for improving learning ability, memory or cognitive function according to claim 11, wherein the compound, its stereoisomer, or a pharmaceutically or food-based acceptable salt thereof exhibits any one or more of the following effects (i) to (iii): (i) The effect of activating PPAR transcription factors in microglial cells and inhibiting inflammatory responses; (ii) the effect of inhibiting the formation of Aβ aggregates in brain tissue; and (iii) Inhibitory effect on gliosis caused by excessive activity of microglial cells and astrocytes.

15. The composition for improving learning ability, memory or cognitive function according to claim 11, wherein the composition is a pharmaceutical or health food composition.

16. A method for preventing, ameliorating, or treating a degenerative brain disease, comprising administering a compound represented by the following chemical formula 1, a stereoisomer thereof, or a pharmaceutically or food-based acceptable salt thereof to an individual in need thereof:

17. 17. The method for preventing, ameliorating, or treating a degenerative brain disease according to claim 16, wherein the stereoisomer comprises a racemate, an enantiomer, a partial stereoisomer, a mixture of enantiomers, or a mixture of partial stereoisomers.

18. The degenerative brain diseases include dementia, autism, Alzheimer's disease, Huntington's disease, vascular dementia, stroke, ischemic stroke, traumatic brain injury, amnesia, Parkinson's disease, Pick's disease, Creutzfeldt-Jakob disease, and peripheral neuropathy.

17. The method for preventing, ameliorating, or treating a degenerative brain disease according to claim 16, comprising any one or more selected from the group consisting of: atherosclerosis, amyotrophic lateral sclerosis, multiple sclerosis, and mild cognitive impairment.

19. The method for preventing, ameliorating, or treating a degenerative brain disease according to claim 16, wherein the compound, its stereoisomer, or a pharmaceutically or food-based acceptable salt thereof activates all of PPARα, PPARβ / δ, and PPARγ.

20. The method for preventing, ameliorating, or treating a degenerative brain disease according to claim 16, wherein the compound, its stereoisomer, or a pharmaceutically or food-based acceptable salt thereof exhibits any one or more of the following effects (i) to (iii): (i) The effect of activating PPAR transcription factors in microglial cells and inhibiting inflammatory responses; (ii) the effect of inhibiting the formation of Aβ aggregates in brain tissue; and (iii) Inhibitory effect on gliosis caused by excessive activity of microglial cells and astrocytes.

21. A method for improving learning ability, memory, or ameliorating cognitive decline, comprising administering a compound represented by the following chemical formula 1, a stereoisomer thereof, or a pharmaceutically or food-based acceptable salt thereof to an individual in need thereof:

22. Use of a compound represented by the following chemical formula 1, a stereoisomer thereof, or a pharmaceutically or food-based acceptable salt thereof for the manufacture of a medicament for preventing, ameliorating, or treating a degenerative brain disease:

23. 23. The use of claim 22, wherein the stereoisomer comprises a racemate, an enantiomer, a partial stereoisomer, a mixture of enantiomers, or a mixture of partial stereoisomers.

24. The degenerative brain diseases include dementia, autism, Alzheimer's disease, Huntington's disease, vascular dementia, stroke, ischemic stroke, traumatic brain injury, amnesia, Parkinson's disease, Pick's disease, Creutzfeldt-Jakob disease, and peripheral neuropathy.

23. The use according to claim 22, comprising any one or more selected from the group consisting of: atherosclerosis, amyotrophic lateral sclerosis, multiple sclerosis, and mild cognitive impairment.

25. The use according to claim 22, wherein the compound, its stereoisomer or a pharmaceutically or food-based acceptable salt thereof activates all of PPARα, PPARβ / δ and PPARγ.

26. The use according to claim 22, wherein the compound, its stereoisomer, or a pharmaceutically or food-based acceptable salt thereof exhibits any one or more of the following effects (i) to (iii): (i) The effect of activating PPAR transcription factors in microglial cells and inhibiting inflammatory responses; (ii) the effect of inhibiting the formation of Aβ aggregates in brain tissue; and (iii) Inhibitory effect on gliosis caused by excessive activity of microglial cells and astrocytes.

27. Use of a compound represented by the following chemical formula 1, a stereoisomer thereof, or a pharmaceutically or food-based acceptable salt thereof for the manufacture of a medicament for improving learning ability, memory, or cognitive decline:

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