WO2021155633A1 - 烷基间苯二酚类化合物在制备预防或治疗阿兹海默症的药物的应用 - Google Patents

烷基间苯二酚类化合物在制备预防或治疗阿兹海默症的药物的应用 Download PDF

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WO2021155633A1
WO2021155633A1 PCT/CN2020/082025 CN2020082025W WO2021155633A1 WO 2021155633 A1 WO2021155633 A1 WO 2021155633A1 CN 2020082025 W CN2020082025 W CN 2020082025W WO 2021155633 A1 WO2021155633 A1 WO 2021155633A1
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disease
mice
alkyl
alkyl resorcinol
brain
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王静
刘洁
王子元
王玉
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北京工商大学
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

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  • the invention relates to the field of biomedicine, in particular to the application of alkyl resorcinol compounds in the preparation of drugs for preventing or treating Alzheimer's disease.
  • AD Alzheimer's disease
  • a ⁇ extracellular amyloid plaques
  • Tau tubulin the accumulation of highly phosphorylated Tau tubulin
  • neurofibrillary tangles and loss of neurons synapses and other abnormal manifestations, which are then manifested as Cognitive impairment, abnormal behavior and even death.
  • ROS reactive oxygen species
  • AD amyloid ⁇
  • An alkyl side chain containing an odd number of carbons is attached to the 5th carbon of the benzene ring, which is mainly composed of C15:0, C17:0, and C19:0 , C21:0, C23:0 and C25:0 composition.
  • Wheat bran has the highest content of C19:0 and C21:0.
  • alkyl resorcinol can protect HepG2 cells by inducing autophagy and apoptosis, thereby playing a protective role against liver cancer; alkyl resorcinol can also protect cells by regulating the Nrf2/HO-1 pathway It can protect against oxidative stress, but its specific application in the anti-oxidative stress of the nervous system has not been reported yet, and it remains to be explored and studied.
  • Chinese patent application 201910981462.9 discloses the application of alkyl resorcinol in the preparation of products for the prevention or treatment of obesity-related diseases.
  • the product contains the active ingredient alkyl resorcinol, and the alkyl resorcinol is composed of monomers in the following weight percentages: heptadecyl resorcinol 1-10%; nonadecyl resorcinol Diphenol 20-25%; Eicosanylresorcinol 50-55%; Tricosylresorcinol 5-10%; Pentadecylresorcinol 5-12%.
  • the present invention clarifies that the alkyl resorcinol can prevent or treat obesity by improving the body's energy metabolism or increasing the body's heat production to prevent or treat the appropriate ratio of the corresponding constituent monomers.
  • Chinese patent application 201910593007.1 discloses a composition containing an amide derivative and its application in cosmetics, the composition comprising: a. at least one amide derivative (A) represented by formula (1); b. At least one resorcinol derivative (B) represented by formula (2); and at least one cosmetically acceptable component (C).
  • the amide derivative contained in the composition of the present application has a positive enhancement effect on the transdermal delivery of the composition, which facilitates the active substance of the composition to penetrate through each layer of the skin to reach the site of action, and cause damage to skin melanin deposition and skin aging.
  • Preventing and/or inhibiting the visible discontinuous appearance changes of the skin caused by other diseases treating, regulating or preventing skin oxidative stress or degenerative process, inhibiting melanin production and precipitation, reducing the darkening of the skin, increasing the skin, and making the skin Keep it translucent and white.
  • the purpose of the present invention is to provide the application of alkyl resorcinol compounds for preparing drugs for preventing or treating Alzheimer's disease.
  • the applicant used animal experiments and cell experiments to study the expression of various pathogenic related proteins and pathway proteins in the brain by alkyl resorcinol compounds, and to adjust the composition of the intestinal flora and the abundance of the intestinal flora to achieve changes to clarify the changes in alkyl resorcinol compounds.
  • Hydroquinone compounds act on the mechanism of Alzheimer's disease and preventive or therapeutic effects.
  • alkyl resorcinol compounds for preparing medicines for preventing or treating Alzheimer's disease.
  • alkyl resorcinol compound is represented by the following general formula (I).
  • R1 is a C5-C50 linear or branched alkyl group; preferably, R1 is a C9-C35 linear or branched alkyl group, more preferably a C15-C30 linear or branched alkyl group; still more preferably C15 linear or branched alkyl, C17 linear or branched alkyl, C19 linear or branched alkyl, C21 linear or branched alkyl, C23 linear or branched alkyl, C25 linear or branched Chain alkyl, C27 linear or branched alkyl, or C29 linear or branched alkyl; further, preferably C17 linear or branched alkyl, that is, heptadecyl resorcinol (AR- C17), as shown in formula (II).
  • the above alkyl resorcinol compounds can change the expression of a variety of pathogenesis-related proteins and pathway proteins in the brain, thereby preventing or treating Alzheimer's disease.
  • the medicine can be prepared into any one of tablets, powders, pastes, liquids, injections and infusions.
  • the dosage of the drug is 150 mg/kg/day.
  • alkyl resorcinol compounds to prevent or treat Alzheimer's disease is achieved by changing the expression of a variety of pathogenic-related proteins and pathway proteins in the brain, and regulating the composition of the flora and the abundance of the characteristic flora.
  • the preparation of alkyl resorcinol compounds to prevent or treat Alzheimer’s disease is to reduce the accumulation of A ⁇ plaques in the brain, reduce the activation and aggregation of microglia and the expression of inflammation, and reduce ⁇ in the brain of mice.
  • -Highly phosphorylated expression of amyloid and Tau protein significantly reducing the expression of ADAM10 and synaptophysin, thereby enhancing AR-C17 intervention, activating the SIRT3 signaling pathway and its downstream effector SOD2, enhancing the bacterial flora that has a protective effect on AD The abundance is achieved.
  • mice All mice are reared in a single cage under a standard SPF environment (20-25°C, humidity 55%, 12-hour light-dark cycle, free access to food and water).
  • the AD model animals (APP/PS1) mice were randomly divided into two groups: the AD control group (APP/PS1+CMC-Na) and the drug-added AR group (APP/PS1+AR), each with 12 mice, and the dose The concentration is 150 mg/kg/day.
  • 12 non-transgenic mice were set as the background group (C57BL/6J), and the same amount of CMC-NA (0.5%) was given every day as a control.
  • the Morris water maze test was performed 1 week before execution.
  • the Morris water maze is a circular water tank with a diameter of 120cm ⁇ 50cm, filled with water (22 ⁇ 1°C), equipped with a platform with a diameter of 10cm in the third quadrant, submerged 0.5cm below the water surface.
  • the hidden platform was fixed in the same place. 4 days before the last probe test, each mouse is allowed to freely search for the platform hidden under the water within 120s.
  • the mouse cannot find the hidden platform within 120s, it will be guided to the platform and stay for 20 seconds to remember Spatial location.
  • the last probe test was performed on the 5th day, the hidden platform was removed, and each mouse was free to search for 120 seconds. Automatically record and collect all data, such as swimming trajectory, the number of crossings of the target quadrant, the time it takes to reach the target area for the first time, etc., and use SPSS software for statistical analysis.
  • sodium pentobarbital 50mg/kg
  • the analysis method is:
  • Iba1/Nissl double staining experiment Take frozen brain tissue sections, block them with blocking solution (3% donkey serum, 10% Triton in 0.1M PBS) for 30 minutes, and incubate with primary antibody (anti-Iba1) overnight at 4°C. After washing 3 times in PBS buffer, the brain slices were placed in secondary antibodies containing target different excitation wavelength secondary antibodies (Donkey anti-Rb 594, for Iba1, Nissl 500/525), and incubated in the dark for 1.5 hours. Then wash 3 times in PBS buffer, mount the slides, and use the Olympus FV1200 confocal microscope to image the sealed slides.
  • a ⁇ /GFAP/Nissl triple staining experiment Take frozen brain tissue sections, block them with blocking solution (3% donkey serum, 10% Triton in 0.1M PBS) for 30 minutes, and incubate with primary antibody (anti-A ⁇ , anti-GFAP) at 4°C overnight. After washing 3 times in PBS buffer, the brain slices are placed in secondary antibodies containing target different excitation wavelengths (Alexa Fluor 488, 1:500, for A ⁇ ; DyLight 594, 1:500, for Iba-1, DyLight 594, 1: 500, for GFAP) secondary antibody, incubate in the dark for 1.5h. Then wash 3 times in PBS buffer, mount the slides, and use the Olympus FV1200 confocal microscope to image the sealed slides.
  • target different excitation wavelengths Alexa Fluor 488, 1:500, for A ⁇
  • DyLight 594, 1:500 for Iba-1
  • DyLight 594, 1: 500 for GFAP
  • the perfused mice were removed, and the remaining mice were killed by decapitation.
  • the cerebral cortex and hippocampus were separated and stored at -80°C for biochemical index analysis.
  • biochemical index analysis By Western blotting, analysis of pathological-related proteins, neurological health-related factors, pathway-related proteins, etc. To analyze and study the biochemical mechanism of how AR can improve the pathological changes of AD.
  • the analysis method is:
  • Western-blot was used to quantitatively analyze related phenotypic proteins. The specific steps are as follows: prepare tissue lysate by RIPA method, and determine total protein by BCA method. After gel electrophoresis with 12% separating gel, the separated protein is transferred to the PVDF membrane, the membrane is washed and the skimmed milk powder antigen is blocked, and the antibody to be detected is incubated overnight at 4°C. Then the membrane was washed with TBST for 5 minutes, and then incubated with goat anti-rabbit IgG H&L (HRP) at room temperature for 1 hour. Then wash the blot with TBST for 5 minutes, and finally use chemiluminescence reagents for detection on the gel imager.
  • HRP goat anti-rabbit IgG H&L
  • mice handling methods All mice were collected the feces one day before the behavioral experiment, and the feces were stored in a refrigerator at -80°C until the intestinal bacteria were detected.
  • Determination of the abundance of intestinal flora Stool samples of each group were analyzed for microbial flora. Extract total DNA from frozen stool samples and detect the concentration of separated DNA. Perform PCR amplification and purification on the V3-V4 region of 16S rRNA, use QIIME software package and Illumina MiSeq platform for sequencing, and perform bioinformatics analysis.
  • AR refers to alkyl resorcinol compounds.
  • alkyl resorcinol compounds are used in the preparation of pharmaceutical compositions or preparations for the prevention or treatment of Alzheimer’s disease, which can significantly improve spatial memory and cognitive abilities, delay the occurrence of AD, and play a Protective effects.
  • the present invention confirms that AR can activate the SIRT3 signal pathway and its downstream effector SOD2.
  • Figure 1 is the escape time (A) of the first 4 days of the three groups of mice in the water maze experiment, the time it took to find the target area on the last day (B), the number of times they crossed the target (C), and the swimming trajectory diagram (D).
  • WT refers to background group mice (C57BL/6J)
  • AD refers to AD control mice (APP/PS1 double transgenic mice)
  • AR-C17 refers to drug-added APP/PS1 transgenic mice (APP/PS1+150mg/kg/day AR-C17);
  • Figure 2 shows the hippocampal pathology of three groups of mice: A ⁇ /GFAP/Nissl triple staining immunofluorescence, where WT refers to the background group of mice (C57BL/6J), and AD refers to the AD control group of mice (APP/PS1 double transgenic Mouse), AR-C17 refers to APP/PS1 transgenic mice (APP/PS1+150mg/kg/day AR-C17);
  • Figure 3 shows the hippocampal pathology of three groups of mice: Iba1/Nissl double staining immunofluorescence image, where WT refers to the background group of mice (C57BL/6J), and AD refers to the AD control group of mice (APP/PS1 double transgenic mice) , AR-C17 refers to APP/PS1 transgenic mice (APP/PS1+150mg/kg/day AR-C17);
  • Figure 4 is the three groups of mouse hippocampus and cortical tissues and AD-related pathological protein expression and neuroinflammation intervention diagram, in which, WT refers to the background group of mice (C57BL/6J), AD refers to the AD control group of mice (APP/PS1 double transgenic Mouse), AR-C17 refers to APP/PS1 transgenic mice (APP/PS1+150mg/kg/day AR-C17);
  • FIG. 5 shows the activation effect of AR-C17 on the SIRT3/SOD2 signaling pathway, where WT refers to background mice (C57BL/6J), AD refers to AD control mice (APP/PS1 double transgenic mice), and AR-C17 refers to mice in the background group (C57BL/6J).
  • WT refers to background mice (C57BL/6J)
  • AD refers to AD control mice (APP/PS1 double transgenic mice)
  • AR-C17 refers to mice in the background group (C57BL/6J).
  • Drug-added APP/PS1 transgenic mice APP/PS1+150mg/kg/day AR-C17
  • Figure 6 is a graph of the abundance of intestinal flora of three kinds of mice, where WT refers to background group mice (C57BL/6J), AD refers to AD control mice (APP/PS1 double transgenic mice), and AR-C17 refers to plus Drug APP/PS1 transgenic mice (APP/PS1+150mg/kg/day AR-C17).
  • WT refers to background group mice (C57BL/6J)
  • AD refers to AD control mice
  • AR-C17 refers to plus Drug APP/PS1 transgenic mice (APP/PS1+150mg/kg/day AR-C17).
  • the heptadecylresorcinol in the following examples was prepared by the following method:
  • Dry wheat bran is selected as the raw material, the raw materials are selected, sorted, and ground, then ethyl acetate is added for ultrasonic extraction, the supernatant is obtained after centrifugation, and the concentrated solution is obtained by rotary evaporation. Then use solid phase extraction or silica gel sample mixing to carry out silica gel column chromatography for separation and purification, and then collect the eluate for further concentration. The mixture of different homologs of alkyl resorcinol is obtained. According to the peak time, the heptadecyl group is collected. The resorcinol sample has a purity of >97%.
  • mice All mice are reared in a single cage under a standard SPF environment (20-25°C, humidity 55%, 12-hour light-dark cycle, free access to food and water).
  • the food-grade carboxymethyl cellulose sodium (CMC-Na) solution is administered by gavage.
  • AD model animals mice were randomly divided into two groups: AD control group (APP/PS1+CMC-Na), AR-C17 group (APP/PS1+AR-C17), 12 mice in each group , The dosage concentration is 150mg/kg/day.
  • 12 non-transgenic mice were set as the background group (C57BL/6J), and the same amount of CMC-NA (0.5%) was given every day as a control.
  • the Morris water maze test was performed 1 week before execution.
  • the Morris water maze is a circular water tank with a diameter of 120cm ⁇ 50cm, filled with water (22 ⁇ 1°C), equipped with a platform with a diameter of 10cm in the third quadrant, submerged 0.5cm below the water surface.
  • the hidden platform was fixed in the same place. 4 days before the last probe test, each mouse is allowed to freely search for the platform hidden under the water within 120s.
  • the mouse cannot find the hidden platform within 120s, it will be guided to the platform and stay for 20 seconds to remember Spatial location.
  • the last probe test was performed on the 5th day, the hidden platform was removed, and each mouse was free to search for 120 seconds. Automatically record and collect all data, such as swimming trajectory, the number of crossings in the target quadrant, the time it takes to reach the target area for the first time, etc., and use SPSS software for statistical analysis.
  • mice tracked obviously disorderly, the escape time and the time to reach the target area for the first time were significantly prolonged, and the number of crossing the target quadrant was significantly reduced; drug (AR-C17) intervention APP/PS1 Mice at 5 months can significantly improve the spatial memory and cognitive abilities of mice.
  • sodium pentobarbital 50mg/kg
  • Iba1/Nissl double staining experiment Take frozen brain tissue sections, block them with blocking solution (3% donkey serum, 10% Triton in 0.1M PBS) for 30 minutes, and incubate with primary antibody (anti-Iba1) overnight at 4°C. After washing 3 times in PBS buffer, the brain slices were placed in secondary antibodies containing target different excitation wavelengths (DyLight 594 for Iba-1, DyLight 500/525 for Nissl) and incubated in the dark for 1.5 hours. Then wash 3 times in PBS buffer, mount the slides, and use the Olympus FV1200 confocal microscope to image the sealed slides.
  • a ⁇ /GFAP/Nissl triple staining experiment Take frozen brain tissue sections, block them with blocking solution (3% donkey serum, 10% Triton in 0.1M PBS) for 30 minutes, and incubate with primary antibody (anti-A ⁇ , anti-GFAP) at 4°C overnight. After washing 3 times in PBS buffer, the brain slices were placed in secondary antibodies containing target different excitation wavelengths (DyLight 488 for A ⁇ , DyLight 594 for GFAP; DyLight 435/455 for Nissl) and incubated in the dark for 1.5 hours . Then wash 3 times in PBS buffer, mount the slides, and use the Olympus FV1200 confocal microscope to image the sealed slides.
  • the A ⁇ /GFAP/Nissl triple-stained fluorescence image showed that A ⁇ plaques and astrocyte aggregation appeared in the brains of the blank APP/PS1 mice, but not transgenic mice (C57 BL/6J) and intragastric AR-17 In APP/PS1 mice, there is no or significantly less in the brain, which proves that AR can reduce the accumulation of A ⁇ plaques in the brain, thereby delaying the occurrence of AD and playing a protective role.
  • the Iba1/Nissl double-stained fluorescence image showed that there were obvious accumulation of microglia in the brains of the blank APP/PS1 mice, but not transgenic mice (C57 BL/6J) and AR-C17 APP/PS1. There is no or significant reduction in mouse brain, which proves that AR-C17 can reduce the activation and aggregation of microglia, thereby delaying the occurrence of AD and playing a protective role.
  • mice were removed, and the remaining mice were killed by decapitation.
  • the cerebral cortex and hippocampus were separated and stored at -80°C for biochemical index analysis.
  • Western blotting the pathological-related proteins and neurological health-related factors were analyzed to study how AR can improve the pathological changes of AD in terms of biochemical mechanisms.
  • Western-blot was used to quantitatively analyze related phenotypic proteins. The specific steps are as follows: prepare tissue lysate by RIPA method, and determine total protein by BCA method. After gel electrophoresis with 12% separating gel, the separated protein is transferred to the PVDF membrane, the membrane is washed and the skimmed milk powder antigen is blocked, and the antibody to be detected is incubated overnight at 4°C. Then the membrane was washed with TBST for 5 minutes, and then incubated with goat anti-rabbit IgG H&L (HRP) at room temperature for 1 hour. Then wash the blot with TBST for 5 minutes, and finally use chemiluminescence reagents for detection on the gel imager.
  • HRP goat anti-rabbit IgG H&L
  • the experimental results show that the large accumulation of ⁇ -amyloid protein and the hyperphosphorylation of Tau protein in the brains of APP/PS1 mice, while the wild-type (WT) and AR-C17 intervention APP/PS1 mice have no or significant brain reduce. Therefore, AR-C17 significantly reduces the expression of ⁇ -amyloid and Tau protein in the mouse brain, thereby delaying the occurrence of AD and playing a protective role. In addition, the expression of ADAM10 and synaptophysin in APP/PS1 model mice was significantly reduced, and AR-C17 intervention could significantly improve, effectively preventing the occurrence and development of AD.
  • Figures 4 and 5 show that, compared to the wild-type mouse WT group, the AD group mouse brain and cortical area microglia specific protein Iba-1, glial fibrillary acidic protein GFAP, inflammasome and its downstream proteins are Significant activation, the expression of inflammatory factors was significantly increased, but AR-C17 intervention can significantly reduce the expression of inflammation in the hippocampus and cortex of the AD group, effectively alleviate neuroinflammation, and slow the occurrence and development of Alzheimer's disease.
  • Sirt3 is an important deacetylation modification enzyme in mitochondria, which can regulate the activity of many metabolic enzymes in mitochondria, thereby regulating the metabolism of cell mitochondria.
  • the activation of Sirt3 is closely related to anti-oxidation, anti-aging, anti-tumor and improving immunity.
  • Western-blot was used to quantitatively analyze related phenotypic proteins, tissue lysate was prepared by RIPA method, and total protein was determined by BCA method. After gel electrophoresis with 12% separating gel, the separated protein is transferred to the PVDF membrane, the membrane is washed and the skimmed milk powder antigen is blocked, and the antibody to be detected is incubated overnight at 4°C.
  • the membrane was washed with TBST for 5 minutes, and then incubated with goat anti-rabbit IgG H&L (HRP) at room temperature for 1 hour. Then wash the blot with TBST for 5 minutes, and finally use chemiluminescence reagents for detection on the gel imager.
  • HRP goat anti-rabbit IgG H&L
  • AR-C17 can activate the SIRT3 signaling pathway and its downstream effector SOD2.
  • the expression of SIRT3/SOD2 signaling pathway was significantly reduced in AD group compared with WT group. After AR-C17 intervention, the signaling pathway was significantly improved.
  • mice handling methods All mice were collected the feces one day before the behavioral experiment, and the feces were stored in a refrigerator at -80°C until the intestinal bacteria were detected. Stool samples from each group were analyzed for microflora. Extract total DNA from frozen stool samples and detect the concentration of separated DNA. Perform PCR amplification and purification on the V3-V4 region of 16S rRNA, use QIIME software package and Illumina MiSeq platform for sequencing, and perform bioinformatics analysis.
  • Figure 6 shows that the APP/PS1 model mouse has a significant decrease in the abundance of the flora relative to the background group, especially Akkermansia (Mucinophilin-Ekkermania) and Lactobacillus (Lactobacillus). These two bacteria have proven to have a protective effect on AD in clinical and different experimental animals.
  • the AR-C17 intervention group can significantly increase the abundance of AD model mice, especially the abundance of the aforementioned two beneficial bacteria.

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Abstract

本发明提供了一种烷基间苯二酚类化合物在制备预防或治疗阿兹海默症的药物的应用，属于生物医药领域。烷基间苯二酚类化合物的结构如通式(I)所示，式中，R1为C5-C50直链或支链烷基中的任一种。本发明通过实验证明，烷基间苯二酚类化合物可通过改变脑内多种致病相关蛋白、通路蛋白的表达及调节肠道菌群组成和特征菌群丰度来实现对阿兹海默症的预防或治疗。

Description

烷基间苯二酚类化合物在制备预防或治疗阿兹海默症的药物的应用 技术领域
本发明涉及生物医药领域，具体涉及烷基间苯二酚类化合物在制备预防或治疗阿兹海默症的药物的应用。
背景技术
阿尔茨海默症(AD)是一种最常见的进行性神经退行性疾病，其发病率随着人口老龄化而呈指数增长。AD的主要病理学特征在于脑细胞外淀粉样蛋白斑块(Aβ)的沉积、高度磷酸化Tau微管蛋白的聚集、神经原纤维缠结和神经元、突触丢失等异常表现，进而表现为认知障碍、行为异常甚至死亡。另外有研究证明，慢性神经炎症是导致神经元丧失和免疫敏感性的原因。炎症反应进一步激活小胶质细胞和星形胶质细胞产生大量活性氧簇(ROS)，氧化应激和神经炎症的共同作用导致β淀粉样蛋白(Aβ)的生成，从而加重AD病情。因此，AD发病与一系列病理有着密切联系，包括炎症、内质网应激、乙酰胆碱能神经传递改变、氧化应激增加和线粒体功能障碍，这些都导致神经细胞的死亡和痴呆。
流行病学调查发现，食用含有麦麸的全谷物制品可以起到抗氧化损伤、降低肥胖、糖尿病和一些癌症的发病率的作用。麦麸脂溶性部位比水溶性部位能够更有效的发挥其生理作用。进一步研究表明，小麦麸皮中的脂溶性活性物质-烷基间苯二酚(Alkylresorcinols，ARs)具有抗氧化、降低血糖、抗肿瘤的良好生物活性。小麦烷基间苯二酚为1，3-二羟基苯衍生物，在苯环第5位碳上连接一个含奇数碳的烷基侧链，主要由C15：0、C17：0、C19：0、C21：0、C23：0和C25：0组成，小麦麦麸中以C19：0和C21：0含量最高。另有研究表明烷基间苯二酚可通过诱导HepG2细胞自噬和凋亡，从而起到抗肝癌的保护作用；烷基间苯二酚还可通过调节Nrf2/HO-1通路起到保护细胞免受氧化应激的作用等，但是其具体应用在神经***抗氧化应激方面的作用和机制尚未见报道，还有待探索和研究。
中国专利申请201910981462.9公开了烷基间苯二酚在制备用于预防或治疗肥胖症相关疾病产品中的应用。所述产品包含活性成分烷基间苯二酚，所述烷基间苯二酚由如下重量百分比的各单体组成：十七烷基间苯二酚1-10％；十九烷基间苯二酚20-25％；二十一烷基间苯二酚50-55％；二十三烷基间苯二酚5-10％；二十五烷基间苯二酚5-12％。本发明明确了烷基间苯二酚通过提高机体能量代谢或提高机体产热以起到预防或治疗肥胖时对应的各组成单体之 间的合适配比。
中国专利申请201910593007.1公开了一种包含酰胺衍生物的组合物及其在化妆品中的应用，所述组合物包括：a.至少一种式(1)所示的酰胺衍生物(A)；b.至少一种式(2)所示的间苯二酚衍生物(B)；以及至少一种化妆品上可接受的组分(C)。本申请所述组合物所包含的酰胺衍生物对所属组合物的透皮递送具有积极的增强作用，利于组合物活性物质透过各层皮肤达到作用部位，并发生对由皮肤黑色素沉着、皮肤老化或其它病症引起的皮肤可见的不连续性外观变化的预防和/或抑制作用，治疗、调控或预防皮肤氧化应激或退化过程，抑制黑色素生成和沉淀、减轻肤色加深、增量皮肤，使皮肤保持透亮白皙。
Figure PCTCN2020082025-appb-000001
但是以上专利申请皆未提到烷基间苯二酚类化合物具体应用在神经***抗氧化应激方面，而且截止目前，并未见有人将烷基间苯二酚类化合物用于制备预防或治疗阿兹海默症的药物的报道。有鉴于此，本发明提供了烷基间苯二酚类化合物用于制备预防或治疗阿兹海默症的药物的应用，这将为阿兹海默症的预防和治疗提供新的思路，具有重要的意义。
发明内容
本发明的目的是提供烷基间苯二酚类化合物用于制备预防或治疗阿兹海默症的药物的应用。申请人通过动物实验及细胞实验研究烷基间苯二酚类化合物对脑内多种致病相关蛋白、通路蛋白的表达以及调节肠道菌群组成和菌群丰度实现改变来阐明烷基间苯二酚类化合物作用于阿兹海默症的机制以及预防或治疗作用。
为了实现上述发明目的，本发明提供以下技术方案：
烷基间苯二酚类化合物用于制备预防或治疗阿兹海默症的药物的应用。
其中，所述烷基间苯二酚类化合物如下通式(I)所示。
Figure PCTCN2020082025-appb-000002
式中，R1为C5-C50直链或支链烷基；优选的，R1为C9-C35直链或支链烷基，进一步优选为C15-C30直链或支链烷基；再进一步优选为C15直链或支链烷基、C17直链或支链烷基、C19直链或支链烷基、C21直链或支链烷基、C23直链或支链烷基、C25直链或支链烷基、C27直链或支链烷基、或C29直链或支链烷基；更进一步地，优选为C17直链或支链烷基，即十七烷基间苯二酚(AR-C17)，如式(II)所示。以上烷基间苯二酚类化合物接可改变脑内多种致病相关蛋白、通路蛋白的表达，进而对阿兹海默症起到预防或治疗作用。
Figure PCTCN2020082025-appb-000003
所述药物可以制备成片剂、粉剂、糊剂、水剂、针剂和输液剂中的任一种。
所述药物的用量为150mg/kg/天。
烷基间苯二酚类化合物制备预防或治疗阿兹海默症的药物是通过改变脑内多种致病相关蛋白、通路蛋白的表达以及调节菌群组成和特征菌群丰度实现的。
具体地，烷基间苯二酚类化合物制备预防或治疗阿兹海默症的药物是通过减少Aβ斑块在脑内聚集、减少小胶质细胞活化聚集及炎症表达、降低小鼠大脑内β-淀粉样蛋白及Tau蛋白的高度磷酸化表达、显著降低ADAM10及突触体素的表达进而提升AR-C17干预，激活SIRT3信号通路及其下游效应因子SOD2、提升对AD有保护作用的菌群丰度实现的。
本发明的研究方法主要包括以下方面：
1、动物饲养：
所有小鼠均在标准SPF级环境下单笼饲养(20-25℃，湿度55％，12小时明暗循环，可自由获取食物和水)。选取三月龄的雄性APP/PS1双转基因敲出小鼠B6C3-Tg[APPswe，PSEN1dE9]，体重在30g左右，将药物烷基间苯二酚(AR)均匀混悬于0.5％食品级羧甲基纤维素钠(CMC-Na)溶液中，采用灌胃方式给药。将AD模型动物(APP/PS1)小鼠随机分为两组：AD对照组(APP/PS1+CMC-Na)、加药AR组(APP/PS1+AR)，每组12只，给药剂量浓度为150mg/kg/天。另外设置12只非转基因型小鼠为背景组(C57BL/6J)，每天给予等量CMC-NA(0.5％)作为对照。持续5个月每日灌胃给药。
2、AR对APP/PS1小鼠认知行为的改善作用：
采取国际公认的动物行为学检测方法：Morris水迷宫实验，对小鼠的空间记忆能力、新记忆形成能力、认知能力进行表观测评，通过测评结果决定继续给药或者处死。于处死前1周进行了Morris水迷宫试验。Morris水迷宫是一个直径120cm×50cm高的圆形水箱，装满水(22±1℃)，在第三象限配备一个直径10cm的平台，淹没在水面以下0.5cm处。在5天的试验中，隐藏的平台被固定在同一个地方。在最后一次探针测试前4天，每只老鼠被允许在120s内自由搜索隐藏在水面下的平台，120s内找不到隐藏平台的老鼠，将被引导到平台上，停留20秒以记住空间位置。在第5天进行最后一次探针测试，移除隐藏的平台，每只小鼠自由寻找120秒。自动记录并收集所有数据，如游泳轨迹、目标象限穿越次数，第一次到达目标区域所用时间等，并用SPSS软件进行统计分析。
3、AR对APP/PS1小鼠脑组织病理改变的改善作用：
行为试验后2天，每组选取4只小鼠(n＝4)腹腔注射戊巴比妥钠(50mg/kg)，然后用生理盐水、4％多聚甲醛溶液经心脏灌注，固定10min左右以后，取完整大脑浸泡于4％多聚甲醛2h，2h后将脑浸泡于蔗糖溶液中脱水，放入4℃冰箱保存，直至切片。
分析方法为：
Iba1/Nissl双染实验：取冰冻脑组织切片，用封闭液(3％驴血清，10％Triton溶于0.1M PBS)封闭30min，4℃一抗(anti-Iba1)孵育过夜。在PBS缓冲液中清洗3遍后，大脑切片置于含有目标不同激发波长二抗(Donkey anti-Rb 594,for Iba1，Nissl 500/525)的二抗中，于黑暗中孵育1.5h。然后在PBS缓冲液中清洗3遍，封片，封好的切片使用Olympus FV1200共聚焦显微镜成像。
Aβ/GFAP/Nissl三染实验：取冰冻脑组织切片，用封闭液(3％驴血清，10％Triton溶于0.1M PBS)封闭30min，4℃一抗(anti-Aβ，anti-GFAP)孵育过夜。在PBS缓冲液中清洗3遍后， 大脑切片置于含有目标不同激发波长二抗(Alexa Fluor 488,1:500,for Aβ；DyLight 594,1:500,for Iba-1,DyLight 594,1:500,for GFAP)的二抗中，于黑暗中孵育1.5h。然后在PBS缓冲液中清洗3遍，封片，封好的切片使用Olympus FV1200共聚焦显微镜成像。
4、AR对APP/PS1小鼠脑组织生化指标改变的改善作用：
除去灌流的小鼠，其余小鼠断头处死，分离大脑皮层和海马于-80℃保存，用于做生化指标分析。通过蛋白免疫印迹法，对病理相关的蛋白、神经健康相关因子、通路相关蛋白等进行分析。对AR具体如何改善AD病理改变，进行生化机制方面的分析和研究。
分析方法为：
采用Western-blot蛋白印迹方法对相关表型蛋白进行定量分析，具体操作步骤如下：用RIPA法制备组织裂解液，用BCA法测定总蛋白。采用12％分离胶进行凝胶电泳后，将分离蛋白质转移到PVDF膜上，经过洗膜和脱脂奶粉抗原封闭后，在4℃过夜孵育要检测的抗体。然后用TBST洗涤膜5分钟，然后与山羊抗兔IgG H&L(HRP)在室温下孵育1小时。再用TBST洗涤印迹5分钟，最后使用化学发光试剂在凝胶成像仪上进行检测。
5、AR对APP/PS1小鼠肠道菌群丰度的改善：
小鼠处理手法：全部小鼠于行为学实验前一天分别收集粪便，粪便冻存于-80℃冰箱中，直至肠道菌的检测。
肠道菌群丰度测定：每组的粪便样本进行微生物区系分析。提取冷冻粪便样本总DNA，检测分离的DNA浓度。对16S rRNA的V3-V4区域进行PCR扩增、纯化，利用QIIME软件包、Illumina MiSeq平台进行测序，进行生物信息学分析。
在本发明中，AR指烷基间苯二酚类化合物。
本发明具有以下有益效果：
烷基间苯二酚类化合物作为一种新工具，应用于制备预防或治疗阿兹海默症的药物组合物或制剂中，可明显提升空间记忆能力和认知能力，延缓AD发生，起到保护作用。另外，本发明证实AR能够激活SIRT3信号通路及其下游效应因子SOD2。
附图说明
图1为三组小鼠在水迷宫实验中的前4天的逃逸时间(A)、最后一天找到目标区域所用时间(B)及穿越目标次数(C)、游泳轨迹图(D)，其中，WT指背景组小鼠(C57BL/6J)，AD指AD对照组小鼠(APP/PS1双转基因鼠)，AR-C17指加药APP/PS1转基因小鼠 (APP/PS1+150mg/kg/天AR-C17)；
图2为三组小鼠的海马病理图：Aβ/GFAP/Nissl三染免疫荧光图，其中，WT指背景组小鼠(C57BL/6J)，AD指AD对照组小鼠(APP/PS1双转基因鼠)，AR-C17指加药APP/PS1转基因小鼠(APP/PS1+150mg/kg/天AR-C17)；
图3为三组小鼠的海马病理图：Iba1/Nissl双染免疫荧光图，其中，WT指背景组小鼠(C57BL/6J)，AD指AD对照组小鼠(APP/PS1双转基因鼠)，AR-C17指加药APP/PS1转基因小鼠(APP/PS1+150mg/kg/天AR-C17)；
图4为三组小鼠海马及皮层组织与AD相关病理蛋白表达及神经炎症干预图，其中，WT指背景组小鼠(C57BL/6J)，AD指AD对照组小鼠(APP/PS1双转基因鼠)，AR-C17指加药APP/PS1转基因小鼠(APP/PS1+150mg/kg/天AR-C17)；
图5为AR-C17对SIRT3/SOD2信号通路激活作用图，其中，WT指背景组小鼠(C57BL/6J)，AD指AD对照组小鼠(APP/PS1双转基因鼠)，AR-C17指加药APP/PS1转基因小鼠(APP/PS1+150mg/kg/天AR-C17)；
图6为三种小鼠肠道菌群丰度图，其中，WT指背景组小鼠(C57BL/6J)，AD指AD对照组小鼠(APP/PS1双转基因鼠)，AR-C17指加药APP/PS1转基因小鼠(APP/PS1+150mg/kg/天AR-C17)。
具体实施方式
为了使本发明实现的技术手段、创作特征、达成目的与功效易于明白了解，下面结合具体实施例，进一步阐明本发明，但下述实施例仅为本发明的优选实施例，并非全部。基于实施方式中的实施例，本领域技术人员在没有做出创造性劳动的前提下所获得其它实施例，都属于本发明的保护范围。
下述实施例中的实验方法，如无特殊说明，均为常规方法，下述实施例中所用的材料、试剂等，如无特殊说明，均可从商业途径得到。
下述实施例中的十七烷基间苯二酚由以下方法制备：
选用干燥小麦麸皮为原材料，将原材料挑选整理磨粉后，加入乙酸乙酯进行超声提取，离心后得上清液，经旋转蒸发得浓缩液。接着利用固相萃取或硅胶拌样进行硅胶柱层析进行分离纯化，再收集洗脱液进一步浓缩，既得烷基间苯二酚不同同系物混合液，按照出峰时间不同，收集十七烷基间苯二酚样品，纯度>97％。
实施例1 动物饲养
所有小鼠均在标准SPF级环境下单笼饲养(20-25℃，湿度55％，12小时明暗循环，可自由获取食物和水)。选取三月龄的雄性APP/PS1双转基因敲出小鼠B6C3-Tg[APPswe，PSEN1dE9]，体重在30g左右，将药物十七烷基间苯二酚(AR-C17)均匀混悬于0.5％食品级羧甲基纤维素钠(CMC-Na)溶液中，采用灌胃方式给药。将AD模型动物(APP/PS1)小鼠随机分为两组：AD对照组(APP/PS1+CMC-Na)、加药AR-C17组(APP/PS1+AR-C17)，每组12只，给药剂量浓度为150mg/kg/天。另外设置12只非转基因型小鼠为背景组(C57BL/6J)，每天给予等量CMC-NA(0.5％)作为对照。持续5个月每日灌胃给药。
实施例2 水迷宫实验
采取国际公认的动物行为学检测方法：Morris水迷宫实验，对小鼠的空间记忆能力、新记忆形成能力、认知能力进行表观测评，通过测评结果决定继续给药或者处死。于处死前1周进行了Morris水迷宫试验。Morris水迷宫是一个直径120cm×50cm高的圆形水箱，装满水(22±1℃)，在第三象限配备一个直径10cm的平台，淹没在水面以下0.5cm处。在5天的试验中，隐藏的平台被固定在同一个地方。在最后一次探针测试前4天，每只老鼠被允许在120s内自由搜索隐藏在水面下的平台，120s内找不到隐藏平台的老鼠，将被引导到平台上，停留20秒以记住空间位置。在第5天进行最后一次探针测试，移除隐藏的平台，每只小鼠自由寻找120秒。自动记录并收集所有数据，如游泳轨迹、目标象限穿越次数，第一次到达目标区域所用时间等等，并用SPSS软件进行统计分析。
结果表明，对比WT组，APP/PS1转基因小鼠轨迹明显杂乱无序，逃逸时间及第一次到达目标区域所用时间明显延长，穿越目标象限次数明显下降；药物(AR-C17)干预APP/PS1小鼠5个月能明显提升小鼠空间记忆能力和认知能力。
实施例3 脑组织病理改变
行为试验后2天，每组选取4只小鼠(n＝4)腹腔注射戊巴比妥钠(50mg/kg)，然后用生理盐水、4％多聚甲醛溶液经心脏灌注，固定10min左右以后，取完整大脑浸泡于4％多聚甲醛2h，2h后将脑浸泡于蔗糖溶液中脱水，放入4℃冰箱保存，直至切片。
Iba1/Nissl双染实验：取冰冻脑组织切片，用封闭液(3％驴血清，10％Triton溶于0.1M PBS)封闭30min，4℃一抗(anti-Iba1)孵育过夜。在PBS缓冲液中清洗3遍后，大脑切片置于含有目标不同激发波长二抗(DyLight 594 for Iba-1，DyLight 500/525 for Nissl)的二抗中，于黑暗中孵育1.5h。然后在PBS缓冲液中清洗3遍，封片，封好的切片使用Olympus FV1200 共聚焦显微镜成像。
Aβ/GFAP/Nissl三染实验：取冰冻脑组织切片，用封闭液(3％驴血清，10％Triton溶于0.1M PBS)封闭30min，4℃一抗(anti-Aβ，anti-GFAP)孵育过夜。在PBS缓冲液中清洗3遍后，大脑切片置于含有目标不同激发波长二抗(DyLight 488 for Aβ，DyLight 594 for GFAP；DyLight 435/455 for Nissl)的二抗中，于黑暗中孵育1.5h。然后在PBS缓冲液中清洗3遍，封片，封好的切片使用Olympus FV1200共聚焦显微镜成像。
Aβ/GFAP/Nissl三染荧光图表明，空白的APP/PS1组小鼠脑内出现Aβ斑块和星形胶质细胞聚集，而非转基因小鼠(C57 BL/6J)和灌胃AR-17的APP/PS1小鼠脑内则没有或显著较少，由此证明AR能减少Aβ斑块在脑内聚集，从而延缓AD发生，起到保护作用。同时，Iba1/Nissl双染荧光图表明，空白的APP/PS1组小鼠脑内明显出现小胶质细胞聚集，而非转基因小鼠(C57 BL/6J)和灌胃AR-C17的APP/PS1小鼠脑内则没有或显著减少，由此证明AR-C17可以减少小胶质细胞活化聚集，从而延缓AD发生，起到保护作用。
实施例4 脑组织关键效应蛋白变化
除去灌流的小鼠，其余小鼠断头处死，分离大脑皮层和海马于-80℃保存，用于做生化指标分析。通过蛋白免疫印迹法，对病理相关的蛋白、神经健康相关因子进行分析，研究AR在生化机制方面是具体如何改善AD病理改变的。
采用Western-blot蛋白印迹方法对相关表型蛋白进行定量分析，具体操作步骤如下：用RIPA法制备组织裂解液，用BCA法测定总蛋白。采用12％分离胶进行凝胶电泳后，将分离蛋白质转移到PVDF膜上，经过洗膜和脱脂奶粉抗原封闭后，在4℃过夜孵育要检测的抗体。然后用TBST洗涤膜5分钟，然后与山羊抗兔IgG H&L(HRP)在室温下孵育1小时。再用TBST洗涤印迹5分钟，最后使用化学发光试剂在凝胶成像仪上进行检测。
实验结果表明：APP/PS1组小鼠脑内β-淀粉样蛋白大量聚集与Tau蛋白的过度磷酸化，而野生型(WT)和AR-C17干预的APP/PS1小鼠脑内则没有或显著减少。所以AR-C17显著降低小鼠大脑内β-淀粉样蛋白及Tau蛋白的表达，从而延缓AD发生，起到保护作用。另外，APP/PS1模型鼠的ADAM10及突触体素的表达显著降低，AR-C17干预能显著提升，有效预防AD的发生和发展。图4、5中显示，相对于野生型小鼠WT组，AD组小鼠大脑及皮层区域小胶质细胞特异性蛋白Iba-1、胶质纤维酸性蛋白GFAP、炎症小体及其下游蛋白被显著激活，炎症因子表达显著增加，但是AR-C17干预后能够显著减少AD组大脑海马区及皮层炎症表达，有效缓解神经炎症，减缓阿尔茨海默症的发生、发展。
实施例5 AR-C17激活SIRT3/SOD2信号通路
通过蛋白免疫印迹法，对通路相关蛋白等进行分析。Sirt3是线粒体中的一个重要的去乙酰化修饰酶，能够调控线粒体中许多代谢酶的活性，进而调控细胞线粒体的代谢，Sirt3的活化与抗氧化、抗衰老、抗肿瘤和提高免疫力等密切相关。采用Western-blot蛋白印迹方法对相关表型蛋白进行定量分析，用RIPA法制备组织裂解液，用BCA法测定总蛋白。采用12％分离胶进行凝胶电泳后，将分离蛋白质转移到PVDF膜上，经过洗膜和脱脂奶粉抗原封闭后，在4℃过夜孵育要检测的抗体。然后用TBST洗涤膜5分钟，然后与山羊抗兔IgG H&L(HRP)在室温下孵育1小时。再用TBST洗涤印迹5分钟，最后使用化学发光试剂在凝胶成像仪上进行检测。
如图5所示，AR-C17能够激活SIRT3信号通路及其下游效应因子SOD2。大脑皮层及海马组织中，AD组相对于WT组，SIRT3/SOD2信号通路表达显著降低，AR-C17干预后，该信号通路得到显著提高。
实施例6 肠道菌群丰度实验
小鼠处理手法：全部小鼠于行为学实验前一天分别收集粪便，粪便冻存于-80℃冰箱中，直至肠道菌的检测。每组的粪便样本进行微生物区系分析。提取冷冻粪便样本总DNA，检测分离的DNA浓度。对16S rRNA的V3-V4区域进行PCR扩增、纯化，利用QIIME软件包、Illumina MiSeq平台进行测序，进行生物信息学分析。
图6显示，APP/PS1模型鼠相对于背景组菌群丰度显著降低，特别是Akkermansia(嗜粘蛋白-艾克曼菌)和Lactobacillus(乳酸杆菌)。这两种菌在临床及不同实验动物中均证实对AD有保护效果。AR-C17干预组能够显著提升AD模型鼠的菌群丰度，特别提升前述两种有益菌的丰度。
以上所述仅为本发明的较佳实施例而已，并不用以限制本发明，凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。

Claims (5)

  1. 烷基间苯二酚类化合物在制备预防或治疗阿兹海默症的药物的应用，其特征在于，所述烷基间苯二酚类化合物如下通式(I)所示，
    Figure PCTCN2020082025-appb-100001
    式中，R1为C5-C50直链或支链烷基中的任一种。
  2. 根据权利要求1所述的应用，其特征在于，所述药物可以制备成片剂、粉剂、糊剂、水剂、针剂和输液剂中的任一种。
  3. 根据权利要求1所述的应用，其特征在于，所述药物的用量为150mg/kg/天。
  4. 根据权利要求1所述的应用，其特征在于，烷基间苯二酚类化合物制备预防或治疗阿兹海默症的药物是通过改变脑内多种致病相关蛋白、通路蛋白的表达以及调节菌群组成和特征菌群丰度实现的。
  5. 根据权利要求1所述的应用，其特征在于，烷基间苯二酚类化合物制备预防或治疗阿兹海默症的药物是通过减少Aβ斑块在脑内聚集、减少小胶质细胞活化聚集及炎症表达、降低小鼠大脑内β-淀粉样蛋白及Tau蛋白的表达、显著降低ADAM10及突触体素的表达、激活SIRT3信号通路及其下游效应因子SOD2、提升对阿尔茨海默症有保护作用的菌群丰度实现的。
PCT/CN2020/082025 2020-02-07 2020-03-30 烷基间苯二酚类化合物在制备预防或治疗阿兹海默症的药物的应用 WO2021155633A1 (zh)

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