WO2022121986A1 - 一种防治神经退行性疾病的新型药物 - Google Patents

一种防治神经退行性疾病的新型药物 Download PDF

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WO2022121986A1
WO2022121986A1 PCT/CN2021/136809 CN2021136809W WO2022121986A1 WO 2022121986 A1 WO2022121986 A1 WO 2022121986A1 CN 2021136809 W CN2021136809 W CN 2021136809W WO 2022121986 A1 WO2022121986 A1 WO 2022121986A1
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cordyceps sinensis
application
extract
extraction
disease
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舒友生
伍贤进
米真
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湖南翱康生物科技有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/49—Fagaceae (Beech family), e.g. oak or chestnut
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • 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
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
    • A61K2236/30—Extraction of the material
    • A61K2236/33—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones
    • A61K2236/333—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones using mixed solvents, e.g. 70% EtOH
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines

Definitions

  • the invention relates to the field of molecular biology, in particular to the use of a plant extract in preventing and treating senile dementia.
  • AD Alzheimer's disease
  • AD Alzheimer's disease
  • the literature shows that in 2010, the prevalence of AD was 2.6% (0.0–28.2%) in the Chinese population aged 65 to 69, and the prevalence in the population aged 95 to 99 was 60.5%. (39.7-81.3%), the estimated number of AD patients in China in 2010 was 5.69 million (3.85-7.53 million), and the median standardized death ratio for AD was 1.94:1 (interquartile range 1.74-2.45).
  • AD is expected to be a persistent and significant public health problem in the coming decades due to its increasing prevalence, long duration, and high cost of care and treatment.
  • amyloid hypothesis which holds that the accumulation of Amyloid ⁇ (A ⁇ ) peptide in brain tissue is the main driver of AD: the hallmark pathological feature of AD is extracellular amyloid.
  • plaques senile plaques
  • amyloid plaques are mainly composed of A ⁇ peptides.
  • soluble oligomers of A ⁇ peptides are neurotoxic and are considered to be pathogenic factors for AD.
  • the accumulation and accumulation of A ⁇ in the brain triggers a cascade of pathophysiological events, including synaptic dysfunction, formation of neurofibrillary tangles, neuronal loss, neurotransmitter deficiency, and dementia.
  • AD Alzheimer's disease
  • the approved drugs are: 1) donepezil, which inhibits acetylcholinease activity in the brain galantamine and rivastigmine 2) Memantine against N-methyl D-aspartate receptors Wait. Although these drugs can temporarily relieve or improve the cognitive and mental symptoms of patients, they cannot prevent or reverse the progression of the disease, and the efficacy is also unsatisfactory.
  • Lithocarpus litseifolius also known as Lithocarpus polystachyrus Rehd or Lithocarpus polystachyaw (wall.) Rehd, alias Xupu Yaocha, sweet tea, sweet leaf tree, Fat thick, sweet tea, big leaf thick seed, glycoside tea, etc., are evergreen trees of the Fagaceae family. It is distributed in the wild state in the low mountains and dense forests of 500 meters to 2500 meters above sea level in the provinces south of the Yangtze River in my country, especially in Jiangxi, Guangxi, Hunan, Anhui and other provinces rich in resources.
  • Cordyceps sinensis The chemical constituents of Cordyceps sinensis are mainly flavonoids and triterpenes, of which dihydrochalcone is the main source of its sweet taste.
  • dihydrochalcone the main source of its sweet taste.
  • Preliminary modern research shows that Cordyceps sinensis has a wide range of biological activities, such as hypoglycemic, antioxidant , anti-allergic and anti-microbial, and safe and non-toxic.
  • the present invention aims to solve the problem whether the extract of Cordyceps sinensis can be used to prevent and treat senile dementia, and to prevent or reverse the progression of the disease from the pathological etiology.
  • Ovarianum officinalis can significantly improve the systemic inflammatory symptoms of Alzheimer's disease model animals, can effectively improve the deposition of senile plaques in the hippocampus of the brain, and effectively inhibit the mammalian target of rapamycin complex (mammalian target of rapamycin).
  • microtubule-associated protein 1A/1B light chain type 3I microtubule-associated protein 1A/1B-light chain 3I, LC 3I, LC 3I
  • LC 3II complex 1, mTORC1 pathway
  • the invention discloses the application of Cordyceps sinensis or a composition comprising Cordyceps sinensis extracts in the preparation of medicines or health care products for preventing or treating neurodegenerative diseases such as senile dementia.
  • the present invention discloses a kind of Mu Jiang Ye Ke, which is used for preventing or treating neurodegenerative diseases such as senile dementia.
  • the present invention discloses a method of preventing or treating neurodegenerative diseases such as senile dementia, wherein by administering to a subject in need an effective dose of A.
  • the Cordyceps sinensis comprises a Cordyceps sinensis extract, or an extract of Cordyceps sinensis.
  • the preparation method of the extract of Cordyceps sinensis is as follows: extracting Cordyceps sinensis to obtain the crude extract of Cordyceps sinensis; optionally, separation and purification to obtain the extract of Cordyceps sinensis.
  • the method for extracting Cordyceps sinensis includes one or any combination of ultrasonic extraction, enzyme extraction, microwave-assisted extraction, solvent extraction, membrane separation such as ultrafiltration and supercritical fluid extraction.
  • the method for extracting Cordyceps sinensis comprises a solvent extraction method, and the solvent is selected from one of inorganic solvents and organic solvents or a combination of any proportion, wherein the inorganic solvent is selected from the one in water, acid and alkali Or any combination, the organic solvent is selected from one or any combination of methanol, ethanol, ether, chloroform, acetone, ethyl acetate and petroleum ether.
  • the method for extracting Cordyceps sinensis further comprises ultrasonic-assisted extraction.
  • the method of purification includes column chromatography such as silica gel column chromatography, polyamide column chromatography, Sephadex column chromatography, recrystallization, thin layer chromatography, resin chromatography, high performance liquid chromatography, high performance Countercurrent chromatography, aqueous two-phase extraction, membrane separation, pH gradient extraction, preferably, the purification method can be selected from the use of resin purification.
  • column chromatography such as silica gel column chromatography, polyamide column chromatography, Sephadex column chromatography, recrystallization, thin layer chromatography, resin chromatography, high performance liquid chromatography, high performance Countercurrent chromatography, aqueous two-phase extraction, membrane separation, pH gradient extraction, preferably, the purification method can be selected from the use of resin purification.
  • the preparation method of the extract of Cordyceps sinensis is as follows: using ethanol to soak the leaves of Cordyceps sinensis, using ultrasonic-assisted extraction, the ethanol solution after the extraction is evaporated under reduced pressure with a rotary evaporator to obtain the leaves of Cordyceps sinensis. Extract; Extract of Cordyceps sinensis was purified using resin.
  • the extract of Cordyceps sinensis includes Cordoflavones.
  • the extract of Ginger is not limited to the above specific extraction methods, as long as the extracts with the following biological activities are within the scope of the present invention, and the biological functions include at least the following A sort of:
  • the dried leaves of Cordyceps sinensis to constant weight are pulverized, passed through a 40-100 mesh sieve such as a 60 mesh sieve, and soaked with 50% to 95% such as 70% ethanol, for example, 12-36 hours, such as 24 hours, and then optionally an ultrasonic-assisted extraction method is used to extract keroflavones.
  • a 40-100 mesh sieve such as a 60 mesh sieve
  • 50% to 95% such as 70% ethanol
  • 12-36 hours such as 24 hours
  • an ultrasonic-assisted extraction method is used to extract keroflavones.
  • the crushed leaves are sieved through 40, 50, 60, 70, 80, 90, or 100 mesh
  • the ethanol concentration of soaking crushed leaves is preferably 50% to 95%, such as 50%, 60%, 70%, 80%, 90%, 95%
  • the soaking time is preferably 12, 16, 20, 24, 28, 32, or 36 hours.
  • the ethanol concentration of the soaked and pulverized leaves is 70%, and the solid-liquid weight ratio of the pulverized leaves and ethanol is 1:20-1:50, such as 1:20, 1:25, 1:30, 1:30, and 1:50. 35, 1:40, 1:45, 1:50, preferably 1:35; the ultrasonic power of the ultrasonic-assisted extraction is 540W, and the ultrasonic extraction is performed for 10-30 minutes, preferably 15 minutes.
  • the extracted ethanol was evaporated under reduced pressure by using a rotary evaporator to obtain coflavonoids from Cordyceps sinensis.
  • Curcumin is purified by AB-8 resin, and the process conditions are as follows: the adsorption flow rate is 0.2-1.0 mL/min, preferably 0.5 mL/min; the concentration of elution ethanol is 30% to 90% such as 90%, and the elution volume is 1.0 -3.0 BV, preferably 1.875 BV (bed volume), eluent flow rate of 0.5-2.0 mL/min, preferably 1 mL/min.
  • the senile dementia is Alzheimer's disease.
  • the dosage form of any of the aforementioned medicines includes, but is not limited to, at least one of the following groups: pills, powders, granules, tablets, decoctions, patches, drop pills, capsules, syrups, mixtures, wines, Tincture, tea, liniment, lotion, film coating, plaster, aerosol, spray, injection, lotion, etc.
  • the medicine also includes a pharmaceutically acceptable carrier or adjuvant
  • the adjuvant includes but is not limited to at least one of the following groups: starch, dextrin, lactose, microcrystalline cellulose, hydroxypropyl methylcellulose, Polyethylene glycol, magnesium stearate, micropowder silica gel, xylitol, lactitol, glucose, glycine, mannitol, glycine, etc.
  • Any of the aforementioned health care products include at least one of tablets, capsules, oral liquids, liquid beverages, health-care teas, and food additives.
  • described Cordyceps sinensis can have more than one of the following biological functions:
  • the beneficial effect of the present invention is that the present invention discloses for the first time the use of the extract of Cordyceps sinensis in the preparation of medicines and health care products for treating Alzheimer's disease.
  • Relevant pharmacological experiments were used to evaluate the pharmacodynamics of the extracts of Cortex chinensis in the prevention and treatment of Alzheimer's disease, which clarified the effects of improving systemic inflammatory symptoms, inhibiting the deposition of A ⁇ , promoting autophagy, and helping repairing cell damage.
  • Fig. 1 shows the effect of the extract of A. chinensis on senile plaques (SP) in the cortex and hippocampus of APP/PS1 double transgenic mice.
  • Fig. 2 shows the effect of the extract of Cordyceps sinensis on inflammatory factors in the serum of APP/PS1 double transgenic mice.
  • Figure 3 shows the inhibitory effect of M. chinensis extract on mTORC1.
  • Figure 4 shows that the extract of Cordyceps sinensis can promote autophagy.
  • Fig. 5 shows that Coleus chinensis extract can maintain the survival of immune cells and promote DNA damage repair.
  • senile dementia and “senile dementia” are used interchangeably and refer to a progressive neurodegenerative disease. Clinically, the symptoms are represented by memory impairment, aphasia, apraxia, agnosia, visual-spatial skills impairment, executive dysfunction, and personality and behavioral changes. Senile dementia includes Alzheimer's disease, vascular dementia (also known as the elderly). One or more of vascular dementia), Alzheimer's disease and vascular dementia coexist with mixed dementia.
  • the Alzheimer's disease pathogenic mechanism hypothesis is the amyloid hypothesis, which proposes that the accumulation of Amyloid ⁇ (A ⁇ ) peptide in brain tissue is a major driver of AD: the hallmark pathological feature of AD is extracellular amyloid plaques (senile plaques) deposits in the brain, these amyloid plaques are mainly composed of A ⁇ peptides.
  • a ⁇ Amyloid ⁇
  • vascular dementia the pathogenic mechanism is mainly because the lesions of blood vessels block blood flow, and brain cells cannot receive sufficient oxygen and nutrients, which will lead to the death of brain cells and impaired cognitive function, resulting in symptoms of dementia. Studies have shown that in the process of vascular dementia, neuroinflammation plays an important role.
  • Fibrinogen activates CD11b and Toll-like receptors, leading to the production of reactive oxygen species, production of pro-inflammatory cytokines, and activation of microglia, astrocytes, etc.
  • Inflammation in turn, exacerbates the breakdown of the blood-brain barrier and induces the expression of endothelial cell adhesion molecules, leading to leukocyte and platelet adhesion and microvascular occlusion, thereby aggravating the symptoms of vascular dementia.
  • the term “Mujiang Yeke” scientific name is Lithocarpus litseifolius (Hance) Chun, also known as “Xupu Yaocha” or “Multisui Shike”, “Multisui Ke” (Latin name Lithocarpus polystachyus (Wall. ) or “Lithocarpus polystachyaw (wall.) Rehd” Rehd., ), refers to the Fagaceae family plants, alias sweet tea, sweet leaf tree, fat thick, sweet tea, big leaf thick seed, glycoside tea, multi-sui Ke Etc., Fagaceae Fagaceae is an evergreen tree.
  • M. chinensis extract refers to active substances such as flavonoids obtained by extraction from M. chinensis.
  • the extract of Cordyceps sinensis can have the function of preventing and treating neurodegenerative diseases such as senile dementia.
  • Embodiment 1 the extraction method of Alpinia officinalis extract (ONC008)
  • the leaves of Cordyceps chinensis powder are sifted through a 60-mesh copper sieve and soaked in 70% ethanol for 24 hours, and then an ultrasonic-assisted extraction method is used to extract Corydalis quinquefolium.
  • the specific parameters are: ethanol concentration 70%, solid-liquid ratio 1:35, Ultrasonic power was 540W, ultrasonic extraction was performed for 15 minutes, and finally, the extracted ethanol was evaporated under reduced pressure with a rotary evaporator to obtain keroflavones.
  • Curcumin is purified with AB-8 resin, and the process conditions are: the adsorption flow rate is 0.5mL/min, the elution ethanol concentration is 90%, the elution volume is 1.875BV (bed volume), and the eluent flow rate is 1mL/min.
  • Example 2 In vivo studies demonstrate that ONC008 has a therapeutic effect on APP/PS1 double transgenic dementia mice
  • APP/PS1 double-transgenic mice Eight 2-month-old APP/PS1 double-transgenic mice, male, weighing 25 ⁇ 2g, SPF grade. APP/PS1 double-transgenic mice can well simulate the pathological changes of AD, and are currently internationally recognized AD transgenic animal models, so they are widely used in AD-related research.
  • TNF- ⁇ antibody Tumor necrosis factor alpha, referred to as TNF- ⁇
  • TNF- ⁇ antibody tumor necrosis factor alpha
  • IL-1 ⁇ Interleukin 1 beta antibody
  • sc-32294 Santa Cruz Biotechnology
  • IL-6 interleukin 6 antibody
  • a ⁇ antibody 6E10, Biolegend
  • APP/PS1 double transgenic mice were randomly divided into control group and ONC008 administration group, with 4 mice in each group.
  • the model group was given ONC008 at 400 mg/kg per day, and the control group was given an equal volume of distilled water.
  • Mice in each group were administered for 8 months, and were sacrificed to extract tissue samples when they were 10 months old.
  • Plasma samples Blood and brain tissue were extracted. Serum was extracted from blood and the cytokines TNF- ⁇ , IL-1 ⁇ and IL-6 were detected. One cerebral hemisphere was used to extract protein samples, and the other hemisphere was fixed with paraformaldehyde and frozen section and immunohistochemically stained.
  • the obtained data were expressed as mean ⁇ standard deviation, and statistical software SigmaPlot12.5 was used for statistical analysis. Student's t test was used to compare data between groups, and P ⁇ 0.05 was considered significant for differences.
  • the wakefulness enhancer Modafinil is widely used as a cognitive enhancer.
  • modafinil did not improve the symptoms of Alzheimer's patients in clinical tests (see Rea R, et al. Apathy in Alzheimer's disease: any effective treatment. Scientific World Journal, 2014:421385).
  • the present invention is the first time to reveal that the sweet tea extract can prevent or reverse the progression of the disease, and has a definite curative effect.
  • Example 3 In vitro studies demonstrate that ONC008 can activate autophagy to promote the elimination of cellular metabolic wastes.
  • the human epithelial cell line MCF-10A was treated with 1 mg/mL ONC008, 100 nM rapamycin, 10 nM mTOR kinase inhibitor Torin1, or DMSO as controls, respectively. After MCF-10A was treated for 5 or 12 hours, the total cell protein was extracted and detected by immunoblotting for pS6 (phosphorylation site S235/6), pS6K1 (phosphorylation site T389) and pAKT (phosphorylation site S473), respectively. ), or the autophagy marker molecule LC3, with GAPDH as the loading control.
  • rapamycin inhibits pS6 and pS6K1/2, but activates Akt, which proves that rapamycin inhibits mTORC1 and activates the S6K1/2-IRS-PI3K negative feedback pathway.
  • the mTOR kinase inhibitor Torin1 inhibits pS6, pS6K1/2 and pAKT, demonstrating that Torin1 inhibits both mTORC1 and mTORC2.
  • ONC008 reduced pS6 and pS6K1/2, but did not alter pAKT, demonstrating that ONC008 inhibited mTORC1 and S6K1/2.
  • ONC008 can convert LC3I to LC3II, indicating that ONC008 can promote autophagy.
  • Hematopoietic stem/progenitor cells were purified and cultured from human umbilical cord blood cells by magnetic sorting using CD34 sorting magnetic beads, and treated with 4 ⁇ g/mLONC008 or control pure water for 72 hours, respectively.
  • Total cell protein was extracted and detected by immunoblotting in which p-NF ⁇ B-65, LC3, cleaved caspase 3, ribonucleotide reductase subunits 1 and 2 (RRM1 and RRM2), p-S6K1, pS6, and ⁇ H2AX were loaded with GAPDH control.
  • ONC008 can promote the conversion of LC3I to LC3II and reduce the caspase 3 cleaved by apoptosis marker molecules, suggesting that ONC008 can enhance immunity by maintaining the survival of immune cells.
  • ONC008 increased the expression of RRM1 and RRM2, which play an important role in DNA repair, suggesting that ONC008 can promote DNA damage repair, thereby improving cell survival.

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Abstract

本发明提供了木姜叶柯在制备预防或治疗神经退行性疾病例如阿尔茨海默病或血管性痴呆药物或保健品中的应用。其中，所述木姜叶柯能够1)抑制皮层和海马中老年斑(Senile Plaques,简称SP)沉积；和2)抑制血清内炎症因子表达。

Description

一种防治神经退行性疾病的新型药物 技术领域
本发明涉及分子生物学领域，具体涉及一种植物提取物在防治老年性痴呆中的用途。
背景技术
阿尔茨海默症(Alzheimer's disease，简称AD)是一种进展性和致命性的神经退行性疾病，主要表现为认知功能下降及日常生活能力逐渐下降，是老年性痴呆最常见的病因，全世界约有4680万患者。迄今虽无中国范围的AD流行病学现况数据；但文献显示2010年中国65至69岁人群的AD现患率为2.6％(0.0–28.2％)、95至99岁人群的现患率为60.5％(39.7-81.3％)，2010年中国AD患者数估计为569万人(385-753万)，AD的标准化死亡比中位数为1.94:1(四分位间距1.74-2.45)。由于AD的患病率不断升高、持续时间较长、护理治疗费用较高等特性，预期AD在未来数十年内将为一个持续的重大的公共卫生问题。
目前最有影响力的AD致病机制假说是淀粉样蛋白假说，该假说认为Amyloidβ(简称Aβ)肽在脑组织中的蓄积是AD的主要驱动因素：AD的标志性病理学特征是细胞外淀粉样斑块(老年斑)在脑内的沉积，这些淀粉样斑块主要由Aβ肽组成。体内、外证据均提示，Aβ肽的可溶性寡聚体具有神经毒性，被认为是AD的致病因素。Aβ在脑内的蓄积和积聚会激发病理生理学事件的级联效应，包括突触功能障碍、形成神经原纤维缠结、神经元丢失、神经递质缺乏和痴呆等。另外，大量神经病理学、临床流行病学及动物模型等研究证实神经炎症是AD重要的神经生物特征，因此神经炎症也是AD治疗药物研究的重要靶点之一。其次，新的研究认为自噬的缺陷也可能会导致包括阿尔茨海默氏病在内的许多神经退行性疾病。
对于确诊的AD痴呆，已批准药物有：1)抑制脑内的乙酰胆碱酶活性的donepezil
Figure PCTCN2021136809-appb-000001
galantamine
Figure PCTCN2021136809-appb-000002
以及rivastigmine
Figure PCTCN2021136809-appb-000003
2)抗N甲基D天冬氨酸受体的memantine
Figure PCTCN2021136809-appb-000004
等。这些药物虽可以暂时缓解或改善患者的认知和精神症状等，但均无法阻止或逆转病情进展，疗效也差强人意。
木姜叶柯(学名：Lithocarpus litseifolius(Hance)Chun)，也称为多穗柯或多穗石柯(Lithocarpus polystachyrus Rehd或Lithocarpus polystachyaw(wall.)Rehd)，别名溆浦瑶茶、甜茶、甜叶子树、胖稠、甜味茶、大叶稠子、苷茶等，系壳斗科石柯属常绿乔木。以野生状态分布于我国长江以南各省区海拔500米至2500米以上的低山密林中，尤以江西、广西、湖南、安徽等省资源丰富。木姜叶柯的化学成分主要为黄酮类和三萜类，其中二氢查尔酮类是其甜味的主要来源，现代研究初步表表明，木姜叶柯具有较广的生物活性，如降血糖、抗氧化、抗过敏和抗微生物，且安全无毒。
因此，研究与开发防治老年痴呆天然安全的药物或保健食品成为当今重要的研究课题。木姜叶柯的提取物是否可以用于防治老年性痴呆，从病理病因上阻止或逆转病情进展，本发明旨在解决该问题。
发明内容
本发明人的研究发现木姜叶柯能明显改善阿尔茨海默症模型动物全身炎症症状，可以有效改善大脑海马区老年斑的沉积，并高效抑制哺乳动物雷帕霉素靶蛋白复合体(mammalian target of rapamycin complex 1，mTORC1)通路，促进自噬标志分子微管结合蛋白1A/1B轻链3I型(microtubule-associated protein 1A/1B-light chain 3I，LC 3I)到LC 3II转化，从而大大强化细胞清理代谢废物机能，使得细胞获得“再生”，对包括阿尔茨海默症为主的老年性痴呆症均有确切的疗效。
本发明公开了木姜叶柯或包含木姜叶柯提取物的组合物在制备预防或治疗神经退行性疾病诸如老年性痴呆的药物或保健品中的应用。
本发明公开了一种木姜叶柯，其用于预防或治疗神经退行性疾病诸如老年性痴呆。
本发明公开了一种预防或治疗神经退行性疾病诸如老年性痴呆的方法，其中通过向所需的受试者施用有效剂量的木姜叶柯。
在一个实施例中，木姜叶柯包括一种木姜叶柯提取物，或为木姜叶柯提取物。
在一个实施例中，所述木姜叶柯的提取物的制备方法为：提取木姜叶柯，得到木姜叶柯的提取物粗品；可选择地，分离纯化，得到木姜叶柯的提取物。
其中，提取木姜叶柯的方法包括超声波提取法、酶提取法、微波辅助提取法、溶剂提取法、膜分离法诸如超过滤法、超临界流体萃取法中的一种或任意组合。
在一个具体实施例中，提取木姜叶柯的方法包括溶剂提取法，所述溶剂选自无机溶剂和有机溶剂的一种或任意比例的组合，其中无机溶剂选自水、酸和碱中的一种或任意组合，有机溶剂选甲醇、乙醇、乙醚、氯仿、丙酮、乙酸乙酯和石油醚的一种或任意组合。优选地，提取木姜叶柯的方法进一步包括超声波辅助提取。
在一个具体实施例中，纯化的方法包括柱色谱法诸如硅胶柱色谱、聚酰胺柱色谱、葡聚糖凝胶柱色谱、重结晶法、薄层色谱法、树脂色谱、高效液相色谱、高效逆流色谱、双水相萃取、膜分离、pH梯度萃取法，优选地，所述纯化方法可以选自使用树脂纯化。
在一个具体实施例中，所述木姜叶柯的提取物的制备方法为：使用乙醇浸泡木姜叶柯的叶子，采用超声波辅助提取，提取后的乙醇溶液用旋转蒸发器减压蒸发乙醇，得到木姜叶柯的提取物；使用树脂纯化木姜叶柯的提取物。所述木姜叶柯的提取物包括木姜叶柯黄酮。本领域技术人员应理解，姜叶柯的提取物并不限于以上的具体提取方法获得，只要是具备了以下生物学活性的提取物应均在本发明的范围中，所述生物学功能包括以下的至少一种：
1)抑制皮层和海马中老年斑(Senile Plaques,简称SP)沉积；
2)抑制血清内炎症因子表达；
3)抑制mTORC1的激活；
4)促进细胞自噬；
5)维持免疫细胞的存活和促进DNA损伤修复。
在一个具体实施例中，所述木姜叶柯的干燥至恒重的叶经过粉粹，过40-100目筛诸如60目筛后，用50％至95％诸如70％乙醇浸泡，例如12-36小时，诸如24小时，然后可选择地采用超声波辅助提取方法提取木姜叶柯黄酮。其中，优选地，粉碎的叶子过40、50、60、70、80、90、或100目筛；浸泡粉碎叶的乙醇浓度优选为50％至95％，例如50％、60％、70％、80％、90％、95％；浸泡的时间优选12、16、20、24、28、32、或36小时。
在一个具体实施例中，浸泡粉碎的叶的乙醇浓度70％、粉碎的叶和乙醇的固液重量比1:20-1:50，例如1:20、1:25、1:30、1:35、1:40、1:45、1:50，优选为1:35；超声波辅助提取的超声功率540W，超声提取10-30分钟，优选为15分钟。
使用旋转蒸发器减压蒸发提取后的乙醇，得到木姜叶柯黄酮。木姜叶柯黄酮用AB-8树脂纯化，工艺条件为：吸附流速为0.2-1.0mL/分钟，优选为0.5mL/分钟；洗脱乙醇浓度为30％至90％诸如90％，洗脱体积为1.0-3.0BV，优选为1.875BV(床体积)，洗脱剂流速为0.5-2.0mL/分钟，优选为1mL/分钟。
如前述的神经退行性疾病选自阿尔茨海默病、血管性痴呆、和阿尔茨海默病和血管性痴呆并存的混合性痴呆中的至少一种。
优选地，老年性痴呆为阿尔茨海默病。
如前任意所述药品的剂型包括但不限于以下组中的至少一种：丸剂、散剂、颗粒剂、片剂、煎膏剂、贴膏剂、滴丸剂、胶囊剂、糖浆剂、合剂、酒剂、酊剂、茶剂、搽剂、洗剂、涂膜剂、膏药、气雾剂、喷雾剂、注射剂、露剂等。
其中，所述药品还包括药学上可接受的载体或辅料，所述辅料包括但不限于以下组中的至少一种：淀粉、糊精、乳糖、微晶纤维素、羟丙甲基纤维素、聚乙二醇、硬脂酸镁、微粉硅胶、木糖醇、乳糖醇、葡萄糖、甘氨酸、甘露醇、甘氨酸等。
如前任意所述保健品包括片剂、胶囊剂、口服液、液体饮料、保健茶、和食品添加剂中的至少一种。
在一个具体实施例中，所述木姜叶柯能够具有以下生物学功能的一种以上：
1)抑制皮层和海马中老年斑(Senile Plaques,简称SP)沉积；
2)抑制血清内炎症因子表达；
3)抑制mTORC1的激活；
4)促进细胞自噬；
5)维持免疫细胞的存活和促进DNA损伤修复。
发明有益效果
与现有技术相比，本发明的有益效果在于本发明首次公开木姜叶柯提取物在制备治疗阿尔茨海默症药物及保健品中的用途。采用相关药理学实验进行木姜叶柯提取物防治阿尔茨海默症的药效学评价，分别从改善全身炎症症状、抑制Aβ的沉积、促进细胞自噬，以及帮助细胞损伤修复等多方面，阐明该提取物多途径、多靶点治疗阿尔茨海默病的用途。因此，木姜叶柯提取物在治疗阿尔茨海默症中具有广泛的应用背景，可应用于制备抗阿尔茨海默症药物和保健品。
附图说明
图1示出木姜叶柯提取物对APP/PS1双转基因小鼠皮层和海马中老年斑(SP)的影响。
图2示出木姜叶柯提取物对APP/PS1双转基因小鼠血清内炎症因子的影响。
图3示出木姜叶柯提取物对mTORC1的抑制作用。
图4示出木姜叶柯提取物可以促进细胞自噬。
图5示出穗柯提取物可以维持免疫细胞的存活和促进DNA损伤修复。
具体实施方式
下面将通过具体描述，对本发明作进一步的说明。
除非另有限定，本文中所使用的所有技术和科学术语具有与本发明所属技术领域的普通技术人员通常理解相同的含义。
本申请中，单数形式“一个”、“该”包括复数对象，除非上下文另外清楚规定。
定义
如本文所用的术语“老年性痴呆”、“老年痴呆”可互换，是指一种进行性发展的神经系统退行性疾病。临床上以记忆障碍、失语、失用、失认、视空间技能损害、执行功能障碍以及人格和行为改变等为代表症状，老年性痴呆包括阿尔茨海默病、血管性痴呆(又称老年人血管性痴呆)、阿尔茨海默病和血管性痴呆并存的混合性痴呆等中的一种以上。阿尔茨海默病致病机制假说是淀粉样蛋白假说，该假说认为Amyloidβ(简称Aβ)肽在脑组织中的蓄积是AD的主要驱动因素：AD的标志性病理学特征是细胞外淀粉样斑块(老年斑)在脑内的沉积，这些淀粉样斑块主要由Aβ肽组成。血管性痴呆中，致病机理主要是由于血管的病变阻碍了血流，脑细胞无法得到充足的氧气与营 养，由此便会导致脑细胞的死亡与认知功能受损，出现痴呆的症状。研究证明，在血管性痴呆进程中，神经炎症反应的起着很重要的作用。脑细胞缺氧导致了内皮细胞功能障碍，从而增加了血脑屏障渗透性，这导致了包括纤维蛋白原在内的血浆蛋白的外渗进入大脑。纤维蛋白原激活了CD11b和Toll样受体，导致活性氧的产生，促炎细胞因子的产生，和小神经胶质细胞、星形胶质细胞等的活化。炎症反过来又加剧了血脑屏障的瓦解，并诱导内皮细胞粘附分子的表达，导致白细胞和血小板粘附和微血管闭塞，从而加重了血管性痴呆的症状。
如本文所用的术语“木姜叶柯”学名为Lithocarpus litseifolius(Hance)Chun，又称为“溆浦瑶茶”或“多穗石柯”、“多穗柯”(拉丁名为Lithocarpus polystachyus(Wall.)或“Lithocarpus polystachyaw(wall.)Rehd”Rehd.、)，是指壳斗科柯属植物，，别名甜茶、甜叶子树、胖稠、甜味茶、大叶稠子、苷茶、多穗柯等，系壳斗科石柯属常绿乔木。
如本文所用的术语“木姜叶柯提取物”是指从木姜叶柯中经过提取获得的活性物质诸如黄酮。其中木姜叶柯提取物可以具有防治神经退行性疾病诸如老年性痴呆的功能。
实施例
通过以下实施例进一步说明本发明。提供实施例仅用于说明目的，并且不应被解释为以任何方式限制本发明的范围或内容。
实施例1：木姜叶柯提取物(ONC008)的提取方法
将干燥至恒重的木姜叶柯叶粉粹过60目铜筛后用70％乙醇浸泡24小时,然后采用超声波辅助提取方法提取木姜叶柯黄酮，具体参数为：乙醇浓度70％、固液比1:35、超声功率540W、超声提取15分钟，最后用旋转蒸发器减压蒸发提取后的乙醇，得到木姜叶柯黄酮。木姜叶柯黄酮用AB-8树脂纯化，工艺条件为：吸附流速为0.5mL/分钟，洗脱乙醇浓度为90％，洗脱体积为1.875BV(床体积)，洗脱剂流速为1mL/分钟。
实施例2：在体研究证明ONC008对APP/PS1双转基因痴呆小鼠具有治疗作用
1材料
1.1实验动物
2月龄APP/PS1双转基因小鼠8只，雄性，体重25±2g，SPF级。APP/PS1双转基因小鼠能够很好地模拟AD的病理变化，是目前国际上公认的AD转基因动物模型，因此被广泛地应用于AD相关的研究。
1.2实验药物及试剂
通过实施例1制备得到的木姜叶柯提取物(编号为ONC008)的粉末，用温蒸馏水溶解；肿瘤坏死因子-α(Tumor necrosis factor alpha，简称TNF-α)抗体(#3707，Cell signaling Technology)、白细胞介素1族(Interleukin 1beta，简称IL-1β)抗体(sc-32294，Santa Cruz Biotechnology)、白细胞介素6族(IL-6)抗体(ab6672，Abcam)和Aβ抗体(6E10，Biolegend)。
1.3主要仪器
Nikon A1R共聚焦显微镜，NIS-Elements计算机彩色图像处理系统，徕卡冰冻组织切片机，Fuji图像分析系统。
2方法
2.1分组与给药
按体重一致原则，随机将APP/PS1双转基因小鼠分为对照组和ONC008给药组，每组4只。模型组给以每日400mg/kg的ONC008，对照组给以等体积蒸馏水。各组小鼠给药8个月，至10月龄时处死提取组织样品。
2.2组织样品处理
提取血液和脑组织。从血液中提取血清并检测其中的细胞因子TNF-α、IL-1β和IL-6。一个脑半球用于提取蛋白样本，对另一半球进行多聚甲醛固定及冰冻切片和免疫组化染色。
2.3统计学处理
所得数据以均数±标准差表示，采用统计软件SigmaPlot12.5进行统计分析，组间数据比较用学生t检验，以P＜0.05为差异有显著性意义。
3实验结果
尽管认知能力的减退包括记忆力障碍是阿尔茨海默症的临床表现之一，但这并不意味着能够改善记忆力的药物就能治疗阿尔茨海默症。例如，现有技术中的相反教导，觉醒促进剂莫达非尼(Modafinil)作为一种认知增强剂被广泛使用。但是莫达非尼在临床测试中并不能改善阿尔茨海默症病人的病症(参见Rea R，et al.Apathy in Alzheimer's disease:any effective treatment.Scientific World Journal,2014:421385)。然而，本发明是首次揭示了多穗柯 甜茶提取物可以阻止或逆转病情进展，具有确切的疗效。
3.1 ONC008对APP/PS1双转基因小鼠中老年斑的影响结果显示，与对照组比较，模型组小鼠皮层中老年斑数量和所占面积没有明显变化，模型组小鼠海马中老年斑数量没有明显变化，但所占脑区面积比显著减少，说明ONC008可减少APP/PS1双转基因小鼠海马中老年斑沉积(参见表1和图1)。
表1 ONC008对APP/PS1双转基因小鼠皮层和海马中老年斑(SP)的影响
Figure PCTCN2021136809-appb-000005
3.2 ONC008对APP/PS1双转基因小鼠血清内炎症因子的影响结果显示，与对照组比较，TNF-α、IL-1β、IL-6的蛋白表达水平，均显著性降低，证明ONC008具有抗炎症作用(参见图2)。
实施例3：体外研究证明ONC008可激活细胞自噬从而促进细胞代谢废物的排除。
1.实验方法
分别给人上皮细胞系MCF-10A以1mg/mL的ONC008、100nM雷帕霉素(rapamycin)、10nM mTOR激酶抑制剂Torin1、或DMSO作为对照。MCF-10A经过处理5或12小时后，提取细胞总蛋白并利用免疫印迹法分别检测其中pS6(磷酸化位点S235/6)、pS6K1(磷酸化位点T389)和pAKT(磷酸化位点S473)，或自噬标志分子LC3，其中以GAPDH为上样对照。
2.实验结果
2.1结果如图3所示雷帕霉素抑制了pS6和pS6K1/2，却激活了Akt，证明 雷帕霉素抑制了mTORC1，同时激活了S6K1/2-IRS-PI3K负反馈通路。mTOR激酶抑制剂Torin1抑制了pS6、pS6K1/2和pAKT，证明Torin1同时抑制了mTORC1和mTORC2。而ONC008减少了pS6和pS6K1/2，但是没有改变pAKT，证明ONC008抑制了mTORC1和S6K1/2。
2.2如图4结果显示ONC008可以将LC3I转换为LC3II，表明ONC008可以促进细胞自噬。
实施例4：ONC008可以维持免疫细胞的存活
1.实验方法
通过磁性分拣法用CD34分选磁珠从人类脐带血细胞中提纯造血干细胞/祖细胞并进行培养，并加入4μg/mLONC008或对照纯水分别处理72小时。提取细胞总蛋白并利用免疫印迹法检测其中p-NFκB-65、LC3、裂解的caspase 3、ribonucleotide reductase subunits 1和2(RRM1and RRM2)、p-S6K1、pS6、和γH2AX，其中以GAPDH为上样对照。
2.实验结果
2.1如图5左所示，ONC008可以促进LC3I转换为LC3II，并减少了细胞凋亡标志分子裂解的caspase 3，提示ONC008可以通过维持免疫细胞的存活来增强免疫力。
2.2如图5右所示，ONC008增加了在DNA修复过程中起到重要作用的RRM1和RRM2的表达，提示ONC008可以促进DNA损伤修复，从而提高细胞的存活率。
通过引用并入
本文引用的每个专利文献和科学文献的全部公开内容通过引用并入本文用于所有目的。
等效
本发明可以在不脱离其基本特征的情况下以其他具体形式实施。因此，前述实施例被认为是说明性的，而不是对本文所述的本发明的限制。本发明的范围由所附权利要求书而不是由前述说明书表示，并且意在将落入权利要求书的等同物的含义和范围内的所有改变包括在其中。

Claims (17)

  1. 木姜叶柯或包含木姜叶柯的组合物在制备预防或治疗神经退行性疾病的药物或保健品中的应用。
  2. 如权利要求1所述的应用，其中，木姜叶柯包括木姜叶柯的提取物。
  3. 如权利要求2所述的应用，其中，所述木姜叶柯的提取物的制备方法为：
    提取木姜叶柯，得到木姜叶柯的提取物粗品；可选择地，分离纯化，得到木姜叶柯的提取物。
  4. 如权利要求3所述的应用，其中，提取木姜叶柯的方法包括超声波提取法、酶提取法、微波辅助提取法、溶剂提取法、膜分离法诸如超过滤法、超临界流体萃取法中的一种或任意组合。
  5. 如权利要求3所述的应用，其中，提取木姜叶柯的方法包括溶剂提取法，所述溶剂选自无机溶剂和有机溶剂的一种或任意比例的组合，其中无机溶剂选自水、酸和碱中的一种或任意组合，有机溶剂选甲醇、乙醇、乙醚、氯仿、丙酮、乙酸乙酯和石油醚的一种或任意组合。
  6. 如权利要求5所述的应用，其中，提取木姜叶柯的方法进一步包括超声波辅助提取。
  7. 如权利要求5所述的应用，其中，提取木姜叶柯的方法进一步包括在提取后将溶剂蒸发，优选地，所述蒸发方法选自旋转蒸发器。
  8. 如权利要求3所述的应用，其中，纯化的方法包括柱色谱法诸如硅胶柱色谱、聚酰胺柱色谱、葡聚糖凝胶柱色谱、重结晶法、薄层色谱法、树脂色谱、高效液相色谱、高效逆流色谱、双水相萃取、膜分离、pH梯度萃取法，优选地，所述纯化方法可以选自使用树脂纯化。
  9. 如权利要求3所述的应用，其中，所述木姜叶柯的提取物包括木姜叶柯黄酮。
  10. 如权利要求5所述的应用，其中，所述浸泡木姜叶柯的溶剂为乙醇，其浓度为50％至95％，所述纯化步骤中洗脱液乙醇浓度为30％至90％。
  11. 如权利要求10所述的应用，其中所述浸泡木姜叶柯的乙醇浓度为70％，所述纯化步骤中洗脱液乙醇浓度为90％。
  12. 如权利要求1所述的应用，其中，所述神经退行性疾病选自阿尔茨海默病、血管性痴呆、和阿尔茨海默病和血管性痴呆并存的混合性痴呆中的 至少一种。
  13. 如权利要求12所述的应用，其中，神经退行性疾病为阿尔茨海默病。
  14. 如权利要求1至13任一项所述的应用，其中，所述药品的剂型选自丸剂、散剂、颗粒剂、片剂、煎膏剂、贴膏剂、滴丸剂、胶囊剂、糖浆剂、合剂、酒剂、酊剂、茶剂、搽剂、洗剂、涂膜剂、膏药、气雾剂、喷雾剂、注射剂、和露剂等的至少一种。
  15. 如权利要求14所述的应用，其中，所述药品还包括药学上可接受的载体或辅料，所述辅料选自淀粉、糊精、乳糖、微晶纤维素、羟丙甲基纤维素、聚乙二醇、硬脂酸镁、微粉硅胶、木糖醇、乳糖醇、葡萄糖、甘氨酸、甘露醇、和甘氨酸等的至少一种。
  16. 如权利要求1至13任一项所述的应用，其中，所述保健品选自片剂、胶囊剂、口服液、液体饮料、保健茶、和食品添加剂的至少一种。
  17. 如权利要求1至13任一项所述的应用，其中，所述木姜叶柯能够具有以下生物学功能的至少一种：
    1)抑制皮层和海马中老年斑(SP)沉积；
    2)抑制血清内炎症因子表达；
    3)抑制mTORC1的激活；
    4)促进细胞自噬；
    5)维持免疫细胞的存活和促进DNA损伤修复。
PCT/CN2021/136809 2020-12-10 2021-12-09 一种防治神经退行性疾病的新型药物 WO2022121986A1 (zh)

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