WO2020259540A1 - 唾液酸类化合物在制备治疗脑部退行性病变药物或营养添加剂或食品中的应用 - Google Patents

唾液酸类化合物在制备治疗脑部退行性病变药物或营养添加剂或食品中的应用 Download PDF

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WO2020259540A1
WO2020259540A1 PCT/CN2020/097945 CN2020097945W WO2020259540A1 WO 2020259540 A1 WO2020259540 A1 WO 2020259540A1 CN 2020097945 W CN2020097945 W CN 2020097945W WO 2020259540 A1 WO2020259540 A1 WO 2020259540A1
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sialic acid
acid
brain
parts
acetylneuraminic
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PCT/CN2020/097945
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English (en)
French (fr)
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都秀波
李翔宇
岳彩萍
张磊
汪志明
项威
石青青
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嘉必优生物技术（武汉）股份有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • 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
    • A61K9/08—Solutions
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • 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

Definitions

  • This application relates to the application of sialic acid compounds in the preparation of drugs for the prevention and/or treatment of brain degeneration, the application of sialic acid compounds in the preparation of drugs for improving cognitive ability, and the application of sialic acid compounds in the preparation of preventive and/or The application of food or nutritional additives for improving brain degeneration and the application of sialic acid compounds in the preparation of food or nutritional additives for improving cognitive ability.
  • Sialic acid compounds also known as neuraminic acid, usually refers to one of the most important members of this class of compounds, N-acetylneuraminic acid, which is widely found in animal tissues and microorganisms, usually located in the outermost layer of the cell membrane.
  • N-acetylneuraminic acid which is widely found in animal tissues and microorganisms, usually located in the outermost layer of the cell membrane.
  • the key positions of partial and secreted glyco complexes are the important material basis for the diversification of the structure and function of glyco complexes.
  • sialic acid With people's further research and understanding of the biological activity and application of sialic acid, products produced from sialic acid have emerged, and the demand for sialic acid has also increased. At present, sialic acid has been approved as a new food material, and its safety and functionality have been affirmed.
  • sialic acid can strengthen the immune system of the elderly; it can improve the cognitive development of fetuses and children; as a prebiotic, it can improve the absorption of vitamins and minerals in the intestine; it has antibacterial and antiviral effects; and inhibits leukocyte adhesion and anti-inflammatory And so on.
  • Alzheimer's disease commonly known as senile dementia
  • senile dementia is a neurodegenerative disease with a slow onset and worsening over time. It is the most common type of disease in senile dementia, accounting for about 60-70% of the causes of dementia.
  • the most common early symptoms are loss of short-term memory. As the disease progresses gradually, symptoms may gradually appear, including language disorders, disorientation (including easy to get lost), emotional instability, loss of motivation, inability to take care of themselves, and many behavioral problems. When the situation worsens, the patient often becomes disconnected from the family or society, and gradually loses physical functions, eventually leading to death. Although the course of the disease varies from person to person, the average remaining life after diagnosis is about three to nine years.
  • Existing drugs can only improve cerebral blood flow and promote the recovery of brain cognitive ability.
  • the main ones include cholinesterase inhibitors, NMDA antagonists, and brain metabolism improving drugs, which cannot be cured. Because the cause and pathogenesis of Alzheimer's disease are not clear, it poses a great challenge to the development of new drugs.
  • CN106728563A discloses a traditional Chinese medicine for the treatment of Alzheimer's disease and a preparation method thereof, which is prepared from the following raw materials in parts by weight: 1-6 parts of Bupleurum vulgaris, 1-6 parts of Astragalus 1-6 parts, 1-4 parts of Shichangpu, 1-3 parts of angelica and 1-3 parts of licorice.
  • the selected medicinal materials of the traditional Chinese medicine preparation of the invention are compatible with traditional Chinese medicine and modern pharmacology. It has the effects of detoxification and resuscitation, nourishing qi and blood, nourishing brain and nourishing intelligence, and is effective for memory loss, fatigue and dizziness caused by Alzheimer’s disease.
  • the improvement and treatment of symptoms such as heart palpitations, deficiency of qi and blood, and dementia have significant effects, are safe and have no toxic side effects, and can be widely used in the clinical treatment of Alzheimer's disease.
  • CN107823643A discloses the application of guanine nucleoside monophosphate reductase 1 as a drug target for preventing or treating Alzheimer's disease, and the drug is Lumacaftor or its derivatives or a pharmaceutical composition containing Lumacaftor.
  • the level of guanine nucleoside monophosphate reductase 1 (GMPR1) is higher in Alzheimer's disease patients than healthy people, and it is a therapeutic target for Alzheimer's disease.
  • the Lumacaftor can inhibit the activity of GMPR1, thereby preventing neuronal death and curing Alzheimer's disease.
  • the invention uses molecular docking technology to screen out Lumacaftor among all known drugs, and verifies its therapeutic effect in Alzheimer's disease model mice.
  • CN109260227A discloses a method for preparing autologous adipose-derived mesenchymal stem cell injection for treating Alzheimer’s disease.
  • Adipose-derived mesenchymal stem cells are separated from adipose tissue collected from the body, and a large amount of adipose mesenchymal stem cells are obtained by in vitro culture and expansion.
  • Mesenchymal stem cells can obtain various cytokines in the culture supernatant at the same time.
  • the autologous adipose-derived mesenchymal stem cell injection made from the cells and the cytokines in the culture supernatant for the treatment of Alzheimer’s disease has a therapeutic effect The above has unique advantages and brings hope for better treatment of Alzheimer's disease.
  • Alzheimer’s disease is an unpredictable senile disease, if it can improve the nutritional environment of the brain, it can help to start damage The re-growth of brain nerve cells and strengthen the connection between brain nerve cells can improve cognitive ability and prevent or treat Alzheimer’s disease. Therefore, it is very meaningful to develop a new type of strategy to prevent or treat Alzheimer's disease.
  • This application provides a new strategy for the prevention and/or treatment of brain degenerative diseases, specifically the application of sialic acid compounds in the preparation of drugs for the prevention and/or treatment of brain degeneration.
  • Application in the preparation of drugs for improving cognitive ability application of sialic acid compounds in the preparation of food or nutritional additives for preventing and/or improving brain degeneration, and application of sialic acid compounds in preparing food or nutrition for improving cognitive ability Application of additives.
  • This application finds for the first time that supplementing sialic acid compounds in the form of drugs, nutritional additives or foods can improve the nutritional environment of the brain, enhance or improve memory, prevent degenerative brain diseases, and improve the brain environment of degenerative brain diseases, especially It has a significant preventive, ameliorating or therapeutic effect on the symptoms of Alzheimer's disease.
  • the present application provides the use of sialic acid compounds in the prevention and/or treatment of brain degenerative diseases.
  • the sialic acid compounds include free sialic acid, a bound form of sialic acid or a sialic acid precursor.
  • the present application provides the application of sialic acid compounds in the preparation of drugs for improving cognitive ability.
  • the sialic acid compounds include free sialic acid, sialic acid in a bound form, or a sialic acid precursor.
  • the present application also provides the application of sialic acid compounds in the preparation of nutritional additives or foods for preventing brain degeneration and/or improving the brain environment.
  • the sialic acid compounds include free sialic acid and combined form Sialic acid or sialic acid precursor.
  • the present application also provides the application of sialic acid compounds in the preparation of nutritional additives or foods for improving cognitive ability.
  • the sialic acid compounds include free sialic acid, sialic acid in a bound form, or sialic acid precursors.
  • sialic acid compounds can be formulated as medicines for preventing or treating brain degenerative diseases, or improving cognitive ability; or, sialic acid compounds can be formulated as nutritional additives Or food, used to prevent brain degeneration, or improve the brain environment, or improve cognitive ability.
  • the "sialic acid compound" referred to in this application relates to any single member of the family of 9-carbon glyconeuraminic acid derivatives known in the art, or a combination with one or more other members.
  • Free sialic acid includes N-acetylneuraminic acid and pharmaceutically acceptable salts of N-acetylneuraminic acid. Since sialic acid has a carboxyl group, it can be regarded as an acid, which is easily converted into alkali metal salts or alkaline earth metals. Salt, after taking sialic acid, it will release hydrogen ions and sialic acid groups in contact with water. The actual functional component is the group after sialic acid is separated from hydrogen ions. Therefore, the pharmaceutically acceptable salts of sialic acid (such as sodium sialic acid) After taking it, it will produce sialic acid groups and alkali metal salts in water, and the sialic acid groups will still achieve the above-mentioned effects.
  • sialic acid has a carboxyl group, it can be regarded as an acid, which is easily converted into alkali metal salts or alkaline earth metals. Salt, after taking sialic acid, it will release hydrogen ions and sialic acid groups in contact with water. The
  • Conjugated form of sialic acid includes oligosaccharide conjugates, lipid conjugates or protein conjugates, all of which generate free sialic acid groups during metabolism, such as binding to proteins (such as casein glycomacropeptide or sticky Protein) sialic acid, sialic acid linked to carbohydrates (such as sialyllactose or bacterial capsular polysaccharide of sialic acid), and sialic acid linked to lipids (such as gangliosides).
  • proteins such as casein glycomacropeptide or sticky Protein
  • sialic acid linked to carbohydrates such as sialyllactose or bacterial capsular polysaccharide of sialic acid
  • sialic acid linked to lipids such as gangliosides
  • Sialic acid precursors include N-acetylmannosamine, N-propionylmannosamine, 2-keto-3-deoxynononulonic acid, N-glycolylneuraminic acid or core sialic acid neuraminic acid molecules Any one or a combination of at least two.
  • the sialic acid compound may include N-acetylneuraminic acid, N-acetylneuraminic acid pharmaceutically acceptable salt, sialic acid oligosaccharide conjugate, sialic acid lipid conjugate, sialic acid protein conjugate Any one or a combination of at least two of the sialic acid precursor, such as a combination of a pharmaceutically acceptable salt of N-acetylneuraminic acid and a sialic acid oligosaccharide conjugate, N-acetyl The combination of pharmaceutically acceptable salts of neuraminic acid and sialic acid lipid conjugates, etc., and other arbitrary combinations are not repeated here.
  • Any source of sialic acid compounds can be used in this application, including but not limited to animal, plant and microbial sources. Including monomeric N-acetylneuraminic acid or polysialic acid, N-acetylneuraminic acid linked to protein (such as casein glycomacropeptide or mucin), and lipid (such as ganglioside) N-acetylneuraminic acid, N-acetylneuraminic acid linked to carbohydrates (such as sialyllactose).
  • the dosage form of the drug or nutritional additive includes tablets, powders, granules, capsules, injections, sprays, films, suppositories, nasal drops or pills.
  • the sialic acid compounds described in this application can be administered alone or in combination with adjuvants to make appropriate dosage forms for administration.
  • the adjuvants include diluents, excipients, fillers, binders, wetting agents, and disintegrants. Any one or a combination of at least two of agents, emulsifiers, solubilizers, solubilizers, osmotic pressure regulators, surfactants, pH regulators, antioxidants, bacteriostatic agents, or buffers.
  • the combination of the at least two kinds such as a combination of a diluent and an excipient, a combination of an emulsifier and a cosolvent, a combination of a filler and a binder and a wetting agent, and the like.
  • Other dosage forms well known to those skilled in the art are also within the protection scope of this application.
  • the dosage form When the dosage form is a tablet, it may contain excipients, such as microcrystalline cellulose, starch or calcium carbonate, etc.; it may also contain disintegrating agents, such as croscarmellose sodium, etc.
  • the unit tablet contains sialic acid
  • the effective content of the compound can be adjusted according to the actual situation.
  • the dosage form When the dosage form is a capsule, it can be prepared as a hard capsule or a soft capsule, and the sialic acid compound and auxiliary materials can be prepared as a powder or granule and filled into the capsule.
  • the dosage form When the dosage form is a suspension, flavoring and suspending agents can be added to adjust the taste and mouthfeel.
  • an emulsifier and co-solvent can be appropriately added to adjust the solubility and emulsification degree for administration.
  • the weight percentage of the sialic acid compound in the drug or nutritional additive is 0.01%-99.9%, such as 0.01%, 0.02%, 0.05%, 0.1%, 0.5%, 1%, 5%, 10%, 20%, 30%, 40%, 50%, 70%, 80%, 90% or 99.9% etc.
  • the route of administration of the drug or nutritional supplement includes intravenous injection, intraperitoneal injection, intramuscular injection, subcutaneous injection, oral administration, sublingual administration, nasal administration or transdermal administration.
  • Oral administration is generally carried out in the form of tablets or capsules.
  • tablets or capsules when tablets or capsules are used for oral administration, they can be prepared into controlled-release preparations or sustained-release preparations. According to the required medicinal effect and time of action, a suitable dosage of control Release excipients or sustained release excipients.
  • the dosage form of the food may include chewing gum; breakfast cereals; cheese products; nuts and/or nut products; gelatin, pudding and/or fillings; frozen dairy products; dairy products; dairy products; gummies; Soup and/or soup powder; snack food; fruit juice; vegetable juice; fat and/or oil; fish products; vegetable protein products; poultry products and/or meat products.
  • the medicine or nutritional supplement or food is equivalent to 1-35mg, preferably 6.5-35mg, such as 1mg, 6.5mg, 6.8mg, 25mg, 30mg, 35mg N-acetylneuraminic acid/Kg body weight/
  • the daily dose is administered to humans.
  • the dosage of the drug is 1-35 mg, preferably 6.5-35 mg N-acetylneuraminic acid/Kg body weight/day.
  • the dosage of the drug is adjusted to be equivalent to 1-35 mg, preferably 6.5-35 mg N-acetylneuraminic acid/Kg body weight/day.
  • drugs or nutritional additives or foods contain sialic acid precursor substances, the dosage of the drug is adjusted to be equivalent to 1-35 mg, preferably 6.5-35 mg N-acetylneuraminic acid/Kg body weight/day.
  • the sialic acid compound is administered to the user at 20 mg-3.5 g N-acetylneuraminic acid per day.
  • the sialic acid compound is a sialic acid compound loaded on a pharmaceutical carrier.
  • the pharmaceutical carrier includes liposomes, micelles, dendrimers, microspheres, or microcapsules.
  • sialic acid compound described in the present application can be compounded with other beneficial ingredients with biological activity in different proportions to form a composition, and work together to exert its effect.
  • the composition further includes docosahexaenoic acid, arachidonic acid, eicosapentaenoic acid, phospholipids, acetylcholine, melatonin, coenzyme Q10, chondroitin, calcium, vitamins Any one or a combination of at least two of B, vitamin E or vitamin C; the combination of at least two such as the combination of melatonin and coenzyme Q10, the combination of chondroitin and vitamin B, the combination of vitamin E and vitamin C Combinations, etc., other arbitrary combinations are not repeated here.
  • the composition further comprises 5-40 parts of docosahexaenoic acid, 1-30 parts of arachidonic acid, 5-40 parts of eicosapentaenoic acid, phospholipid 5- 10 parts, 0.25-9 parts of acetylcholine, 0.5-0.8 parts of melatonin, 0.1-0.2 parts of coenzyme Q10, 2-8 parts of chondroitin, 15-25 parts of calcium, any one of vitamin B, vitamin E or vitamin C Or a combination of at least two.
  • the composition further includes 5-40 g of docosahexaenoic acid, 1-30 g of arachidonic acid, 5-40 g of eicosapentaenoic acid, 5-10 g of phospholipids, and 0.25 acetylcholine. -9g, melatonin 0.5-0.8g, coenzyme Q10 0.1-0.2g, chondroitin 2-8g, calcium 15-25g, vitamin B, vitamin E, or vitamin C, any one or a combination of at least two.
  • the mass of the docosahexaenoic acid may be 5g, 10g, 20g, 30g or 40g.
  • the mass of the arachidonic acid can be 1g, 5g, 10g, 20g or 30g.
  • the mass of the eicosapentaenoic acid may be 5g, 10g, 20g, 30g or 40g.
  • the mass of the phospholipid can be 5g, 6g, 7g, 8g or 10g.
  • the mass of the acetylcholine may be 0.25g, 1g, 2g, 3g, 5g, 7g or 9g.
  • the mass of the melatonin may be 0.5g, 0.6g, 0.7g, 0.8g, etc.
  • the mass of the coenzyme Q10 can be 0.1g, 0.12g, 0.14g, 0.16g, 0.18g, 0.2g, etc.
  • the mass of the chondroitin can be 2g, 3g, 4g, 5g, 6g, 7g or 8g.
  • the mass of the calcium can be 15g, 17g, 18g, 19g, 20g, 22g, 24g or 25g.
  • the drug or nutritional supplement or food is suitable for people over 25 years old, such as 30 years old, 40 years old, 50 years old, 60 years old, 70 years old, 80 years old, etc., preferably people over 40 years old.
  • the brain degenerative disease includes Alzheimer's disease.
  • the medicine or nutritional supplement or food is suitable for people who carry Alzheimer's mutation genes.
  • the administration time of the sialic acid compound is at least 4 months, and the administration time can be 4 months, 12 months, 1 year, 2 years, 4 years, 8 years, 12 years, 24 years , Continuous application.
  • the sialic acid compound is administered at least ten times a day.
  • the application also provides the application of sialic acid compounds in the preparation of drugs for preventing or treating brain degeneration or improving cognitive ability, wherein the sialic acid compounds include N-acetylneuraminic acid, N-acetylneuraminic acid polymer or N-acetylneuraminic acid derivative; wherein the N-acetylneuraminic acid derivative includes N-acetylneuraminic acid pharmaceutically acceptable salt, oligosaccharide conjugate, lipid conjugate Any one or a combination of at least two of the substances or protein conjugates.
  • this application also provides a medicine for preventing and/or treating brain degenerative diseases, which includes sialic acid compounds including free sialic acid, bound form of sialic acid or Sialic acid precursors.
  • the present application also provides a drug for improving cognitive ability, which includes a sialic acid compound including free sialic acid, sialic acid in a bound form, or a sialic acid precursor.
  • this application also provides a food or nutritional additive for preventing brain degeneration and/or improving the brain environment, which includes sialic acid compounds, and the sialic acid compounds include free sialic acid, combined Forms of sialic acid or sialic acid precursors.
  • the present application also provides a food or nutritional additive for improving cognitive ability, which includes a sialic acid compound, the sialic acid compound including free sialic acid, a bound form of sialic acid or a sialic acid precursor .
  • sialic acid compounds can not only improve the cognitive ability of the brain degenerative disease group, improve the brain environment, and thereby prevent brain degeneration or treat early brain degeneration; it can also improve the recognition of normal groups. Knowing ability. It can exert the above-mentioned beneficial effects not only in the form of medicine but also in the form of food or nutritional additives.
  • Figure 1 is a diagram of the swimming path of each group of mice in Example 2 (in the figure, WT represents the normal mouse group administered placebo, and WT+SA(H) represents the normal mouse group administered high-dose N-acetylneuraminic acid , AD means the group of diseased mice given placebo, AD+SA (H) means the group of disease mice given high-dose N-acetylneuraminic acid, AD+SA (M) means the middle-dose N-acetylneuraminic acid is administered The diseased mouse group, AD+SA(L) means the diseased mouse group administered low-dose N-acetylneuraminic acid);
  • Figure 2 is a statistical diagram of the residence time of mice in the original platform quadrant after 24 hours in Example 2;
  • Figure 3 is a statistical diagram of the residence time of mice in the original platform quadrant after 72h in Example 2;
  • Figure 4 is a statistical diagram of the number of times the mouse crossed the original platform position after 24h in Example 2;
  • Figure 5 is a statistical diagram of the number of times the mouse crosses the original platform position after 72 hours in Example 2;
  • Figure 6 is a statistical diagram of the number of crossed grid scores of mice in each group in Example 3.
  • Figure 7 is a statistical diagram of the scores of standing times of each group of mice in Example 3.
  • Figure 8 shows the detection of thioflavin T staining to detect the misfolding of the hippocampus and cortical areas of the mouse brain (CA3: mouse hippocampal CA3 area; CA1: mouse hippocampal CA1 area; Cor: cortical area; DG: hippocampal dentate Back area);
  • Figure 9 shows the detection of neurofibrillary tangles in the hippocampus and cortex of mice by silver staining (CA3: mouse hippocampal CA3 area; CA1: mouse hippocampal CA1 area; Cor: cortical area; DG: hippocampal dentate gyrus area);
  • Figure 10 shows the detection of neuronal activity in the hippocampus and cortex of mice by Nissl staining (CA3: mouse hippocampal CA3 area; CA1: mouse hippocampal CA1 area; Cor: cortical area; DG: hippocampal dentate gyrus area) ;
  • Figure 15 shows structural NMR: a heat map of the connection value of each brain area, the abscissa and ordinate indicate different brain areas;
  • Figure 16 shows the intra-group comparison: the difference in the connection value of different cortical subregions and hippocampus in different groups of mice;
  • Figure 17 shows the intra-group comparison: the difference of the connection value between different cortical subregions in different groups of mice;
  • Figure 18 shows the APP/PS1 qPCR map of 2 ⁇ Tg-AD experimental mice.
  • the following examples take Alzheimer’s mice as a model (APP/PS1 2 ⁇ Tg-AD male mice.
  • the model has been transferred to mice with APP/PS1 two genes, which can produce a large amount of A ⁇ in the brain.
  • the control group used B6129SF2/J-WT male mice).
  • Figure 18 shows the large expression of APP and PS1 genes in the brain of transgenic mice compared with control mice.
  • mice The experiment is divided into six groups, each with 12 mice, namely:
  • the normal mouse group administered placebo (the placebo dosage is 420mg/Kg/day, expressed as WT);
  • a group of diseased mice administered with a medium dose of N-acetylneuraminic acid (the amount of N-acetylneuraminic acid used is 84mg/Kg/day, expressed as AD+SA(M));
  • the N-acetylneuraminic acid used is a commercial product produced by Jiabiyou Biotechnology (Wuhan) Co., Ltd., and the content of N-acetylneuraminic acid is ⁇ 98%.
  • the Morris water maze experiment is very effective in the study of brain degenerative diseases such as Alzheimer’s disease. The biggest feature of these diseases is the decline of cognitive ability.
  • the Morris water maze experiment detects in the training of mice. Learn to find the ability to find a hidden platform at a fixed location to form a stable spatial position cognition. The experimental steps are as follows:
  • mice were fed with a normal diet to 3 months of age, each dose of N-acetylneuraminic acid or placebo was mixed into the mouse feed, and the mice were fed freely for 4 months;
  • FIG 1 The path diagram for the positioning of the mouse on the platform is shown in Figure 1.
  • the swimming of the mouse is borderline and marginal, and the platform is far away from the periphery and close to the center of the pool. If the mouse changes its swimming route in the area near the center of the pool The long distance in the middle movement indicates that the mice have good spatial memory ability. If the mice move in the area around the pool, their spatial memory ability is poor. It can be seen from Figure 1 that the diseased mice administered with placebo have obvious marginal and marginal properties.
  • mice Compared with the mice administered with N-acetylneuraminic acid, they move more in the central area of the pool and can move faster
  • the location of the platform indicates that the mice in the medication group have stronger memory ability, and their Alzheimer’s disease symptoms have been relieved; and the higher the dose of N-acetylneuraminic acid, the better the effect.
  • High-dose N-acetyl The effect of neuraminic acid diseased mice was even better than that of normal mice given placebo.
  • the open field experiment reflects the autonomous behavior and anxiety of mice in an unfamiliar environment.
  • the experimental steps are as follows:
  • mice were fed with a normal diet to 3 months of age, each dose of N-acetylneuraminic acid or placebo was mixed into the mouse feed, and the mice were fed freely for 4 months;
  • N-acetylneuraminic acid After feeding with N-acetylneuraminic acid for 4 months, compared with normal mice, AD mice showed typical depression/anxiety behaviors, including grid crossing and feeding frequency was significantly reduced ( Figure 6, 7). Compared with AD mice, the N-acetylneuraminic acid treatment group significantly improved depression/anxiety behavior, and significantly increased the crossing grid and standing frequency of AD mice ( Figures 6, 7). The above behaviors indicate that N-acetylneuraminic acid can effectively improve the cognitive deterioration and depression/anxiety behaviors of AD mice, especially at medium and high N-acetylneuraminic acid concentrations.
  • Thioflavin T staining was used to detect the misfolding of proteins in the hippocampus and cortex of the mouse brain, which reflects the aggregation and distribution of A ⁇ in the brain to a certain extent. From the results, there are differences between WT and AD in hippocampal CA3 area. AD+SA(L) has more error proteins than AD, while AD+SA(M) and AD+SA(H) are less than AD; hippocampal CA1 area also has WT and AD.
  • neurofibrillary tangles in the hippocampus and cortex of the mouse brain were detected by silver glycine staining.
  • the formation of neurofibrillary tangles is due to the hyperphosphorylation of Tau protein, which makes it detached from the microtubules and entangled with each other.
  • Neurofibrillary tangles The results show that there are significant differences in neurofibrillary tangles between WT and AD in hippocampal CA area, CA1 area, dentate gyrus and cortex.
  • the activity of neurons can be judged by detecting the number of Nissl bodies.
  • the Nissl staining is to detect the number of Nissl bodies in the rough endoplasmic network in the brain tissue of mice. The more the number of Nissl bodies is indicated. The fewer neurons are lost, and the less the number of stained Nissan bodies is stained, the more neurons are lost. From the results, the number of Nissl bodies in the CA3, CA1, dentate gyrus, and cortex of AD is significantly less than that of WT, and the number of Nissl bodies in the WT+SA(H) cortex is significantly less than WT; AD mice fed with sialic acid had different responses at low, medium and high doses.
  • Liquid NMR mainly detects and analyzes the relative content of the following small molecules in the mouse brain, including inositol, taurine, aspartic acid, glutamic acid, glutamine, ⁇ -aminobutyric acid, and N -Acetyl-L-aspartic acid, alanine.
  • Myo-Inositol (MI) is also called "cyclohexanol", one of the B vitamins. It is an essential nutrient for microorganisms and many animals. When inositol is lacking in the animal's diet, hair loss occurs and affects development. Widely distributed in animals and plants, its structure is similar to glucose, and it is a growth factor.
  • N-acetyl-L-aspartate is only found in neurons and processes in the brain. It is a marker that reflects the severity of neuronal damage. NAA content is considered to be the number of neurons Increase or decrease signal.
  • Taurine is a sulfur-containing amino acid that exists in high concentrations in mammalian tissues and is involved in brain development and neurotransmission processes. Current studies have shown that it participates in cell volume regulation and membrane potential regulation, thereby weakening electrical activity and hyperpolarizing neurons. From the results (Figure 11), in the hippocampus, cortex and olfactory bulb regions, the concentration of taurine in AD was significantly lower than that in WT (*p ⁇ 0.05). Feeding different concentrations of N-acetylneuraminic acid can increase taurine Concentration but no significant difference.
  • N-Acetyl-L-Aspartic acid is an important biochemical indicator of neuronal damage.
  • a decrease in NAA indicates neuronal metabolism disorder.
  • Figure 12 after feeding N-acetylneuraminic acid, the concentration of NAA in AD increased or remained unchanged. Although there was no significant difference, the increasing trend of NAA concentration can be used as N-acetylneuraminic acid to protect nerves. A corroborating indicator of normal metabolites.
  • the NAA concentration of WT+SA(H) varies from high to low in different brain regions, and there is no significant difference. This may be the result of individual differences, or there may be a downward trend, but the degree of decline cannot be To the extent that the normal metabolic process of neurons is destroyed.
  • the ratio of glutamic acid to N-acetylaspartic acid is used to comprehensively explain the degree of glucose metabolism and the normal metabolism of neurons. From the results (Figure 13), the Glu/NAA of AD+SA(M) was significantly lower than AD (*p ⁇ 0.05), and the Glu/NAA of AD+SA(H) was also significantly lower than AD (*p ⁇ 0.05) It shows that feeding N-acetylneuraminic acid has a certain effect on improving neuronal metabolism disorders and alleviating AD symptoms in AD rats.
  • the ratio of glutamic acid to ⁇ -aminobutyric acid is used to comprehensively explain the effects of neurotransmitters. From the results ( Figure 14), the Glu/GABA-C4 for WT+SA(H) is generally higher than that of WT, and the same is true for AD+SA(L/M/H) compared with AD, indicating that feeding N-acetylneuraminic acid is better than inferior in improving the neurotransmission process; the relative amount of Glu/GABA-C4 in the hippocampus and cortex is much higher than other areas, and the Glu/GABA-C4 ratio in the midbrain area AD Significantly higher than WT.
  • fMRI functional magnetic resonance imaging
  • BOLD blood oxygen level dependent
  • Resting-state fMRI refers to a type of magnetic resonance that allows subjects to stay awake, close their eyes, breathe calmly, and do not engage in any thinking activities or voluntary movements in a resting state. Imaging technology, the BOLD signal collected reflects the spontaneous activity of brain tissue neurons. Resting state fMRI does not require complicated task design and receiving any stimuli. It can avoid the unreliability of experimental results due to differences in experimental design or tasks performed by subjects, and has high repeatability and practicability. The study of spontaneous neuronal activity in the resting state is of great significance for understanding neurological diseases. The resting state has been used in many neuropsychiatric diseases research, including Alzheimer's disease.
  • the analysis method of this study is functional connection analysis, which mainly detects the connection value of different brain regions, reflecting the correlation between brain regions.
  • the NMR results analyzed the connections between 37 regions of interest (Region of Interest, ROI).
  • ROI regions of interest
  • the applicant mainly focuses on the connection between the cortex and the hippocampus. There is only one zone in the hippocampus, namely zone 28.
  • Region5 Prelimbic Cortex (front edge cortex); Region6: Cingulate Cortex (cingulate cortex); Region7: Piriform Cortex (pear-shaped cortex): Region8-Somatosensory Cortex (somatosensory cortex) ;Region9: Auditory Cortex (auditory cortex); Region13: Insular Cortex (insular cortex); Region17: Perirhinal Cortex (perinasal cortex); Region18: Ectorhinal Cortex (outer nasal cortex); Region19: Entorhinal Cortex (entorhinal cortex); Region20: Temporal Associatin Cortex (temporal cortex); Region22: Visual Cortex (visual cortex); Region23: Retrosplenial Cortex (post-compression cortex); Region24: Motor Cortex (motor cortex); Region32: Orbital Cortex (frontal orbital cortex) .
  • connection values between different cortical subregions and hippocampus were extracted from the connection values between different cortical subregions and hippocampus and compared the differences in the connection values in each group of mice ( Figure 16).
  • Several phenomena of interest to Ling Ran such as brain areas 5-28, namely the anterior limbic cortex and hippocampus, are weakly negatively correlated in WT mice, but positively correlated in AD mice, with low and medium doses
  • the connection value becomes a negative correlation.
  • brain areas 6-28 the cingulate cortex and hippocampus
  • 9-28 an auditory cortex and hippocampus
  • 17-28 perinasal cortex and hippocampus
  • 22- 28 visual cortex and hippocampus
  • 32-28 frontal orbital cortex and hippocampus
  • SA has a positive regulatory effect on the connection value (correlation) between multiple brain regions in AD mice, including the anterior marginal cortex, cingulate gyrus cortex, auditory cortex, Perinasal cortex, synaptic temporal cortex, motor cortex, hippocampus, etc., suggest that SA may have positive significance on learning, memory, hearing, and movement of animals.
  • Sialic acid is a naturally occurring transmitter of gangliosides in the brain, with the highest content in the human brain. Current studies have shown that it can improve the learning and behavioral ability of animals; it helps newborn brains Partial development and memory formation may promote the formation of synapses and strengthen the development of the nervous system; affect the development of immune cells; maintain the balance of immune response. On the other hand, with the occurrence of inflammation and the formation of malignant tumors, sialic acid also appears concomitantly increased.
  • sialic acid can improve the learning ability and anxiety of mice, prevent neuron loss, reduce the accumulation of some A ⁇ oligomers and the formation of neurofibrillary tangles; it may improve AD symptoms by affecting neurotransmitters.
  • Drug prevention from the early onset of AD may play a role in alleviating the symptoms of AD.
  • the adult dosage is converted from the dosage of the mouse, and the dosage can be calculated according to the weight of the adult
  • the converted daily human intake of sialic acid is 82.62 mg for low dose, 408.24 mg for medium dose, and 2041.2 mg for high dose.
  • this application uses the above-mentioned examples to illustrate the application of the sialic acid compounds of the application in the preparation of drugs for the prevention and/or treatment of brain degeneration, and the use of sialic acid compounds in the preparation of drugs for improving cognitive ability.
  • Application application of sialic acid compounds in the preparation of food or food additives for improving brain degeneration, and application of sialic acid compounds in the preparation of food or food additives for improving cognitive ability.
  • this application is not limited to the above-mentioned embodiments, which does not mean that this application must rely on the above-mentioned embodiments to be implemented.
  • Those skilled in the art should understand that any improvement to this application, the equivalent replacement of each raw material of the product of this application, the addition of auxiliary components, the selection of specific methods, etc., fall within the scope of protection and disclosure of this application.

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Abstract

本申请涉及唾液酸类化合物在制备预防和/或治疗脑部退行性病变药物或食品中的应用，所述唾液酸类化合物包括游离唾液酸、结合形式的唾液酸或唾液酸前体。本申请通过补充唾液酸类化合物来改善脑部营养环境，改善认知能力，其能够预防和/或治疗脑部退行性病变，尤其是对阿尔茨海默症的病例症状有显著的预防、改善或治疗作用，其既可以以药物的形式也可以以食品或食品添加剂的形式发挥上述有益效果。

Description

唾液酸类化合物在制备治疗脑部退行性病变药物或营养添加剂或食品中的应用 技术领域
本申请涉及唾液酸类化合物在制备预防和/或治疗脑部退行性病变药物中的应用，唾液酸类化合物在制备改善认知能力的药物中的应用，唾液酸类化合物在制备预防和/或改善脑部退行性病变的食品或营养添加剂中的应用和唾液酸类化合物在制备改善认知能力的食品或营养添加剂中的应用。
背景技术
唾液酸类化合物又称神经氨酸，通常也指代此类化合物中最重要的成员之一N-乙酰神经氨酸，其广泛存在于动物组织及微生物中，通常位于细胞膜最外层的糖类部分和分泌的糖复合物(糖脂、糖蛋白和脂多糖)的关键位置，是糖复合物结构和功能多样化的重要物质基础。随着人们对唾液酸生物学活性和应用的进一步研究和了解，由唾液酸生产的产品应运而生，对唾液酸的需求也随之增加。目前，唾液酸已获批为新食品原料，在安全性和功能性上得到了肯定。已有报道唾液酸能够强化老年人免疫***；对胎儿及儿童认知发育具有改善作用；作为益生元提高肠道对维生素及矿物质的吸收；具有抗菌和抗病毒作用；以及抑制白细胞黏附和消炎等作用。
阿尔茨海默症，俗称老年痴呆，是一种发病进程缓慢、随着时间不断恶化的神经退化性疾病，是老年性痴呆最常见的疾病种类，约占痴呆病因的60-70％。最常见的早期症状为丧失短期记忆，当疾病逐渐进展，症状可能逐渐出现，包括语言障碍、定向障碍(包括容易迷路)、情绪不稳、丧失动机、无法自理和许多行为问题。当情况恶化时，患者往往会因此和家庭或社会脱节，并逐渐丧失身体机能，最终导致死亡。虽然疾程因人而异，但诊断后的平均余命约为三到九年。现有药物只能达到改善脑血流量，促进脑认知能力恢复的作用，主要有胆碱酯酶抑制剂、NMDA拮抗剂以及脑代谢改善药，无法根治。由于阿尔茨海默症的致病原因和发病机制不明确，给新药研发提出了很大的挑战。
CN106728563A公开了一种治疗阿尔茨海默症的中药及其制备方法，其由如下重量份的原料药配制而成：柴胡1-6份、黄芪1-6份、石菖蒲1-4份、当归1-3份和甘草1-3份。该发明中药制剂所选药材配伍相宜，符合中药学和现代医药学理论，具有解毒开窍、补气养血、健脑益智之功效，对于阿尔茨海默症引起的记忆力减退、倦怠乏力、头晕心悸、气血亏虚以及痴呆等症状的改善及治疗具有显著效果，且安全无毒副作用，可广泛应用于阿尔茨海默症的临床治疗。
CN107823643A公开了鸟嘌呤核苷单磷酸还原酶1作为预防或治疗阿尔茨海默症的药物靶标的应用，所述药物为Lumacaftor或其衍生物或含有Lumacaftor的药物组合物。鸟嘌呤核苷单磷酸还原酶1(GMPR1)的水平在阿尔茨海默症患者中高于健康者，是阿尔茨海默症的治疗靶点。该Lumacaftor可以抑制GMPR1的活性，进而阻止神经元死亡，治愈阿尔茨海默症。该发明通过分子对接技术在所有已知药物中筛选出Lumacaftor，并在阿尔茨海默症模型小鼠中验证了其治疗效果。
CN109260227A公开了一种用于治疗阿尔茨海默症的自体脂肪间充质干细胞注射液制备方法，从自体采集的脂肪组织中分离出脂肪间充质干细胞，经体外培养扩增得到大量的脂肪间充质干细胞，同时获得培养上清液中各种细胞因子，用细胞和培养上清中的细胞因子制成的用于治疗阿尔茨海默症的自体脂肪间充质干细胞注射液，在治疗效果上有独特的优势，为阿尔茨海默症的更好治疗带来了希望。
但现有技术中关于有效预防或治疗阿尔茨海默症的策略的报道还很有限，阿尔茨海默症虽然是不可预见性的老年病，但如果能改善脑部营养环境，帮助开始受损的脑神经细胞重新生长，增强脑神经细胞间联系，则能够改善认知能力，预防或治疗阿尔茨海默病症。因此，开发出一种新型的预防或治疗阿尔茨海默病症的策略是非常有意义的。
发明内容
本申请提供了一种新的预防和/或治疗脑部退行性病变的策略，具体提供了唾液酸类化合物在制备预防和/或治疗脑部退行性病变药物中的应用，唾液酸类化合物在制备改善认知能力的药物中的应用，唾液酸类化合物在制备预防和/或改善脑部退行性病变的食品或营养添加剂中的应用和唾液酸类化合物在制备改善认知能力的食品或营养添加剂中的应用。
本申请首次发现通过药物、营养添加剂或食品的形式补充唾液酸类化合物，能够改善脑部营养环境，提升或改善记忆力，能够预防脑部退行性病变、改善脑部退行性病变脑部环境，尤其是对阿尔茨海默症的病例症状有显著的预防、改善或治疗作用。
一方面，本申请提供唾液酸类化合物在预防和/或治疗脑部退行性病变药物中的应用，所述唾液酸类化合物包括游离唾液酸、结合形式的唾液酸或唾液酸前体。
另一方面，本申请提供唾液酸类化合物在制备改善认知能力的药物中的应用，所述唾液酸类化合物包括游离唾液酸、结合形式的唾液酸或唾液酸前体。
另一方面，本申请还提供唾液酸类化合物在制备预防脑部退行性病变和/或改善脑部环境的营养添加剂或食品中的应用，所述唾液酸类化合物包括游离唾液酸、结合形式的唾液酸或唾液酸前体。
另一方面，本申请还提供唾液酸类化合物在制备改善认知能力的营养添加剂或食品中的应用，所述唾液酸类化合物包括游离唾液酸、结合形式的唾液酸或唾液酸前体。
在本申请中，可以将唾液酸类化合物配制为药物，用于预防脑部退行性病变，或治疗脑部退行性病变，或改善认知能力；或者，可以将唾液酸类化合物配制为营养添加剂或食品，用于预防脑部退行性病变，或改善脑部环境，或改善认知能力。
本申请所涉及的“唾液酸类化合物”涉及本领域已知的9-碳糖神经氨酸衍生物家族中的任意单个成员，或与一个或多个其他成员的组合。
“游离唾液酸”包括N-乙酰神经氨酸、N-乙酰神经氨酸可药用盐，由于唾液酸具有羧基，所以它可以视为为一种酸，它容易转化成为碱金属盐或碱土金属盐，服用唾液酸后，遇水会释放氢离子和唾液酸基团，实际产生功效作用的成分就是唾液酸脱离氢离子后的基团，因此唾液酸的可药用盐(例如唾液酸钠)在服用后遇水产生唾液酸基团和碱金属盐，唾液酸基团依然会实现上述功效。
“结合形式的唾液酸”包括低聚糖结合物、脂类结合物或蛋白结合物，它们都会在代谢中产生游离的唾液酸基团，例如键连到蛋白(如酪蛋白糖巨肽或粘蛋白)的唾液酸、键连到碳水化合物(如唾液乳糖或唾液酸的细菌荚膜多糖)的唾液酸和键连到脂(如神经节苷脂)的唾液酸。
“唾液酸前体”包括N-乙酰甘露糖胺、N-丙酰甘露糖胺、2-酮-3-脱氧壬酮糖酸、N-羟乙酰神经氨酸或核心唾液酸神经氨酸分子中的任意一种或至少两种的组合。
在本申请中，所述唾液酸类化合物可包括N-乙酰神经氨酸，N-乙酰神经氨酸可药用盐、唾液酸低聚糖结合物、唾液酸脂类结合物、唾液酸蛋白结合物、唾液酸前体中的任意一种或 至少两种的组合，所述至少两种的组合例如N-乙酰神经氨酸可药用盐和唾液酸低聚糖结合物的组合、N-乙酰神经氨酸可药用盐和唾液酸脂类结合物的组合等，其他任意的组合方式不在此一一赘述。
唾液酸类化合物的任何来源都可以在本申请中使用，包括但不限于动物、植物和微生物来源。包括单体的N-乙酰神经氨酸或聚唾液酸、键连到蛋白(如酪蛋白糖巨肽或黏蛋白)的N-乙酰神经氨酸、键连到脂(如神经节苷脂)的N-乙酰神经氨酸、键连到碳水化合物(如唾液乳糖)的N-乙酰神经氨酸。
在一个实施方案中，所述药物或营养添加剂的剂型包括片剂、散剂、颗粒剂、胶囊剂、注射剂、喷雾剂、膜剂、栓剂、滴鼻剂或滴丸剂。
本申请所述唾液酸类化合物可单独给药也可以与辅料搭配做成适当的剂型进行给药，所述辅料包括稀释剂、赋形剂、填充剂、粘合剂、润湿剂、崩解剂、乳化剂、助溶剂、增溶剂、渗透压调节剂、表面活性剂、pH调节剂、抗氧剂、抑菌剂或缓冲剂中的任意一种或至少两种的组合。所述至少两种的组合例如稀释剂和赋形剂的组合、乳化剂和助溶剂的组合、填充剂和粘合剂和润湿剂的组合等。本领域技术人员所熟知的其他剂型也在本申请的保护范围内。
当剂型为片剂时，可包含有赋形剂，例如微晶纤维素、淀粉或碳酸钙等；也可以包含崩解剂，例如交联羧甲基纤维素钠等，单位片剂中唾液酸类化合物的有效含量可以根据实际情况进行调节。当剂型为胶囊剂时，其可制备成为硬胶囊或软胶囊，唾液酸类化合物及辅料可以制备成为粉末状或颗粒状填充进入胶囊中。当剂型为混悬剂时，可加入矫味剂、助悬剂等调节口味与口感。当剂型为乳剂时，可适当添加乳化剂、助溶剂来调节溶解度、乳化度进行给药。
在一个实施方案中，所述唾液酸类化合物在药物或营养添加剂中的重量百分比为0.01％-99.9％，例如0.01％、0.02％、0.05％、0.1％、0.5％、1％、5％、10％、20％、30％、40％、50％、70％、80％、90％或99.9％等。
在一个实施方案中，所述药物或营养添加剂的施用途径包括静脉注射、腹腔注射、肌肉注射、皮下注射、口服给药、舌下给药、鼻腔给药或经皮给药。
一般以片剂或胶囊剂的方式进行口服施用，另外，以片剂或胶囊剂进行口服时，可以制备成控释制剂或缓释制剂，根据需要的药效及作用时间，选择合适剂量的控释辅料或缓释辅料。
在一个实施方案中，所述食品的剂型可包括口香糖；早餐麦片；奶酪制品；坚果和/或坚果制品；明胶、布丁和/或填充物；冷冻乳制品；奶制品；乳制品；软糖；汤和/或汤粉；休闲食品；果汁；蔬菜汁；脂肪和/或油；鱼制品；植物蛋白制品；家禽制品和/或肉制品。
在一个实施方案中，所述药物或营养添加剂或食品以相当于1-35mg，优选6.5-35mg，例如1mg、6.5mg、6.8mg、25mg、30mg、35mg N-乙酰神经氨酸/Kg体重/日的剂量施用于人类。当药物包含游离唾液酸时，药物的给药剂量为1-35mg，优选6.5-35mg N-乙酰神经氨酸/Kg体重/日。当药物或营养添加剂或食品包含结合形式的唾液酸时，调整药物的给药剂量，使之相当于1-35mg，优选6.5-35mg N-乙酰神经氨酸/Kg体重/日。当药物或营养添加剂或食品包含唾液酸前体物质时，调整药物的给药剂量，使之相当于1-35mg，优选6.5-35mg N-乙酰神经氨酸/Kg体重/日。
在一些实施方案中，所述唾液酸类化合物以20mg-3.5g N-乙酰神经氨酸/日给予使用者。
在一个实施方案中，所述唾液酸类化合物为负载于药用载体上的唾液酸类化合物。
在一些实施方案中，所述药用载体包括脂质体、胶束、树枝状大分子、微球或微囊。
本申请所述唾液酸类化合物可以与其他具有生物活性的有益成分按照不同比例进行复配形成组合物，共同作用发挥功效。
在一个实施方案中，所述组合物中还包括二十二碳六烯酸、花生四烯酸、二十碳五烯酸、磷脂、乙酰胆碱、褪黑素、辅酶Q10、软骨素、钙、维生素B、维生素E或维生素C中的任意一种或至少两种的组合；所述至少两种的组合例如褪黑素和辅酶Q10的组合、软骨素和维生素B的组合、维生素E和维生素C的组合等，其他任意的组合方式不在此一一赘述。
优选地，以重量份数计，所述组合物还包括二十二碳六烯酸5-40份、花生四烯酸1-30份、二十碳五烯酸5-40份、磷脂5-10份、乙酰胆碱0.25-9份、褪黑素0.5-0.8份、辅酶Q10 0.1-0.2份、软骨素2-8份、钙15-25份、维生素B、维生素E或维生素C中的任意一种或至少两种的组合。
例如，以100g组合物计，所述组合物还包括二十二碳六烯酸5-40g、花生四烯酸1-30g、二十碳五烯酸5-40g、磷脂5-10g、乙酰胆碱0.25-9g、褪黑素0.5-0.8g、辅酶Q10 0.1-0.2g、软骨素2-8g、钙15-25g、维生素B、维生素E或维生素C中的任意一种或至少两种的组合。
所述二十二碳六烯酸的质量可以为5g、10g、20g、30g或40g等。
所述花生四烯酸的质量可以为1g、5g、10g、20g或30g等。
所述二十碳五烯酸的质量可以为5g、10g、20g、30g或40g等。
所述磷脂的质量可以为5g、6g、7g、8g或10g等。
所述乙酰胆碱的质量可以为0.25g、1g、2g、3g、5g、7g或9g等。
所述褪黑素的质量可以为0.5g、0.6g、0.7g或0.8g等。
所述辅酶Q10的质量可以为0.1g、0.12g、0.14g、0.16g、0.18g或0.2g等。
所述软骨素的质量可以为2g、3g、4g、5g、6g、7g或8g等。
所述钙的质量可以为15g、17g、18g、19g、20g、22g、24g或25g等。
在一个具体方案中，所述药物或营养添加剂或食品适用于年龄大于25岁，例如30岁、40岁、50岁、60岁、70岁、80岁等，优选大于40岁的人。
在一个具体方案中，所述脑部退行性病变包括阿尔茨海默症。
在一个具体方案中，所述药物或营养添加剂或食品适用于携带阿尔茨海默症突变基因的人。
在一些实施方案中，所述唾液酸类化合物的施用时间至少为4个月，施用时间可以为4个月、12个月、1年、2年、4年、8年、12年、24年，持续性施用。
在一些实施方式中，以至少一天一次、至少一天两次、至少一天三次、至少一天四次、至少一天五次、至少一天六次、至少一天七次、至少一天八次、至少一天九次、至少一天十次将唾液酸类化合物进行施用。
另一方面，本申请还提供了唾液酸类化合物在制备预防或治疗脑部退行性病变或改善认知能力的药物中的应用，其中，所述唾液酸类化合物包括N-乙酰神经氨酸、N-乙酰神经氨酸 聚合物或N-乙酰神经氨酸衍生物；其中所述N-乙酰神经氨酸衍生物包括N-乙酰神经氨酸可药用盐、低聚糖结合物、脂类结合物或蛋白结合物中的任意一种或至少两种的组合。
另一方面，本申请还提供了一种用于预防和/或治疗脑部退行性病变的药物，其包括唾液酸类化合物，所述唾液酸类化合物包括游离唾液酸、结合形式的唾液酸或唾液酸前体。
另一方面，本申请还提供了一种用于改善认知能力的药物，其包括唾液酸类化合物，所述唾液酸类化合物包括游离唾液酸、结合形式的唾液酸或唾液酸前体。
另一方面，本申请还提供了一种用于预防脑部退行性病变和/或改善脑部环境的食品或营养添加剂其包括唾液酸类化合物，所述唾液酸类化合物包括游离唾液酸、结合形式的唾液酸或唾液酸前体。
另一方面，本申请还提供了一种用于改善认知能力的食品或营养添加剂其包括唾液酸类化合物，所述唾液酸类化合物包括游离唾液酸、结合形式的唾液酸或唾液酸前体。
相对于现有技术，本申请具有以下有益效果：
本申请首次发现通过补充唾液酸类化合物，改善认知能力，能够预防脑部退行性病变，改善脑部营养环境，治疗早期脑部退行性病变，尤其是对阿尔茨海默症的高风险人群有显著的预防、改善或治疗作用。具体来说，唾液酸类化合物既可以提高脑部退行性病变群体的认知能力，改善脑部环境，进而预防脑部退行性病变或治疗早期脑部退行性病变；也可以提高正常群体的认知能力。其既可以以药物的形式也可以以食品或营养添加剂的形式发挥上述有益效果。
附图说明
图1是实施例2中各组小鼠游泳的路径图(图中WT表示施用安慰剂的正常小鼠组、WT+SA(H)表示施用高剂量N-乙酰神经氨酸的正常小鼠组、AD表示施用安慰剂的疾病小鼠组、AD+SA(H)表示施用高剂量N-乙酰神经氨酸的疾病小鼠组、AD+SA(M)表示施用中剂量N-乙酰神经氨酸的疾病小鼠组、AD+SA(L)表示施用低剂量N-乙酰神经氨酸的疾病小鼠组)；
图2是实施例2中24h后小鼠在原平台象限的停留时间统计图；
图3是实施例2中72h后小鼠在原平台象限的停留时间统计图；
图4是实施例2中24h后小鼠穿越原平台位置的次数统计图；
图5是实施例2中72h后小鼠穿越原平台位置的次数统计图；
图6是实施例3中各组小鼠的穿越格子数得分统计图；
图7是实施例3中各组小鼠的站立次数得分统计图；
图8示出了硫黄素T染色检测小鼠脑内海马和皮层区的错误蛋白折叠情况(CA3：小鼠海马CA3区；CA1：小鼠海马CA1区；Cor：皮层区；DG：海马齿状回区)；
图9示出了银染检测小鼠海马区、皮层区神经纤维缠结(CA3：小鼠海马CA3区；CA1：小鼠海马CA1区；Cor：皮层区；DG：海马齿状回区)；
图10示出了尼氏染色检测小鼠海马区、皮层区神经元活性情况(CA3：小鼠海马CA3区；CA1：小鼠海马CA1区；Cor：皮层区；DG：海马齿状回区)；
图11示出了液体核磁分析脑中各区牛磺酸(Taurine)的相对含量(n＝4)；
图12示出了液体核磁分析脑中各区N-乙酰-L-天门冬氨酸(NAA)的相对含量(n＝4)；
图13示出了液体核磁分析脑中各区谷氨酸比N-乙酰天门冬氨酸(Glu/NAA)的相对含量(n＝4)；
图14示出了液体核磁分析脑中各区谷氨酸/γ-氨基丁酸(Glu/GABA-C4)的相对含量(n＝4)；
图15示出了结构核磁：各脑区连接值的热图，横纵坐标表示不同的脑区；
图16示出了组内比较：不同皮层亚区与海马区的连接值在不同组小鼠中的差异；
图17示出了组内比较：不同皮层亚区之间的连接值在不同组小鼠中的差异；
图18示出了2×Tg-AD实验小鼠的APP/PS1qPCR图。
具体实施方式
下面通过具体实施方式来进一步说明本申请的技术方案。本领域技术人员应该明了，所述实施例仅仅是帮助理解本申请，不应视为对本申请的具体限制。
下述实施例以阿尔茨海默症小鼠为模型(APP/PS1 2×Tg-AD雄性小鼠，该模型对小鼠转入了APP/PS1两种基因，可于大脑中大量产生Aβ，对照组使用的是B6129SF2/J-WT雄性小鼠)，图18显示了与对照小鼠相比，转基因小鼠脑内APP、PS1基因的大量表达。通过行为学实验：水迷宫实验和旷场实验、神经元活性及突触功能实验、核磁共振等实验来验证唾液酸类化合物能够改善脑部营养环境，提升或改善记忆力，能够预防和/或治疗脑部退行性病变，尤其是对阿尔茨海默症的病例症状有显著的预防、改善或治疗作用。
实施例1
实验分组情况：
本实验共分为六组，每组12只小鼠，分别是：
(1)施用安慰剂的正常小鼠组(安慰剂使用量为420mg/Kg/day，以WT表示)；
(2)施用高剂量N-乙酰神经氨酸的正常小鼠组(N-乙酰神经氨酸使用量为420mg/Kg/day，以WT+SA(H)表示)；
(3)施用安慰剂的疾病小鼠组(安慰剂使用量为420mg/Kg/day，以AD表示)；
(4)施用高剂量N-乙酰神经氨酸的疾病小鼠组(N-乙酰神经氨酸使用量为420mg/Kg/day，以AD+SA(H)表示)；
(5)施用中剂量N-乙酰神经氨酸的疾病小鼠组(N-乙酰神经氨酸使用量为84mg/Kg/day，以AD+SA(M)表示)；
(6)施用低剂量N-乙酰神经氨酸的疾病小鼠组(N-乙酰神经氨酸使用量为17mg/Kg/day，以AD+SA(L)表示)。
所施用的N-乙酰神经氨酸为嘉必优生物技术(武汉)有限公司生产的市售产品，N-乙酰神经氨酸含量≥98％。
实施例2
水迷宫实验
Morris水迷宫实验在脑部退行性疾病如阿尔茨海默症的研究中是非常有效的，这些疾病最大的特征就是认知能力的减退，Morris水迷宫实验所检测的是在小鼠训练中，学会寻找固定位置隐蔽平台的能力，形成稳定的空间位置认知，实验步骤如下：
(1)各组小鼠正常饮食喂养至3月龄后，将各剂量的N-乙酰神经氨酸或安慰剂分别混入小鼠饲料中，小鼠采用自由取食方式喂养4个月；
(2)采用Morris水迷宫实验标准进行隐蔽站台试验和空间探索试验，隐蔽站台试验结束24h或72h后记录小鼠定位平台的路径、60s内小鼠在原平台象限的停留时间、60s内小鼠穿越原平台的次数。
实验结果：
(1)小鼠进行平台定位的路径图如图1所示，小鼠游泳有绕边性和边缘性，而站台是远离周边靠近水池中心的，若小鼠改变了游泳路线在靠近水池中心区域中活动路程较长，说明小鼠的空间记忆能力好，若小鼠在水池周边区域内活动，则其空间记忆能力差。由图1可知：施用安慰剂的疾病小鼠有明显的绕边性和边缘性，与其相比，施用N-乙酰神经氨酸的小鼠更多地在水池中心区域内活动，且能够更加快速地定位平台，说明用药组的小鼠记忆能力更强，且其阿尔茨海默病症状有所缓解；而且N-乙酰神经氨酸的剂量越高，其效果越好，施用高剂量N-乙酰神经氨酸的疾病小鼠的效果甚至优于施用安慰剂的正常小鼠。
(2)隐蔽站台试验结束并撤去平台24h后小鼠在原平台象限的停留时间统计图如图2所示，由图2可知：与正常组的小鼠相比，具有疾病的小鼠其在原站台象限的停留时间显著低于正常组；在施用N-乙酰神经氨酸后，其停留时间显著延长，且随着剂量的升高，其效果更加明显，说明N-乙酰神经氨酸有提高小鼠记忆力、改善其认知能力、缓解阿尔茨海默症病症的功效。
(3)隐蔽站台试验结束并撤去平台72h后小鼠在原平台象限的停留时间统计图如图3所示，由图3可知：与正常组的小鼠相比，具有疾病的小鼠其在原站台象限的停留时间显著低于正常组；在施用N-乙酰神经氨酸后，其停留时间显著延长，且随着剂量的升高，其效果更加明显，说明N-乙酰神经氨酸有提高小鼠记忆力、改善其认知能力、缓解阿尔茨海默症病症的功效。
(4)隐蔽站台试验结束并撤去平台24h后小鼠穿越原平台位置的次数统计图如图4所示，在一定的时间内，小鼠穿越原平台位置的次数越多，说明其空间学***台位置的次数显著提高，说明N-乙酰神经氨酸也能够提高正常小鼠的认知能力，与正常组相比，具有疾病的小鼠其穿越原平台位置的次数明显降低，在施用N-乙酰神经氨酸后，其穿越原平台位置的次数明显增多，说明N-乙酰神经氨酸有提高小鼠记忆力、改善其认知能力、缓解阿尔茨海默症病症的功效。
(5)隐蔽站台试验结束并撤去平台72h后小鼠穿越原平台位置的次数统计图如图5所示，由图5可知：正常小鼠组在施用N-乙酰神经氨酸后其穿越原平台位置的次数显著提高，说明N-乙酰神经氨酸也能够提高正常小鼠的认知能力，与正常组相比，具有疾病的小鼠其穿越原平台位置的次数明显降低，在施用N-乙酰神经氨酸后，其穿越原平台位置的次数明显增多，说明N-乙酰神经氨酸有提高小鼠记忆力、改善其认知能力、缓解阿尔茨海默症病症的功效。
实施例3
旷场实验
旷场实验反映小鼠在陌生环境中的自主行为与焦虑情绪，实验步骤如下：
(1)各组小鼠正常饮食喂养至3月龄后，将各剂量的N-乙酰神经氨酸或安慰剂分别混入小鼠饲料中，小鼠采用自由取食方式喂养4个月；
(2)采用旷场实验标准进行实验，记录小鼠的穿越格子和站立次数。
实验结果及结论：
施用N-乙酰神经氨酸喂养4个月后，与正常小鼠相比，AD小鼠表现出典型的抑郁/焦虑行为，包括网格交叉和饲养频率显著降低(图6、7)。与AD小鼠相比，N-乙酰神经氨酸处理组显著改善了抑郁/焦虑行为，显著增加了AD疾病小鼠的穿越格子和站立频率(图6、7)。以上行为表明，N-乙酰神经氨酸可以有效改善AD小鼠的认知恶化和抑郁/焦虑行为，特别是在中、高N-乙酰神经氨酸浓度下。
实施例4
Aβ病理检测
硫黄素T染色检测小鼠脑内错误折叠蛋白情况
通过硫黄素T染色检测小鼠脑内海马区和皮层区的错误蛋白折叠情况，在一定程度上反应Aβ在脑部的聚集和分布情况。由结果知，海马CA3区WT和AD有差异，AD+SA(L)错误蛋白比AD多，而AD+SA(M)、AD+SA(H)比AD少；海马CA1区WT和AD也有差异，WT+SA(H)比WT更多，AD+SA(L)、AD+SA(M)比AD少，AD+SA(H)比AD多，皮层区(cortex区)AD+SA(L)、AD+SA(H)错误折叠蛋白比AD多；齿状回区(DG区)结果与CA3区一致(图8，n＝4)。此结果可作为反应脑部Aβ聚集状况和老年斑形成分布的参考。
实施例5
Tau病理检测
银染检测小鼠脑内神经纤维缠结情况
通过甘氨酸银染色检测小鼠脑内海马区和皮层区的神经纤维缠结(NFT)情况，神经纤维缠结的形成是由于Tau蛋白的过度磷酸化，使其从微管上脱落后相互缠绕形成神经纤维缠结。由结果知，WT与AD在海马CA区、CA1区、齿状回区和皮层区中的神经纤维缠结有明显差异，WT+SA(H)中神经纤维缠结比WT少，AD+SA(L/M/H)中神经纤维缠结都比AD少，随着剂量的升高，各脑区中神经纤维缠结的数量也逐渐变少(图9，n＝4)。
实施例6
小鼠脑内神经元活性和突触相关蛋白表达情况
尼氏染色检测神经元活性
神经元的活性情况可通过检测尼氏小体的数量来判断，尼式染色是检测小鼠脑组织细胞中的粗面内质网上尼氏小体的数量，尼式小体着色数量越多说明神经元丢失越少，尼式小体受染液着色数量越少说明神经元丢失越多。由结果知，AD的海马CA3区、CA1区、齿状回区和皮层区中尼氏小体数量都明显少于WT，WT+SA(H)皮层区尼氏小体数量明显少于WT；喂食唾液酸的AD小鼠在低中高剂量反应有所不同，AD+SA(L)海马CA3区、CA1区、齿状回区和皮层区中尼氏小体数量明显多于AD，AD+SA(M)、AD+SA(H)的海马CA3区、CA1 区、齿状回区和皮层区中尼氏小体数量也多于AD，但是低于AD+SA(L)(图10，n＝4)。由此可知，可能会减少AD中神经元活性的丢失，但是剂量上不成依赖性。
实施例7
液体核磁及功能磁共振成像实验结果
(1)液体核磁
液体核磁主要检测和分析了以下几种小分子物质在小鼠大脑中的相对含量，包括肌醇、牛磺酸、天门冬氨酸、谷氨酸、谷氨酰胺、γ-氨基丁酸、N-乙酰-L-天门冬氨酸、丙氨酸。肌醇(Myo-Inositol,MI)又叫“环己六醇”，B族维生素之一。为微生物和许多动物的必需营养素，动物膳食中缺乏肌醇时，出现脱毛，影响发育。广泛分布在动植物体内，结构与葡萄糖类似，是一种生长因子。已有研究发现，其有代谢脂肪和胆固醇的作用，有助预防动脉硬化。同时肌醇在供给脑细胞营养上，扮演重要的角色。神经***中存在有大量的氨基酸，这些物质除参与神经***的一般代谢过程与维持细胞内、外水分及电解质平衡外，还做为化学传递物质参与神经兴奋及抑制调节，其中包括对神经细胞有兴奋作用的氨基酸如谷氨酸(Glu)、天冬氨酸(Asp)等酸性氨基酸，具有抑制作用的如γ-氨基丁酸(GABA)。谷氨酰胺(Gln)具有保护大脑的功能，作为大脑的一种能量来源，谷氨酰胺能改善心情，增强智力，并有益于长期与短期记忆。牛磺酸(Taurine)与脑发育关系,可促进大白鼠的学习与记忆能力。补充适量牛磺酸不仅可以提高学习记忆速度，而且还可以提高学习记忆的准确性，并且对神经***的抗衰老也有一定作用。N-乙酰-L-天门冬氨酸(N-acetylaspartate,NAA)仅存在于脑内神经元及突起中，是反映神经元损伤严重程度的标记物，NAA含量的高低被认为是神经元数目的增加或减少的信号。
牛磺酸是哺乳动物组织中以高浓度存在的含硫氨基酸，涉及大脑发育和神经传递等过程，目前研究证明其参与细胞体积调节和调节膜电位从而减弱电活动并使神经元超极化。由结果知(图11)，在海马、皮层和嗅球区域，AD中牛磺酸浓度显著低于WT(*p<0.05)，喂食不同浓度的N-乙酰神经氨酸后能升高牛磺酸浓度但是无显著差异。
N-乙酰-L-天门冬氨酸是神经元损伤程度的一项重要生化指标，NAA下降表明神经元代谢紊乱。由结果知(图12)，在喂食N-乙酰神经氨酸后，AD中NAA浓度升高或不变，虽然没有显著性差异，但是NAA浓度上升的趋势能够作为N-乙酰神经氨酸保护神经元正常代谢的佐证指标。另外，WT+SA(H)的NAA浓度在各个不同脑区中的变化有高有低，不具有显著性差异，这可能是个体差异导致的结果，也可能是存在下降趋势，但是下降程度不能达到破坏神经元的正常代谢过程的程度。
用谷氨酸与N-乙酰天冬氨酸的比值综合说明糖代谢程度和神经元正常代谢状况。由结果知(图13)，AD+SA(M)的Glu/NAA显著低于AD(*p<0.05)，AD+SA(H)的Glu/NAA也显著低于AD(*p<0.05)，说明喂食N-乙酰神经氨酸对改善AD鼠神经元代谢紊乱和缓解AD症状有一定的作用。
用谷氨酸与γ-氨基丁酸的比值来综合性说明神经递质的效果。由结果知(图14)，给WT+SA(H)的Glu/GABA-C4与WT相比总体是升高的，AD+SA(L/M/H)与AD相比也是如此，说明喂食N-乙酰神经氨酸对改善神经传递过程的优大于劣；Glu/GABA-C4的相对量在海马区域、皮层区域中的比值比其他区域高很多，中脑区域AD的Glu/GABA-C4比值显著高于WT。
(2)功能磁共振成像结果
基于血氧水平依赖(BOLD)效应的功能磁共振成像(functional magnetic resonance imaging, fMRI)技术，可以重复进行无创伤性的实验，能够有效地检测出认知任务刺激下大脑皮层中不同功能区的激活,并且可以获取准确的空间定位信息。因此，fMRI技术是脑与认知科学研究中最为有效的手段之一。大脑活动时(包括运动、语言、记忆、认知、情感、听觉、视觉等)并不是全脑都参与，而是其中一个区域或几个区域参与。可以利用BOLD技术对大脑活动变化时产生的血液动力学和代谢改变进行测量，通过脑皮层的MRI信号变化，从而对功能区进行定位，揭示脑的奥秘。
本次功能磁共振成像实验中采用了静息态fMRI。静息态fMRI(resting-state fMRI，rs-fMRI)是指让受试者保持清醒、闭眼、平静呼吸且不进行任何思维活动和自主运动的静息状态下进行数据采集的一种磁共振成像技术，其采集的BOLD信号反映了脑组织神经元的自发活动。静息态fMRI无需进行复杂的任务设计和接受任何刺激，可以避免由于实验设计或被试执行任务是的差异导致的实验结果的不可靠性，具有较高的可重复性和实用性。研究静息状态下自发神经元活动对理解神经功能疾病有着重要的意义，当前静息态已被用于许多神经精神领域的疾病研究，包括阿尔茨海默症。
本研究的分析方法为功能连接分析，主要检测不同脑区的连接值，反映了脑区之间的相关性。核磁结果共分析了37个感兴趣的脑区(Region of interested,ROI)之间的连接，在此，申请人主要关注皮层区和海马区的连接。海马区只有一个区，即28区。皮层区分了14个亚区，分别为：Region5:Prelimbic Cortex(前边缘皮层)；Region6:Cingulate Cortex(扣带回皮层)；Region7:Piriform Cortex(梨状皮层):Region8-Somatosensory Cortex(体感皮层)；Region9:Auditory Cortex(听觉皮层)；Region13:Insular Cortex(脑岛皮层)；Region17:Perirhinal Cortex(鼻周皮层)；Region18:Ectorhinal Cortex(鼻外皮层)；Region19:Entorhinal Cortex(内嗅皮层)；Region20:Temporal Associatin Cortex(颞叶联合皮层)；Region22:Visual Cortex(视觉皮层)；Region23:Retrosplenial Cortex(压后皮层)；Region24:Motor Cortex(运动皮层)；Region32:Orbital Cortex(额眶部皮层)。
基于图15的热图，我们提取了不同皮层亚区与海马区的连接值并比较了该连接值在各组小鼠内的差异(图16)。发现几个凌然感兴趣的现象，如脑区5-28之间，即前边缘皮层区和海马区，在WT小鼠中是弱负相关，而在AD小鼠内是正相关，中低剂量的SA处理后，其连接值又变为负相关。其他有这种调控作用的包括脑区6-28(扣带回皮层区和海马区)、9-28(听觉皮层区和海马区)、17-28(鼻周皮层和海马区)、22-28(视觉皮层区和海马区)和32-28(额眶部皮层区和海马区)。
此外，我们比较了不同皮层亚区之间的连接值在不同组小鼠中的差异(图17)，发现SA对5-24(前边缘皮层区和运动皮层区)、9-20(听觉皮层区和颞叶联合皮层区)、9-23(听觉皮层区和压后皮层区)等几组脑区之间的相关性具有积极的调控作用。
实施例7结论：
(1)从液体核磁的结果分析得出，SA改善了AD小鼠脑内多个代谢物(牛磺酸、N-乙酰-L-天门冬氨酸等)的水平，说明SA可在一定程度上抑制神经元代谢损伤，改善神经功能。
(2)从功能磁共振成像结果可以看到，SA对AD小鼠多个脑区之间的连接值(相关性)具有积极的调控作用，包括前边缘皮层、扣带回皮层、听觉皮层、鼻周皮层、颞叶联合皮层、运动皮层、海马区等，提示SA可能对动物体的学习记忆、听觉、运动等有积极的意义。
综合以上所有实验及结果：唾液酸是一种大脑中天然存在的神经节苷脂的传递递质，在人的大脑中含量最高，目前研究证明其能提高动物的学***衡，另一方面，随着炎症的发生及恶性肿瘤形成时唾液酸也出现伴随性增高。由目前取得的研究可知，唾液酸能改善小鼠学习能力和焦虑情绪，防止神经元丢失，减少部分Aβ寡聚体的积累和神经纤维缠结的形成；可能通过影响神经递质改善AD症状，从AD发病早期开始进行药物预防可能对减缓AD症状起到一定作用。
根据FDA推荐的指导方案Guidance for Industry:Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers中的记载，由小鼠给药量进行成人用量的换算，此用量可按照成人的体重进行给药换算，例如，按照成年人体重为60kg计算，换算后的唾液酸每日人体摄入量分别为：低剂量82.62mg，中计量408.24mg，高剂量2041.2mg。
申请人声明，本申请通过上述实施例来说明本申请的唾液酸类化合物在制备预防和/或治疗脑部退行性病变药物中的应用、唾液酸类化合物在制备改善认知能力的药物中的应用、唾液酸类化合物在制备改善脑部退行性病变的食品或食品添加剂中的应用和唾液酸类化合物在制备改善认知能力的食品或食品添加剂中的应用。但本申请并不局限于上述实施例，即不意味着本申请必须依赖上述实施例才能实施。所属技术领域的技术人员应该明了，对本申请的任何改进，对本申请产品各原料的等效替换及辅助成分的添加、具体方式的选择等，均落在本申请的保护范围和公开范围之内。
以上详细描述了本申请的优选实施方式，但是，本申请并不限于上述实施方式中的具体细节，在本申请的技术构思范围内，可以对本申请的技术方案进行多种简单变型，这些简单变型均属于本申请的保护范围。
另外需要说明的是，在上述具体实施方式中所描述的各个具体技术特征，在不矛盾的情况下，可以通过任何合适的方式进行组合，为了避免不必要的重复，本申请对各种可能的组合方式不再另行说明。

Claims (15)

  1. 唾液酸类化合物在制备用于预防脑部退行性病变或治疗脑部退行性病变或改善认知能力的药物，或用于预防脑部退行性病变或改善脑部环境或改善认知能力的营养添加剂或食品中的应用，其中，所述唾液酸类化合物包括游离唾液酸、结合形式的唾液酸或唾液酸前体。
  2. 如权利要求1所述的应用，其中，
    所述游离唾液酸包括N-乙酰神经氨酸和/或N-乙酰神经氨酸可药用盐，
    所述结合形式的唾液酸包括低聚糖结合物、脂类结合物和蛋白结合物之中的任意一种或至少两种的组合，
    所述唾液酸前体包括N-乙酰甘露糖胺、N-丙酰甘露糖胺、2-酮-3-脱氧壬酮糖酸和N-羟乙酰神经氨酸中的任意一种或至少两种的组合。
  3. 如权利要求1或2所述的应用，其中，所述药物和所述营养添加剂的剂型包括片剂、散剂、颗粒剂、胶囊剂、注射剂、喷雾剂、膜剂、栓剂、滴鼻剂或滴丸剂。
  4. 如权利要求1-3中任一项所述的应用，其中，所述唾液酸类化合物在所述剂型中的重量百分比为0.01％-99.9％。
  5. 如权利要求1-4中任一项所述的应用，其中，所述药物和所述营养添加剂的施用途径包括静脉注射、腹腔注射、肌肉注射、皮下注射、口服给药、舌下给药、鼻腔给药或经皮给药。
  6. 如权利要求1-5中任一项所述的应用，其中所述唾液酸类化合物以相当于1-35mg N-乙酰神经氨酸/Kg体重/日的剂量施用于人类。
  7. 如权利要求1-5中任一项所述的应用，其中所述唾液酸类化合物以相当于20mg-3.5g N-乙酰神经氨酸/日的剂量给药。
  8. 如权利要求1-7中任一项所述的应用，其中，所述唾液酸类化合物负载于药用载体上；
    优选地，所述药用载体包括脂质体、胶束、树枝状大分子、微球或微囊。
  9. 如权利要求1-8中任一项所述的应用，其中，所述唾液酸类化合物与二十二碳六烯酸、花生四烯酸、二十碳五烯酸、磷脂、乙酰胆碱、褪黑素、辅酶Q10、软骨素、钙、维生素B、维生素E或维生素C中的任意一种或至少两种联合使用；
    优选地，以重量份数计，所述唾液酸类化合物与二十二碳六烯酸5-40份、花生四烯酸1-30份、二十碳五烯酸5-40份、磷脂5-10份、乙酰胆碱0.25-9份、褪黑素0.5-0.8份、辅酶Q10 0.1-0.2份、软骨素2-8份、钙15-25份、维生素B、维生素E或维生素C中的任意一种或至少两种联合使用。
  10. 如权利要求1-9中任一项所述的应用，其中，所述唾液酸类化合物适用于年龄大于25岁，优选大于40岁的人。
  11. 如权利要求1-10中任一项所述的应用，其中，所述唾液酸类化合物适用于携带阿尔茨海默症突变基因的人。
  12. 如权利要求1-11中任一项所述的应用，其中，所述脑部退行性病变包括阿尔茨海默症。
  13. 唾液酸类化合物在制备预防或治疗脑部退行性病变或改善认知能力的药物中的应用，其中，所述唾液酸类化合物包括N-乙酰神经氨酸、N-乙酰神经氨酸聚合物或N-乙酰神经氨酸衍生物，
    其中所述N-乙酰神经氨酸衍生物包括N-乙酰神经氨酸可药用盐、低聚糖结合物、脂类结合物或蛋白结合物中的任意一种或至少两种的组合。
  14. 一种用于预防脑部退行性病变或治疗脑部退行性病变或改善认知能力的药物组合物，其包括唾液酸类化合物，所述唾液酸类化合物包括游离唾液酸、结合形式的唾液酸或唾液酸前体。
  15. 一种用于预防脑部退行性病变或改善脑部环境或改善认知能力的食品或营养添加剂，其包括唾液酸类化合物，所述唾液酸类化合物包括游离唾液酸、结合形式的唾液酸或唾液酸前体。
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