WO2010058517A1 - STIMULATEUR DE CELLULES NERVEUSES COMPRENANT IgG ET/OU UN FRAGMENT Fc D’IgG - Google Patents

STIMULATEUR DE CELLULES NERVEUSES COMPRENANT IgG ET/OU UN FRAGMENT Fc D’IgG Download PDF

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WO2010058517A1
WO2010058517A1 PCT/JP2009/005291 JP2009005291W WO2010058517A1 WO 2010058517 A1 WO2010058517 A1 WO 2010058517A1 JP 2009005291 W JP2009005291 W JP 2009005291W WO 2010058517 A1 WO2010058517 A1 WO 2010058517A1
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igg
fragment
memory
learning ability
pharmaceutical
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PCT/JP2009/005291
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English (en)
Japanese (ja)
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横山峰彦
浅見幸夫
内田勝幸
紀光助
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明治乳業株式会社
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • 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
    • A23L33/17—Amino acids, peptides or proteins
    • A23L33/185—Vegetable proteins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/64—Proteins; Peptides; Derivatives or degradation products thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • 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
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • 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
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/08—Anti-ageing preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q7/00—Preparations for affecting hair growth
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/80—Process related aspects concerning the preparation of the cosmetic composition or the storage or application thereof
    • A61K2800/92—Oral administration

Definitions

  • the present invention relates to a nerve cell stimulating agent containing IgG and / or an Fc fragment of IgG, particularly Fc ⁇ as an active ingredient, and a food and pharmaceutical composition containing the nerve cell stimulating agent in an effective amount.
  • the present invention further relates to a method for preventing or treating various diseases and conditions related to aging, particularly a method for improving memory / learning ability, using the nerve cell stimulating agent.
  • Memory is a function that is exhibited by storing and fixing information processed based on experience in the brain and recalling and using it.
  • the process from the acquisition to the storage of necessary information in the process of exhibiting this memory function is referred to as learning, and the functions such as learning and memory can be referred to as “cognition”.
  • learning the functions
  • cognitive function has become a social problem, since this cognitive function has been significantly impaired, and learning, memory, and recall and use of memory are not possible.
  • These are widely known, for example, as those having a major cerebral cortex such as Alzheimer's disease and Pick's disease, and diseases having a major cerebral basal nucleus such as Parkinson's disease.
  • it is considered that the number of patients with these diseases will increase with the aging of the society in the future, and it is necessary to take measures in both medical and social measures against the increase in the number of patients. .
  • Patent Document 1 discloses that the amount of acetylcholine in the central nervous system is increased as a drug related to the prevention, improvement, and treatment of Alzheimer-type memory disorders.
  • therapeutic drugs including erythropoietin have been proposed.
  • Patent Document 2 proposes a composition for improving brain function using a component of an alkali-stable lipid derived from acetic acid bacteria in order to improve a decrease in memory and learning ability due to a decrease in acetylcholinergic nerve function.
  • Patent Document 3 proposes a brain function improving agent containing a specific extract component of black ganoderma since it exhibits inhibitory activity against acetylcholinesterase and prolyl endopeptidase.
  • the brain function improvement composition derived from egg yolk which contains many brain function improvement components, such as a phosphatidylcholine and sialic acid which improved the problems, such as the smell at the time of using for foodstuffs, a stable supply, etc.
  • a composition having an effect of improving memory impairment, which contains a trisulfide derived from the genus Allium in consideration of safety, daily intake, and the like.
  • Japanese Patent No. 3156236 Japanese Patent No. 4040069 JP 2008-156240 A JP-A-9-12597 Special table 2006-516538 gazette Japanese Patent Laid-Open No. 2003-300891 JP 2004-175695 A
  • an organic solvent is essential for the extraction of the active ingredient, so that the residual solvent may be a problem particularly in edible and pharmaceutical preparations. is there.
  • the intake required to obtain a physiological effect is very large, and there are economic problems in production and implementation.
  • the active ingredient is not concentrated, there are safety problems such as the need to ingest a large amount of crushed cells to obtain an effective amount.
  • Patent Document 3 The specific extract of black ganoderma described in Patent Document 3 is very expensive by itself, and since only a very small amount of active ingredient can be separated from the expensive raw material, it must be solved economically. The problem that must be included. Moreover, the effect is still insufficient.
  • compositions disclosed in Patent Documents 6 and 7 are easy to obtain raw materials in terms of using egg yolk, leeks, etc., the effect is still insufficient.
  • whey protein which is a by-product during cheese manufacture, has an effect of improving learning and memory functions.
  • administration of IgG and / or an Fc fragment of IgG to a subject has found an effect that has never been known so far that learning and memory functions are remarkably improved.
  • pharmaceutical and food compositions use natural food ingredients that do not cause irritation to the digestive tract and have no side effects, it has been demonstrated that the intended purpose can be achieved by a safe technique.
  • the present inventors have released calcitonin gene-related peptide (CGRP) from sensory nerves by administering or ingesting IgG and / or Fc fragments of IgG, and as a result, insulin-like growth factor-I. Ascertaining that the production of (IGF-I) is improved, memory / learning ability is improved, and it is effective not only in memory / learning but also in the treatment and prevention of various diseases and conditions related to aging. We have found that we have obtained the invention.
  • CGRP calcitonin gene-related peptide
  • the present invention relates to a nerve cell stimulating agent comprising an effective amount of IgG and / or an Fc fragment of IgG.
  • the present invention also relates to the nerve cell stimulating agent, wherein IgG is derived from whey protein.
  • the present invention further relates to the nerve cell stimulating agent that induces the release of CGRP from nerve cells.
  • the present invention is also selected from the group consisting of ischemia-reperfusion liver injury, stress gastric mucosal lesion formation, cardiovascular disorder, diabetes, diseases related to apoptosis, amyloidosis, and Alzheimer's disease for improving memory / learning ability It relates to said nerve cell stimulating agent for treatment or prevention of one or more diseases, improvement or prevention of skin aging, and / or hair growth.
  • the present invention particularly relates to the nerve cell stimulating agent for improving memory / learning ability.
  • the present invention also relates to a pharmaceutical or food composition containing the nerve cell stimulating agent.
  • the present invention also relates to said composition, wherein the medicament is in an oral dosage form.
  • the present invention also relates to said composition, wherein the content of IgG and / or Fc fragment of IgG is 0.02-90% (w / w).
  • the present invention further relates to said composition, wherein the content of IgG and / or Fc fragment of IgG is 8-25% (w / w).
  • the invention also relates to a method of stimulating nerve cells comprising administering or ingesting a pharmaceutical or food composition comprising an effective amount of IgG and / or an Fc fragment of IgG.
  • the invention also relates to said method, wherein the IgG is derived from whey protein.
  • the invention further relates to the method, wherein the method induces the release of CGRP from nerve cells.
  • the present invention is also selected from the group consisting of ischemia-reperfusion liver injury, stress gastric mucosal lesion formation, cardiovascular disorder, diabetes, diseases related to apoptosis and Alzheimer's disease for improving memory / learning ability 1 Or for the treatment or prevention of two or more diseases, for the improvement or prevention of skin aging and / or for hair growth.
  • the invention particularly relates to said method for improving memory and learning ability.
  • the present invention also provides that the pharmaceutical or food composition comprises IgG in the range of 1 mg to 5 g / kg body weight and / or the Fc fragment of IgG in the range of 0.1 mg to 0.5 g / kg body weight. About.
  • the invention further relates to the method wherein the pharmaceutical or food composition comprises IgG in the range of 10 mg to 1 g / kg body weight and / or the Fc fragment of IgG in the range of 1 mg to 0.1 g / kg body weight.
  • the invention also relates to said method wherein the medicament is administered orally.
  • the present invention also relates to a memory / learning ability improving agent comprising an effective amount of IgG and / or an Fc fragment of IgG.
  • the present invention also relates to the agent for improving memory / learning ability, wherein IgG is derived from whey protein.
  • the present invention also relates to the agent for improving memory / learning ability, wherein the content of IgG and / or Fc fragment of IgG is 0.02 to 90% (w / w).
  • the present invention further relates to the agent for improving memory / learning ability, wherein the content of IgG and / or Fc fragment of IgG is 8 to 25% (w / w).
  • the present invention also relates to a pharmaceutical or food composition containing the memory / learning ability improving agent.
  • the present invention also relates to said composition, wherein the medicament is in an oral dosage form.
  • the present invention also relates to a method for improving memory / learning ability, comprising administering or ingesting a pharmaceutical or food composition containing an effective amount of IgG and / or an Fc fragment of IgG.
  • the invention also relates to said method, wherein the IgG is derived from whey protein.
  • the present invention also provides that the pharmaceutical or food composition comprises IgG in the range of 1 mg to 5 g / kg body weight and / or the Fc fragment of IgG in the range of 0.1 mg to 0.5 g / kg body weight. About.
  • the invention further relates to said method, wherein the medicament is administered orally.
  • the nerve cell stimulator of the present invention promotes the release of CGRP from nerve endings, it can be expected to have a wide range of preventive and therapeutic effects on various diseases and conditions associated with aging. For example, it can be expected to have an effect of reducing ischemia-reperfusion liver injury and stress gastric mucosal lesion formation, an effect of increasing bone density, and the production of IGF-I is increased by releasing CGRP.
  • FIG. 1A is a side view of the Morris water maze
  • FIG. 1B is a plan view thereof.
  • FIG. 2 is a diagram showing measurement results of swimming time (seconds) of the administration group and the comparison group measured in the water maze test after IgG administration.
  • FIG. 3 is a diagram showing the measurement results of swimming time (seconds) of the administration group and the comparison group measured in the water maze test after administration of the Fc fragment of IgG.
  • FIG. 4 is a diagram showing that CGRP is released from neurons into the medium when an Fc fragment (Fc ⁇ ) prepared from IgG is added to an in vitro nerve cell culture system.
  • FIG. 5 shows that CGRP was released from DRG neurons stimulated with an Fc fragment (Fc ⁇ ).
  • FIG. 6 is a diagram showing that the CGRP release assay system using an Fc fragment (Fc ⁇ ) using DRG neurons is pharmacologically valid.
  • FIG. 7 shows that the Fc fragment (Fc ⁇ ) releases CGRP to DRG neurons in a concentration-dependent manner.
  • FIG. 8 shows that DRG neurons stimulated with an Fc fragment (Fc ⁇ ) transiently release CGRP within 30 minutes after stimulation.
  • FIG. 9 is a diagram showing that high affinity Fc ⁇ receptor is expressed in DRG neurons.
  • Immunoglobulin G immunoglobulin G
  • Immunoglobulin G is an abbreviation for Immunoglobulin G (immunoglobulin G) and is a kind of antibody.
  • Immunoglobulins are proteins, made from B cells and first analyzed as molecules involved in the immune response and are now the most well understood molecules. Immunoglobulins are biochemically and functionally divided into five classes, but all immunoglobulins are composed of four polypeptide chains, which further comprise two subunits, namely H There are a heavy chain and a light chain. There are five classes of heavy chains, and this class divides immunoglobulin classes.
  • IgG immunoglobulin G
  • IgM immunoglobulin M
  • IgD immunoglobulin D
  • IgA immunoglobulin A
  • IgE immunoglobulin E
  • IgG is further divided into four subclasses, that is, in the case of humans, IgG1, IgG2, IgG3, and IgG4. In this specification, IgG including these IgG subclasses is described.
  • IgG is a humoral immune system that binds to and neutralizes pathogens. It has functions such as promoting uptake of pathogenic bacteria into phagocytic cells by binding, and further promoting complement activation by binding to pathogenic bacteria.
  • the blood content of IgG is the highest compared to other immunoglobulin classes. IgG molecules therefore play a very important role in the immune system. However, although IgG plays an important role in the immune system in this way, little is known about functions that are effective outside the immune system.
  • CGRP calcitonin gene-related peptide
  • IGF-I Insulin-like growth factor-I
  • IGF-I is a peptide hormone with a molecular weight of approximately 7,500 daltons that has a structure and action very similar to insulin (Organization and sequence of human insulin-like growth factor I gene. Alternative RNA processing produces two insulin-like growth factor I precursor peptides.Rotwein P, et al. J. Biol. Chem. vol. 261 (11), 4828-4832, (1986) .
  • IGF-I is a polypeptide that is known to be produced mainly in the liver by stimulation of growth hormone secretion, and exists in the blood as a polymer complex by binding to an IGF-binding protein.
  • IGF-I insulin growth factor-binding protein
  • IGF-binding protein regulated by growth hormone (Humbel RE, The above).
  • IGF-I is known to actively maintain cells in a healthy state and suppress the progression of aging, such as promoting cell differentiation and helping cell growth (Insulin-like growth factorIandII, Review) Humbel RE, Eur. J. Biochem., Vol. 190, 445-462, (1990)).
  • IGF-I insulin-like growth factor-I
  • IGF-I growth hormone
  • GH growth hormone
  • IGF-I production amount of each tissue was increased by stimulating.
  • GH and IGF-I may be administered, but these components are still expensive even if they are genetically modified drugs, and they are decomposed by oral administration. Therefore, it is limited to subcutaneous injection and intravenous administration in medical institutions.
  • hypoglycemia may be caused by the same action as insulin.
  • the method of increasing the IGF-I production amount of hippocampal tissue by stimulating the sensory nerves of the stomach using other components is caused by neurotransmission via CGRP release, and is therefore concerned about the permeability of the blood brain barrier.
  • food ingredients have attracted attention as a means to promote the secretion of IGF-I in each tissue in a safer and cheaper manner, and there have been many reports that capsaicin has been effective so far.
  • hippocampal CGRP and IGF-I production increases in wild-type mice, and angiogenesis and neurogenesis increase in hippocampal dentate gyrus, but in CGRP gene knockout mice These phenomena do not occur. Further, in wild-type mice, spatial recognition ability is improved by administration of capsaicin, but the improvement is suppressed when an antibody against IGF-I or an antagonist of CGRP receptor is administered. These results indicate that stimulation of sensory nerves with capsaicin and the like increases CGRP levels and promotes IGF-I production in the hippocampus, which may improve cognitive functions through the formation of blood vessels and neurons.
  • substances having sensory nerve stimulating action such as capsaicin stimulate sensory nerves in the digestive tract when orally administered.
  • the signal may stimulate parasympathetic nerves via the spinal thalamic tract and vagus sensory nerves and increase IGF-I production throughout the body. That is, signals that reach the thalamus through these pathways act on the vagal motor nucleus of the medulla and cause acetylcholine secretion from the vagus nerve endings distributed throughout the body. Since acetylcholine has a sensory nerve stimulating action, it is considered that CGRP release is promoted from sensory nerve endings distributed throughout the body, and as a result, IGF-I production is promoted in systemic tissues such as the central nervous system.
  • the orally administered IgG of the present invention and / or the Fc fragment of IgG allows the sensory nerve endings of the gastrointestinal tract to be used. Not only promotes the release of CGRP, but also enhances the production of IGF-I in tissues throughout the body via a signal transduction system originating from this, and as a result, CGRP and IGF- also in the central nervous system It is strongly suggested that the production amount of I is increased, and particularly the learning / memory function in the hippocampus is enhanced.
  • the effect expected by the nerve cell stimulating agent of the present invention is not limited to the memory / learning improving effect, but by enhancing IGF-I production in the whole body tissue through sensory nerve stimulation of the digestive tract, The effect etc. which prevent or improve the various diseases shown are mentioned.
  • the nerve cell stimulator of the present invention by increasing the production of IGF-I, it protects against cardiovascular disorders, reduces blood glucose in diabetic patients, suppresses apoptosis of cells, amyloid ⁇ in the hippocampus Effects such as protein removal and therapeutic effects on Alzheimer's disease, collagen production and elastin production increase in the skin, and hair growth effects can be expected.
  • CGRP released from sensory nerve endings in ischemia-reperfusion liver injury and stress gastric mucosal lesion models is also used for vascular endothelial cell nitric oxide (NO) and PGI 2.
  • NO vascular endothelial cell nitric oxide
  • PGI 2 vascular endothelial cell nitric oxide
  • TNF ⁇ tumor necrosis factor
  • Stimulation of sensory neurons by capsaicin increases tissue levels of IGF-I, thus reducing reperfusion-induced apoptosis in mice.
  • CGRP has the effect of promoting IGF-I production in osteoblasts and increasing bone density
  • the neuropeptide calcitonin gene-related peptide stimulates insulin-like growth factor-I production by primary fetal rat osteoblasts.Vignery A. and McCarthy TL, Bone, vol. 18 (4), 331-335, (1996); Effects of calcitonin gene-related peptide on bone turnover invariotomomized rats.Valentijn K. et al. , Vol. 21 (3), 269-274, (1997); Targeted expression of calcitonin gene-related peptide to osteoblasts increases bone density in mice. Ballica R. et al., J. Bone Miner. Res., Vol. 14 (7), 1067-1074, (1999)).
  • the nerve cell stimulating agent of the present invention induces CGRP release from sensory nerve cells, treatment (reduction and improvement) and prevention effect of ischemia-reperfusion liver injury and stress gastric mucosal lesion formation, and An effect of increasing bone density is expected.
  • the IgG used in the present invention is preferably found in the milk of mammals including humans, and can also be obtained from whey, which is a by-product of the cheese manufacturing process.
  • the IgG is preferably derived from whey protein. Whey, a by-product of cheese manufacture, is highly nutritious because it contains many useful proteins in its composition.
  • the IgG used in the present invention it is preferable to use high-purity IgG obtained by combining ion exchange resin chromatography and molecular sieve technology using a UF membrane from whey protein.
  • IgG obtained by the method described in JP-T-2001-516599 can be used.
  • the nerve cell stimulating agent of the present invention When the nerve cell stimulating agent of the present invention is orally administered, IgG is degraded by pepsin in the digestive tract, and is degraded into F (ab ′) 2 and a number of Fc fragments.
  • the active ingredient when administered orally (via the stomach) or taken as food, the active ingredient may be IgG or an Fc fragment of IgG. In the case of parenteral administration, the active ingredient preferably contains an Fc fragment.
  • the Fc fragment of IgG used in the present invention can be obtained by subjecting IgG to a predetermined enzyme treatment (for example, IgG papain digestion), fragmenting and purifying.
  • a purification method there is a method of using a column having affinity for IgG such as a protein G column.
  • the nerve cell stimulating agent of the present invention can be used only with IgG and / or Fc fragment of IgG, or with other active substances, or with other pharmacological active substances.
  • active substances include therapeutic agents for Alzheimer's disease (eg secretase inhibitors, acetylcholinesterase inhibitors such as donepezil), inflammatory cytokine production inhibitors, gastric or intestinal mucosal protective agents, cardiovascular disease therapeutic agents, diabetes
  • therapeutic drugs eg, hypoglycemic drugs, thiazolidine derivatives, GLP-1 receptor agonists, insulin, etc.
  • osteoporosis therapeutic drugs eg, calcitonin, estrogen, calcium, vitamin D, vitamin K, etc.
  • the present invention is a pharmaceutical or food composition
  • an effective amount is an amount sufficient to exert a desired physiological effect in a subject, for example, an amount that promotes the release of CGRP from nerve cells, an amount that promotes production of IGF-I, cell apoptosis Suppressing amount, promoting vascular and neuronal neogenesis, promoting amyloid ⁇ protein deposit removal, Alzheimer's disease, cardiovascular disorder, ischemia reperfusion liver injury and / or stress gastric mucosa
  • An amount that reduces the onset of lesion formation, reduces symptoms and / or prevents progression, an amount that improves memory and learning ability, an amount that promotes the production of collagen and elastin, or an amount that promotes hair growth is there.
  • an amount that does not cause adverse effects exceeding the benefits of administration is preferred.
  • Such an amount can be appropriately determined by an in vitro test using cultured cells or the like, or a test in a model animal such as a mouse, rat, dog or pig, and such a test method is well known to those skilled in the art. .
  • the pharmaceutical composition of the present invention is not particularly limited as long as it can be used effectively as a human medicine or veterinary medicine and can stimulate sensory nerves.
  • oral, transdermal, transmucosal, subcutaneous It can be administered by various administration routes such as sublingual, rectal, intraperitoneal, and intranasal.
  • Oral administration is preferable because administration is easy and a high effect is obtained.
  • Suitable dosage forms for oral administration include tablets, pills, coated tablets, capsules, granules, powders, dispersible powders, solutions, syrups, juices, emulsions, suspensions or drops.
  • Dosage forms suitable for rectal administration include suppositories, and dosage forms suitable for parenteral administration include injectable solutions, preferably oil-based or aqueous solutions, suspensions, emulsions or transplants. .
  • Suitable dosage forms for transdermal or transmucosal administration include ointments, creams, emulsions, lotions, powders or patches (patches).
  • excipients are usually used in the pharmaceutical formulation technical field such as excipients, binders, disintegrants, lubricants, coloring agents, flavoring agents, solubilizers, suspension agents, coating agents and the like according to conventional methods. It can be formulated with known adjuvants.
  • excipients suitable for oral administration include mannitol, lactose, maltose, saccharose, starch, magnesium stearate and the like.
  • Suitable excipients for parenteral or topical administration include inert organic or inorganic substances such as water, vegetable oil, benzyl alcohol, alkylene glycol, polyethylene glycol, glycerol triacetate, gelatin, talc or petrolatum.
  • the food composition of the present invention various foods and drinks (milk, soft drinks, fermented milk, yogurt, cheese, cream, bread, biscuits, crackers, bars, jelly, pizza crust, prepared milk powder, fluid Food, food for the sick, food such as infant formula, food such as milk powder for lactating women, nutritional food, etc.) and ingesting this.
  • This active ingredient can be used according to a conventional method in ordinary food compositions, such as being used as it is, or mixed with other foods or food ingredients.
  • the state of the food or drink normally used for example, any of solid (powder, granule, etc.), paste, liquid or suspension may be used.
  • composition of the present invention may be provided as a so-called health food composition having a pharmaceutical-like form.
  • the composition of the present invention can also be used by adding it to dairy products such as cheese, yogurt, fermented milk, milk and ice cream, and other foods.
  • the present invention relates to a method for stimulating nerve cells, comprising administering the above pharmaceutical composition to a subject. Moreover, this invention relates to the stimulation method of a nerve cell including making a subject ingest the said food composition in another aspect.
  • the IgG or IgG Fc fragment in the composition administered or ingested in these methods promotes the secretion of CGRP from nerve cells and induces the production of IGF-I, for example, to improve learning / memory ability. It improves, removes amyloid ⁇ deposits in the brain, and brings about effects such as increasing collagen production in the skin.
  • the specific dose of the composition administered or ingested in the method of the present invention depends on its purpose (improvement of memory / learning ability, treatment or prevention of a disease or condition, hair growth, etc.) and use (pharmaceutical or food, etc.) , Various conditions related to the subject to be administered or ingested, such as severity of symptoms, general health status of the subject, age, weight, subject sex, diet, timing and frequency of administration, route of administration, drugs used in combination , Responsiveness to treatment, compliance with treatment, and the like.
  • the above dose is preferably in the range of 1 mg to 5 g / kg body weight, for example, 10 mg to 1 g / kg body weight, or 75 to 150 mg / kg body weight. Further, the above dose is preferably in the range of 0.1 mg to 0.5 g / kg body weight, for example, 1 mg to 0.1 g / kg body weight, or 5 mg to 20 mg / kg when using an Fc fragment of IgG as an active ingredient.
  • the frequency of administration or intake varies depending on the properties of the composition used and the conditions of the subject as described above. For example, many times a day (ie, 2, 3, 4 or 5 times a day), once a day Every few days (ie every 2, 3, 4, 5, 6, 7 etc.) several times a week (eg 2, 3, 4 etc. per week) every week, every few weeks (ie 2 Every three, four weeks, etc.).
  • the content of IgG and / or the Fc fragment of IgG as an active ingredient in the composition of the present invention can be appropriately determined according to the use (pharmaceutical or food), the form of taking or eating or the dosage form. Is generally in the range of 0.02 to 90% (w / w), for example 0.2 to 50% (w / w), or 8 to 25% (w / w) relative to the total composition. Can be used. When a high-concentration composition is desired, for example, when used in small foods such as orally-applied preparations and tablets, or in sustained-release preparations or reservoir-type preparations, for example, it is used at a content exceeding 50 to 90% (w / w). May be.
  • composition containing the nerve cell stimulating agent containing the IgG of the present invention and / or the Fc fragment of IgG is not particularly limited with respect to other components, but the food composition of the present invention is composed of water, protein, carbohydrate, lipid. , Vitamins, minerals, organic acids, organic bases, fruit juices, flavors and the like.
  • the protein examples include whole milk powder, skim milk powder, partially skimmed milk powder, casein, whey powder, whey protein, whey protein concentrate, whey protein isolate, ⁇ -casein, ⁇ -casein, ⁇ -casein, ⁇ -lactoglobulin , ⁇ -lactalbumin, lactoferrin, soy protein, chicken egg protein, meat protein and other animal and vegetable proteins, hydrolysates thereof; butter, milk minerals, cream, whey, non-protein nitrogen, sialic acid, phospholipid, lactose, etc. And various milk-derived components.
  • saccharide examples include saccharides, processed starch (in addition to dextrin, soluble starch, British starch, oxidized starch, starch ester, starch ether, etc.), dietary fiber, and the like.
  • lipid examples include animal oils such as lard, fish oil, etc., fractionated oils, hydrogenated oil, transesterified oil, etc .; palm oil, sunflower oil, corn oil, rapeseed oil, coconut oil, fractionated oils thereof, Examples include vegetable oils such as hydrogenated oils and transesterified oils.
  • vitamins include vitamin A, carotene, vitamin B group, vitamin C, vitamin D group, vitamin E, vitamin K group, vitamin P, vitamin Q, niacin, nicotinic acid, pantothenic acid, biotin, inositol, choline.
  • minerals include calcium, potassium, magnesium, sodium, copper, iron, manganese, zinc, and selenium.
  • organic acid include malic acid, citric acid, lactic acid, and tartaric acid. Two or more of these components can be used in combination, and a synthetic product and / or a food containing a large amount thereof may be used.
  • Water maze learning test (Morris water maze learning test) The Morris water maze test is a test that observes the spatial cognitive ability using the habit of mice dislike water and try to escape from water. Water is stretched to a depth of 13 cm in a pool with a predetermined shape, the water temperature is kept at 23 ° C., and as shown in FIG. The platform was set so that it could not be seen from the mouse. Spatial cues around the device (experimenter, table, fluorescent lamp, experimental machine, etc.) were kept constant throughout the experiment.
  • the mouse In the test, the mouse is placed on the wall of the pool so that the mouse cannot see the platform position from one of the three starting positions (A, B, C) as shown in FIG. Gently put it in water. On the day before the test, the mouse was allowed to swim for 90 seconds with the platform removed from the pool in order to acclimate the mouse to water.
  • the start position of the test is a random combination, so that the last start position of the previous day and the first start position of the next day are not the same, the mouse is submerged from three places a day until it reaches the platform Was measured for a maximum of 90 seconds for 5 consecutive days. If the mouse escaped from the water within 90 seconds and stayed on the platform for 20 seconds, the time when the mouse arrived on the platform was taken as the swimming time of the mouse. If the experiment did not arrive within 90 seconds, the experimenter placed the mouse on the platform for 30 seconds to finish, and 90 seconds was the swimming time for the mouse.
  • Example 1 Enhancement of learning memory ability in mice by oral administration of IgG
  • IgG oral 8-week old 10 C57BL / 6 strain male mice weighing about 20 ⁇ 25 g, 1 group 5 mice
  • IgG lyophilized Sigma-Aldrich Inc., trade name: BOVINE IgG Lyophilized, Product No .: I5506, Purified Immunoglobulin Reagent Grade, purity: at least 95% by SDS electrophoresis
  • physiological saline 25 mg / mL
  • 0.1 mL was orally administered for 14 consecutive days .
  • the dose of IgG was 2.5 mg / mouse (100 to 125 mg / kg body weight).
  • the water maze test was conducted for 5 days from the day after the final administration.
  • physiological saline was orally administered at 0.1 mL / mouse.
  • changes in the average value of the body weight of each group during the administration test period were observed, there was no difference in the change in body weight between the mouse control group and the IgG administration group.
  • Example 2 Papain digested with IgG Papain crystallized twice in phosphate buffer / 20 mM cysteine hydrochloride / 20 mM ethylenediaminetetraacetic acid (EDTA ⁇ 2Na) (pH 6.0) containing bovine IgG at a concentration of 10.0 mg / mL MP Biomedicals product) was added at 0.1 mg / mL after activation. This was digested at 37 ° C. for 4 hours so that no undigested IgG remained. After completion of the reaction, an equal volume of 100 mM iodoacetamide / 0.2 M Tris buffer (pH 8.0) was added to stop the reaction. After adjusting the pH to 5.0, the Fc fragment was purified by a protein G Sepharose column (GE Healthcare product).
  • EDTA ⁇ 2Na ethylenediaminetetraacetic acid
  • Bovine-derived IgG has very weak adsorptivity to protein A, while it can be adsorbed to protein G.
  • the following literature shows that the binding power of bovine IgG to the protein G column is the maximum at pH 5.0, and the purification conditions for the Fc fragment were also referred to the following literature. (Bo Akerstrom and Lars Bjorck, J. Biological Chemistry, vol.261, 10240-47, 1986).
  • the digest after the reaction was stopped was diluted 2-fold with a protein G binding buffer (20 mM phosphate-citrate buffer containing 0.05% Tween®20, pH 5.0), and further diluted with 1N hydrochloric acid to pH 5. Adjusted again to zero. This was loaded onto a protein G column that had been equilibrated in advance with a protein G binding buffer, and an Fab fraction was obtained as an unadsorbed fraction. Further, after the column was sufficiently washed with protein G binding buffer, the Fc fragment bound to the column was eluted with 0.1 M glycine hydrochloride buffer (pH 2.5), and immediately 1 M Tris hydrochloride buffer (pH 8. The Fc fraction was obtained by neutralization at 0).
  • the obtained Fab fraction and Fc fraction were dialyzed against PBS at 4 ° C., and the dialyzate was measured for protein concentration, and if necessary, an ultrafiltration membrane having a molecular weight of 10 kDa cut (Centricon YM- manufactured by Amicon). 10).
  • the obtained Fc fraction was orally administered once a day for 4 weeks to a C57BL / 6 male mouse of 8 to 10 weeks of age (body weight: about 20 to 25 g, 5 mice per group) once a day for 4 weeks. I went there.
  • the dose of Fc fragment was 10 mg / kg body weight / day.
  • the water maze test was conducted for 5 days from the day after the final administration.
  • physiological saline was orally administered at 0.1 mL / mouse. Changes in the average value of the body weight of each group during the administration test period were observed, but there was no difference in the change in body weight between the mouse control group and the IgG Fc fragment administration group.
  • Example 3 Culture of Primary Neurons HBSS (Hanks' Balanced Salt Solution) in which dorsal root ganglion (DRG) was ice-cooled from male mice such as C57BL / 6, Balb / c and ICR under a stereomicroscope. ) And in vitro culture of primary neurons.
  • HBSS Human Brain's Balanced Salt Solution
  • DRG dorsal root ganglion
  • the collected DRG was suspended in 0.25% collagenase II (GIBCO) dissolved in MEM (Minimal Essential Medium, GIBCO) and aseptically treated at 37 ° C. for 2 hours.
  • collagenase II-treated DRG was recovered after centrifugation, resuspended in HBSS and washed. After this operation was performed twice to remove collagenase II, the suspension was suspended in 0.25% trypsin (DIFCO) dissolved in HBSS and subjected to enzyme treatment at 37 ° C. for 15 minutes.
  • DIFCO trypsin
  • the obtained primary nerve cells were seeded in a 35 mm dish (Becton-Dickinson, BioCoat) coated with type I collagen, and cultured overnight at 37 ° C. under 5% CO 2 .
  • cytosine arabinofuranoside Cytosine Arabinofuranoside: Ara-C, Sigma
  • the medium was changed every 3 days, and the culture was continued. In the course of such culture, proliferative fibroblasts and the like were removed, and most of the dishes became neurons with neurites extended.
  • Example 4 When sufficient extension of CGRP-releasing neurites by Fc fragment was confirmed (usually on culture day 7-9), the culture medium was aspirated and rinsed with serum-free D-MEM / F12 medium Later, the medium was replaced with basal medium (D-MEM / F-12 containing 1% FCS) containing IgG or an Fc fragment of IgG.
  • IgG was affinity purified from whey by protein G column. For the Fc fragment, affinity-purified bovine IgG was digested with papain, and the column-adsorbed fraction was recovered again by protein G affinity purification.
  • the IgG or IgG Fc fragment was prepared in advance by adding a basic medium (D-MEM / F-12 containing 1% FCS) at a target concentration, and the nerve cells were rinsed with D-MEM / F12. Later 1 mL was added to the dish. This was transferred to a CO 2 incubator and incubated at 37 ° C. for 30 minutes, and the culture supernatant was collected. The collected culture supernatant was stored frozen at ⁇ 30 ° C. or lower until measurement, and CGRP concentration measurement in the culture supernatant was performed according to the protocol of the measurement kit (SPI-Bio).
  • Example 6 Validation of CGRP release test with Fc fragment (FC ⁇ ) In this assay system, it is verified whether CGRP release of neurons induced by Fc fragment (Fc ⁇ ) is pharmacologically valid. In order to achieve this, capsaicin, which is a known stimulating factor, was examined.
  • Example 7 Concentration Dependence of Fc Fragment (Fc ⁇ ) in CGRP Release It was investigated whether CGRP release by neurons was a concentration-dependent response to the added Fc fragment (Fc ⁇ ).
  • Fc fragment (Fc ⁇ ) was added to the basal medium at concentrations of 0.25 mg / mL, 0.5 mg / mL and 1 mg / mL, and 1 mL of each was added to the nerve cells and incubated at 37 ° C. for 30 minutes. .
  • Fc fragment (Fc ⁇ ) was added to the basal medium at concentrations of 0.25 mg / mL, 0.5 mg / mL and 1 mg / mL, and 1 mL of each was added to the nerve cells and incubated at 37 ° C. for 30 minutes. .
  • Fc fragment (Fc ⁇ ) was added to the basal medium at concentrations of 0.25 mg / mL, 0.5 mg / mL and 1 mg / mL, and 1 mL
  • Example 8 Temporal change in CGRP release The CGRP release test so far has examined the culture supernatant after incubation at 37 ° C for 30 minutes after adding a medium containing Fc fragment (Fc ⁇ ) to nerve cells. However, for the purpose of verifying whether or not the release amount further increases in a time-dependent manner, the time dependency of the CGRP release amount was examined.
  • the Fc fragment (Fc ⁇ ) was added to the basic medium at a concentration of 1 mg / mL, and 1 mL each was added to each of the 4 dishes of nerve cells.
  • 1 mL of basal medium was added to 1 dish of neurons. All were incubated at 37 ° C., and after 30 minutes, 60 minutes, 90 minutes and 120 minutes, the cells were removed from the incubator and the culture supernatant was collected. Control culture supernatants were collected after 30 minutes.
  • Example 9 Confirmation of high-affinity Fc ⁇ receptor (Fc ⁇ RI) expression in neurons For the purpose of confirming whether CGRP release by Fc fragment (Fc ⁇ ) occurs via the receptor, high affinity in neurons The expression of the sex Fc ⁇ receptor was verified immunochemically.
  • the cultured DRG neurons were fixed with methanol, double-stained with an antibody against a mouse high affinity Fc ⁇ receptor and an antibody against a neuron-specific marker, and a fluorescence-labeled secondary antibody against each antibody was used. The localization of the high affinity Fc ⁇ receptor was examined.
  • Fc ⁇ receptor green fluorescence
  • FITC-labeled donkey anti-goat IgG Santa Cruz Biotechnology
  • guinea pig antibody against neuron-specific marker PPP 9.5
  • Texas Red labeled goat anti-guinea pig IgG GPP 9.5
  • Texas Red labeled goat anti-guinea pig IgG GPP 9.5
  • the Fc ⁇ receptor (green fluorescence) observed by FITC is localized on a typical neuron having red neurites (red fluorescence), as shown by an image (yellow) in which two colors of fluorescence are superimposed. became.
  • DRG neurons express Fc ⁇ receptors. Considering the phenomenon in which CGRP release occurs when Fc fragment (Fc ⁇ ) is stimulated by external addition of Fc fragment (Fc ⁇ ) to cultured neurons, DRG neurons receive high affinity Fc ⁇ receptor on the cell surface. It is inferred that the body (Fc ⁇ RI) is expressed (FIG. 9).
  • Fc ⁇ RI is expressed in cultured dorsal root ganglion cells (Andoh and Kuraishi, 2003, FASEB Journal, 2003, 18 (1): 182-4). Activation was recognized only by the body, and cells were not excited by IgG alone. Therefore, it was an unexpected result that neurons were activated only by Fc ⁇ purified from whey as described above.
  • Example 10 In order to clarify the mechanism of action in the central nervous system of orally administered IgG, which improves the memory learning ability by enhancing the IGF-I production of the hippocampus, IgG is used to introduce bovine colostrum rich in IgG to mice Was orally administered.
  • IGF-I contributes to improving memory learning ability by regenerating hippocampal nerves.
  • the above results indicate that, upon administration of colostrum, IgG in the colostrum is digested in the stomach to produce Fc ⁇ , which stimulates the gastric sensory nerve and is released from the sensory nerve (CGRP). It is thought that memory learning ability is improved by inducing angiogenesis and nerve regeneration in the hippocampus by enhancing the production of IGF-I in the brain.
  • memory / learning ability can be improved by safe, inexpensive and simple means, and various diseases accompanying aging and aging such as ischemia-reperfusion liver injury, stress gastric mucosa
  • various diseases accompanying aging and aging such as ischemia-reperfusion liver injury, stress gastric mucosa
  • ischemia-reperfusion liver injury such as ischemia-reperfusion liver injury, stress gastric mucosa
  • improvement or prevention of skin aging and hair restoration effects can be expected.

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Abstract

L’invention concerne une composition pharmaceutique ou alimentaire destinée à améliorer la capacité de mémoire/lecture à l’aide d’un moyen approprié et sûr, et un procédé pour améliorer la capacité de mémoire/lecture. L’invention concerne plus spécifiquement un stimulateur de cellules nerveuses comprenant une quantité efficace d’IgG et/ou un fragment FC d’IgG. IgC est de préférence dérivé d’une protéine de lactosérum. La composition pharmaceutique ou alimentaire contenant le stimulateur de cellules nerveuses peut améliorer la capacité de mémoire/lecture, et est prévue pour avoir de nombreux effets, notamment dans le traitement ou la prévention de maladies associées au vieillissement, telles que les lésions ischémiques hépatiques de reperfusion, la formation de lésions des muqueuses gastriques dues au stress, les troubles cardio-vasculaires, le diabète, les maladies associées à l’apoptose, la maladie d’Alzheimer, et l’amélioration ou la prévention du vieillissement de la peau et/ou la croissance des cheveux.
PCT/JP2009/005291 2008-11-20 2009-10-09 STIMULATEUR DE CELLULES NERVEUSES COMPRENANT IgG ET/OU UN FRAGMENT Fc D’IgG WO2010058517A1 (fr)

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JP2016210696A (ja) * 2015-04-30 2016-12-15 丸大食品株式会社 学習記憶能力増強剤
WO2018199130A1 (fr) * 2017-04-26 2018-11-01 株式会社 明治 Composition destinée à améliorer la capacité de travail intellectuel et composition destinée à améliorer la capacité cognitive
JP2019199482A (ja) * 2019-08-20 2019-11-21 丸大食品株式会社 学習記憶能力増強剤

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JP2016210696A (ja) * 2015-04-30 2016-12-15 丸大食品株式会社 学習記憶能力増強剤
WO2018199130A1 (fr) * 2017-04-26 2018-11-01 株式会社 明治 Composition destinée à améliorer la capacité de travail intellectuel et composition destinée à améliorer la capacité cognitive
JP2018184369A (ja) * 2017-04-26 2018-11-22 株式会社明治 知的作業能力向上用組成物および認知能力向上用組成物
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JP2019199482A (ja) * 2019-08-20 2019-11-21 丸大食品株式会社 学習記憶能力増強剤

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