JPWO2010058517A1 - Neuronal cell stimulating agent comprising IgG and / or Fc fragment of IgG - Google Patents

Abstract

The present invention aims to provide a pharmaceutical or food composition for improving memory / learning ability by a simple and safe means, and a method for improving memory / learning ability, and an effective amount of IgG and / or IgG. Provided is a neuronal cell stimulator comprising an Fc fragment. IgG is preferably derived from whey protein. The medicinal or food composition containing the nerve cell stimulating agent of the present invention can improve memory / learning ability, and is associated with aging-related diseases such as ischemia / reperfusion liver injury, stress gastric mucosal lesion A wide range of effects such as treatment or prevention of formation, cardiovascular disorder, diabetes, diseases relating to apoptosis and Alzheimer's disease, improvement or prevention of skin aging, and / or hair growth can be expected.

Description

  The present invention relates to a nerve cell stimulating agent containing IgG and / or an Fc fragment of IgG, particularly Fcγ as an active ingredient, and a composition for food and medicine 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 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”. In recent years, so-called “dementia” 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. In particular, 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. .

  As countermeasures against such disorders such as dementia including memory and learning, for example, 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. For the purpose of prevention, improvement and treatment of Alzheimer's type memory impairment, 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. Furthermore, 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.

  Further, a memory disorder / brain function improving agent using fibroblast growth factor (FGF-18) or a derivative thereof (αFGF), which has been conventionally known to have a memory improving action, has also been proposed (patent) Literature 4 and Patent literature 5).

  Furthermore, the brain function improvement composition derived from egg yolk (patent document 6) 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. In addition, a composition (Patent Document 7) 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 Japanese Patent Laid-Open No. 9-12597 JP-T-2006-516538 Japanese Patent Laid-Open No. 2003-300891 JP 2004-175695 A

However, the proposed therapeutic agents and compositions have the following problems.
For example, although erythropoietin described in Patent Document 1 is mass-produced as a high-purity anemia treatment by genetic engineering means, it is expensive as a pharmaceutical and has an economic problem. Regarding the effect, no clear disorder healing effect has been obtained.

  In addition, with respect to the component of the alkali-stable lipid derived from acetic acid bacteria described in Patent Document 2, 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. In addition, the intake required to obtain a physiological effect is very large, and there are economic problems in production and implementation. Furthermore, when 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.

  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.

  On the other hand, the fibroblast growth factor and derivatives thereof disclosed in Patent Documents 4 and 5 require various complicated processes associated with the production thereof, and their effects are still insufficient.

  Moreover, although the composition disclosed by patent document 6 or 7 is easy to acquire a raw material at the point which uses egg yolk or a leek, the effect is still inadequate level.

  Therefore, there is a need for a pharmaceutical or food that is inexpensive, easy to manufacture, and highly safe for improving memory and learning ability.

  As a result of intensive studies to solve the above problems, the present inventors have surprisingly found that whey protein, which is a by-product during cheese manufacture, has an effect of improving learning and memory functions. In particular, administration of IgG and / or an Fc fragment of IgG to a subject has found an effect that has not been known at all, that is, learning and memory functions are significantly improved. Since 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. As a result of further studies, 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 promoted improves memory / learning ability, and is effective not only in memory / learning but also in the treatment and prevention of various diseases and conditions related to aging. The inventors have found that the invention has been obtained and have completed the invention.

That is, 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 the 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 the 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.

By using the nerve cell stimulating agent and the pharmaceutical or food composition containing the same according to the present invention, memory / learning ability can be improved by a simple and safe means.
Moreover, since 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. Protective action against cardiovascular disorders causing myocardial infarction, etc., hypoglycemic action in diabetics, cell apoptosis-suppressing action, removal of amyloid β protein and treatment of Alzheimer's disease in hippocampus, increased production of collagen and elastin in skin Expected to have effects and hair growth.

1A is a side view of the Morris water maze, and 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 nerve cells into the culture medium when an Fc fragment (Fcγ) 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 (Fcγ). FIG. 6 is a diagram showing that the CGRP release assay system using an Fc fragment (Fcγ) using DRG neurons is pharmacologically valid. FIG. 7 shows that the Fc fragment (Fcγ) releases CGRP to DRG neurons in a concentration-dependent manner. FIG. 8 shows that DRG neurons stimulated with an Fc fragment (Fcγ) transiently release CGRP within 30 minutes after stimulation. FIG. 9 is a diagram showing that high affinity Fcγ receptor is expressed in DRG neurons.

BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described in detail, but the present invention is not limited to the individual forms described below.
IgG used in the present invention 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. They are called immunoglobulin G (IgG), immunoglobulin M (IgM), immunoglobulin D (IgD), immunoglobulin A (IgA), immunoglobulin E (IgE). In addition, 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.

  There are various pathogens around us, but we have an immune system to protect the organism from these pathogens. There are two types of immune systems: cellular immunity centered on cells such as lymphocytes, and humoral immunity centered on antibodies, etc. 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. In addition, 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.

  As described hereinafter, release of calcitonin gene related peptide (CGRP) from sensory nerves by a nerve cell stimulator containing IgG of the present invention and / or an Fc fragment (Fcγ) of IgG. Has been demonstrated to improve learning and memory abilities and increase production of insulin-like growth factor-I (IFG-I) in the hippocampus in animal models.

  Insulin-like growth factor-I (IGF-I) is a peptide hormone with a molecular weight of about 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. It is known that the metabolism of IGF-I and its affinity for the receptor are regulated by this IGF-binding protein, and the expression of IGF-binding protein is regulated by growth hormone (Humbel RE, The above). IGF-I is known to actively maintain the cells in a healthy state, for example, by promoting cell differentiation and helping cell growth (Insulin-like growth factor IandII, Review Humbel RE, Eur. J. Biochem., Vol. 190, 445-462, (1990)).

  Until now, as an action of IGF-I, the protective action of the cardiovascular disorder causing the myocardial infarction etc. (The GH-IGF-I axis and the cardiovascular system: clinical implications. Annamaria Colao, Clinical Endocrinology, vol. 69, 347-358, (2008)), The role of insulin-like growth factor-I and its binding proteins in glucose homeostasis and type 2 diabetes. Swapnil NR et al, Diabetes Metab. Res. And Rev , vol. 25, 3-12, (2009)), IGF-I inhibition of apoptosis is associated with decreased expression of prostate apoptosis response-4. Hyunju C. et al., J. Endocrinology, vol. 194, 77-85, (2007), removal of amyloid β protein in the hippocampus and therapeutic effect of Alzheimer's disease (therapeutic prospects? Eva C. and Ignacio TA, Expert Rev. Neurotherapeutics, vol. 4 (1), 79-86, (2004)) Epidermal Homeostasis: The Role of the Growth Hormone and Insulin-Like Growth Factor Systems. Stephanie R. et al., Endocrine Reviews, vol. 24 (6), 737-764, (2003) ) And hair growth (Administration of capsaicin and isoflavone promotes hair growth by increasing insulin-like growth factor-I production in mice and in humans with alopecia. Harada N. et al., Growth Horm. IGF Res., Vol. 17 ( 5), 408-415, (2007)).

  In a recent research report, by activating vanilloid receptors present in sensory nerves distributed throughout the body, CGRP is released from sensory nerves, which are present in immature cells of various organs. Has been reported to promote insulin-like growth factor-I (IGF-I) production (Effect of topical application of capsaicin and its related compounds on dermal insulin-like growth factor-I levels in mice and on facial skin elasticity in humans. Harada N. and Okajima K., Growth Horm IGF Res.vol.17 (2): 171-176, (2007); Effect of capsaicin on plasma and tissue levels of insulin-like growth factor- I in spontaneously hypertensive rats. Harada N. and Okajima K., Growth Horm IGF Res. Vol.18 (1): 75-81, (2008)).

  The method of increasing IGF-I has so far been known only by administration of growth hormone (GH), but according to recent research (Harada N. and Okajima K., 2007 and 2008, supra), sensory nerves are used. It became clear that the IGF-I production amount of each tissue was increased by stimulating. In order to expect similar effects, 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. Furthermore, regarding IGF-I, there is a concern that when it is administered intravenously, hypoglycemia is caused by the same action as insulin.

  On the other hand, 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. There is no need. Against this background, food ingredients have attracted attention as a means to promote the secretion of IGF-I in each tissue more safely and inexpensively, and there have been many reports that capsaicin has been effective so far.

  When capsaicin is administered orally to stimulate sensory neurons, 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. Furthermore, 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 or the like increases CGRP levels and promotes IGF-I production in the hippocampus, which may improve cognitive function through the formation of blood vessels and neurons. (Stimulation of sensory neurons improves cognitive function by promoting the hippocampal production of insulin-like growth factor-I in mice. Harada N. et al. Transl Res. Vol. 154 (2), 90-102, (2009 ), Donepezil improves cognitive function in mice by increasing the production of insulin-like growth factor-I in the hippocampus.Narimatsu N. et al. J. Pharmacol. Exp. Ther. Vol. 330 (1), 2-12, ( 2009)).

  For example, a substance having a sensory nerve stimulating action such as capsaicin stimulates sensory nerves in the digestive tract when orally administered. It is inferred that the signal stimulates the parasympathetic nerve via the spinal cord thalamus and the vagus sensory nerve and increases the production of IGF-I 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 tissues throughout the body, for example, the central nervous system.

  By combining the results of the experiments described below with the results of the studies reported so far in the present specification, 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 systemic tissues 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.

  Therefore, 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 the IGF-I production of 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. For example, the nerve cell stimulating agent of the present invention increases the production of IGF-I, thereby protecting the cardiovascular system, reducing blood glucose in diabetic patients, inhibiting apoptosis of cells, and amyloid β 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.

On the other hand, for the calcitonin gene-related peptide, 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 , Promotes the production of prostaglandins such as PGE ₂ , suppresses the production of tumor necrosis factor (TNFα), an inflammatory cytokine, and reduces ischemic reperfusion liver injury and stress gastric mucosal lesion formation (Stimulation of sensory neurons by capsaicin increases tissue levels of IGF-I, thus reducing reperfusion-induced apoptosis in mice. Harada N. et al., Neuropharmacology, vol. 52 (5), 1303-1311, (2007 ); Antithrombin prevents reperfusion-induced hepatic apoptosis by enhancing insulin-like growth factor-I production in mice. Harada N. et al., Crit Care Med., Vol. 36 (3), 971-974, (2008)).

  It has also been reported that 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 in ovariectomized rats. Valentijn K. et al., Bone , 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)).

  Therefore, since 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 byproduct of the cheese manufacturing process. In the food composition according to the present invention, 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. As 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. For example, in the present invention, IgG obtained by the method described in JP-T-2001-516599 can be used.

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. Thus, 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, papain digestion of IgG), fragmenting and purifying. As 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 pharmacologically active substances. Examples of such 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 Examples include, but are not limited to, therapeutic agents (eg, hypoglycemic agents, thiazolidine derivatives, GLP-1 receptor agonists, insulin, etc.) and osteoporosis therapeutic agents (eg, calcitonin, estrogen, calcium, vitamin D, vitamin K, etc.).

  In one aspect, the present invention is a pharmaceutical or food composition comprising an effective amount of the nerve cell stimulating agent containing the IgG and / or the Fc fragment of IgG as an active ingredient. 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, amount promoting vascular and neuronal neogenesis, amount promoting amyloid β protein deposit removal, Alzheimer's disease, cardiovascular disorder, ischemia reperfusion liver injury and / or stress gastric mucosa In 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. In addition, 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. For example, 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).

  These various preparations are usually used in the pharmaceutical formulation technical field such as excipients, binders, disintegrants, lubricants, coloring agents, flavoring agents, solubilizing agents, suspending agents, and coating agents in accordance with conventional methods. It can be formulated with known adjuvants. For example, 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.

  Specifically, as the food composition of the present invention, various foods and drinks (milk, soft drinks, fermented milk, yogurt, cheese, cream, bread, biscuits, crackers, bars, jellies, pizza crusts, formula milk powder, fluid Food, foods for sick people, infant milk powder, foods such as infant milk powder, and nutritional foods). 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. Moreover, about the property, the state of the food / beverage products normally used, for example, any of solid (powder, granule, etc.), paste, liquid or suspension may be sufficient.

  Further, the composition of the present invention may be provided as a so-called health food composition having a form similar to a pharmaceutical product. 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.

  In one aspect, 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, thereby improving learning and memory ability. It improves, removes amyloid β 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. When IgG is used as an active ingredient, 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. 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. Can be used by weight. However, when ingested for the purpose of treatment or prevention over a long period of time, the amount may be smaller than the above range, and since this active ingredient is naturally derived and has no safety problems, Can also be used in large quantities.

  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 (that is, 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 0.02-90% (w / w), for example 0.2-50% (w / w), or 8-25% (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 and reservoir-type preparations, it is used at a content exceeding 50 to 90% (w / w), for example. May be.

  The 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. Examples of the protein include whole milk powder, skim milk powder, partially skimmed milk powder, casein, whey powder, whey protein, whey protein concentrate, whey protein isolate, α-casein, β-casein, κ-casein, β-lactoglobulin , Α-lactalbumin, lactoferrin, soy protein, egg protein, meat protein and other animal and plant proteins, hydrolysates thereof; butter, milk mineral, cream, whey, non-protein nitrogen, sialic acid, phospholipid, lactose, etc. And various milk-derived components. Examples of the saccharide include saccharides, processed starch (in addition to dextrin, soluble starch, British starch, oxidized starch, starch ester, starch ether, etc.), dietary fiber, and the like. Examples of the lipid 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. Examples of 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. Examples of minerals include calcium, potassium, magnesium, sodium, copper, iron, manganese, zinc, and selenium. Examples of the 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.

  EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated, this invention is not limited by this. In the present specification, “%” indicates “% by weight” unless otherwise specified.

Water maze learning test (Morris water maze learning test)
The Morris water maze test is a test in which a mouse dislikes water and observes the spatial cognitive ability using the habit of trying to escape from water. Water is stretched to a depth of 13 cm in a pool of a predetermined shape, the water temperature is kept at 23 ° C., and as shown in FIG. 1 (A) (side view), a circular (diameter: about 12 cm) circular shape about 1 cm below the water surface 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.

  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 administration 8-10 week old C57BL / 6 strain male mice (body weight about 20-25 g, 5 animals per group), IgG lyophilized (Sigma-Aldrich Inc., trade name: BOVINE IgG Lyophilized, Product No .: I5506, Purified Immunoglobulin Reagent Grade, purity: at least 95% by SDS electrophoresis) was dissolved in physiological saline (25 mg / mL), and once daily, 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. To the control group of mice, physiological saline was orally administered at 0.1 mL / mouse. Although 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.

Measurement results (average value and standard error) of swimming time (seconds) of each group measured in the above water maze test
Is shown in FIG. As is apparent from these results, among the C57BL / 6 mice, in the IgG administration group, the escape swimming time gradually decreased from the first day as compared with the control group. In particular, on the 4th and 5th day of the test, a significant decrease in the escape swimming time was shown. From this result, it was found that administration of IgG has an effect of enhancing learning memory in mice.

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).

  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 dialysis-recovered solution 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).

Administration test The obtained Fc fraction was orally administered once a day for 4 weeks to C57BL / 6 male mice (body weight: about 20 to 25 g, 5 mice per group) of 8 to 10 weeks old using a sonde. 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. To the control group of mice, 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.

  FIG. 3 shows the measurement results (average value and standard error) of the swimming time (seconds) of each group measured in the water maze test. As is clear from these results, among the C57BL / 6 mice, in the Fc fragment administration group, a decrease in the escape swimming time was gradually observed from the first day as compared with the control group. In particular, on days 3 to 5 of the test, a significant decrease in escape swimming time was shown. From this result, it was found that administration of an Fc fragment of IgG had a very high effect of enhancing learning memory in mice.

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.

  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. Next, 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.

  After collecting DRG by centrifugation, 10% FCS (GIBCO), antibiotics and antifungal agents (100 U / mL penicillin, 100 μg / mL streptomycin, 0.25 μg / mL amphotericin B; GIBCO), 100 ng / mL natural nerve growth The remaining trypsin was removed by washing twice with a D-MEM / F12 medium (GIBCO) containing factor 7S (GIBCO), and the cells were pipetted in the same medium to release neurons from the DRG.

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 . From the next day onward, in order to suppress the growth of cells other than sensory neurons, cytosine arabinofuranoside (Cytosine Arabinofuranoside: Ara-C, Sigma), which is a DNA synthesis inhibitor, is adjusted to the final concentration of 5 μM. 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 solution was removed by aspiration 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 (1% FCS-containing D-MEM / F-12) at a desired 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).

  When affinity-purified IgG was added to the basic medium at 1 mg / mL, the amount of CGRP released was the same as that of the basic medium, whereas when purified Fc fragment (Fcγ) after papain digestion was added. Increased the amount of CGRP released approximately 3 times (FIG. 4).

Example 5 Confirmation that Neurons Release CGRP in Response to Fc Fragment (Fcγ) When CFC was released when Fc fragment (Fcγ) was added, Fc fragment (Fcγ) in the medium was observed. In order to confirm that the concentration of CGRP in the culture supernatant was increased as a result of the action on the nerve cells, the following examination was performed.

  There was no increase in CGRP by measuring the concentration of the medium alone with the Fc fragment (Fcγ) added to the basal medium, but in the culture supernatant after adding this medium to neurons, the CGRP was about 3 times that of the basal medium. Was detected. On the other hand, when IgG was added, no increase in CGRP concentration was observed (FIG. 5). From this result, it was confirmed that the increase in CGRP concentration was the result of Fc fragment (Fcγ) acting directly on neurons.

Example 6: Validation of CGRP release test with Fc fragment (FCγ) In this assay system, it is verified whether CGRP release of neurons induced by Fc fragment (Fcγ) is pharmacologically valid. In order to achieve this, capsaicin, which is a known stimulating factor, was examined.

  It has been clarified that when 10 μM capsaicin is added to a culture system of DRG neurons, CGRP is released through stimulation of the vanilloid receptor (VR1) of the neurons (Harada N. and Okajima K .: Effect of topical application of capsaicin and its related compounds on dermal insulin-like growth factor-I levels in mice and on facial skin elasticity in humans. Growth Horm IGF Res. vol.17 (2): 171-176, 2007). As a result of examining whether or not CGRP release was observed by addition of capsaicin in this experimental system, CGRP was expressed from neurons in a concentration-dependent manner with respect to capsaicin (Santa Cruz Biotechnology) within a range of addition concentration of 1 μM to 10 μM. It was confirmed that it was released (FIG. 6). It should be noted that the amount of CGRP released decreased with the addition of capsaicin at a final concentration of 30 μM and 100 μM depending on the concentration of capsaicin, which was presumed to be due to the influence of ethanol as the solvent for capsaicin.

Example 7: Concentration Dependence of Fc Fragment (Fcγ) in CGRP Release It was investigated whether CGRP release by neurons was a concentration-dependent response to the added Fc fragment (Fcγ). Fc fragment (Fcγ) 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. . As a result, it was confirmed that the amount of CGRP released in the culture supernatant increased in a concentration-dependent manner with respect to the Fc fragment (Fcγ) added to the basic medium (FIG. 7).

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 (Fcγ) 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.

  Fc fragment (Fcγ) was added to the basic medium at a concentration of 1 mg / mL, and 1 mL each was added to 4 dishes of nerve cells. As a control, 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.

  As a result of measuring the CGRP concentration in the culture supernatant, incubation at 60 minutes, 90 minutes, and 120 minutes was equivalent to the CGRP concentration at 30 minutes incubation. Therefore, it was inferred that nerve cells transiently released CGRP within 30 minutes by stimulation with Fc fragment (Fcγ) (FIG. 8).

Example 9: Confirmation of high-affinity Fcγ receptor (FcγRI) expression in neurons For the purpose of confirming whether CGRP release by Fc fragment (Fcγ) occurs via the receptor, high affinity in neurons The expression of the sex Fcγ receptor was verified immunochemically.

  The cultured DRG neurons were fixed with methanol, double-stained with an antibody against a mouse high affinity Fcγ 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 Fcγ receptor was examined.

  Fcγ receptor was stained (green fluorescence) with goat IgG (Santa Cruz Biotechnology) and FITC-labeled donkey anti-goat IgG (Santa Cruz Biotechnology) against mouse Fcγ receptor, and guinea pig antibody (Novus) against neuron-specific marker (PGP 9.5) Biologicals) and Texas Red labeled goat anti-guinea pig IgG (Gene Tex) stained DRG neurons (red fluorescence). The Fcγ 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. This result strongly suggested that DRG neurons express Fcγ receptors. Considering the phenomenon in which CGRP release occurs when Fc fragment (Fcγ) is stimulated by external addition of Fc fragment (Fcγ) to cultured neurons, DRG neurons receive high affinity Fcγ receptor on the cell surface. It is inferred that the body (FcγRI) is expressed (FIG. 9).

  It has been reported that FcγRI 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 Fcγ purified from whey as described above.

Example 10:
In order to elucidate the mechanism of action in the central nervous system of orally administered IgG that improves memory learning ability by enhancing IGF-I production in the hippocampus Was orally administered.

  When colostrum was orally administered to wild-type mice for 4 weeks, it was confirmed that the production levels of CGRP and IGF-I and the expression level of IGF-I mRNA were increased in the hippocampus. Moreover, in the dorsal horn of the spinal cord, the paranucleus of the connecting arm, the nucleus of the solitary tract, and the hippocampus, the expression level of c-fos, which is one of transcription factors and is a marker of nerve excitation, increased after colostrum administration. Furthermore, it was observed that nerves were significantly regenerated in the dentate gyrus of the hippocampus by colostrum administration. Moreover, it was confirmed by Morris water maze test that the spatial recognition ability of mice was significantly improved by colostrum administration. The same effect as colostrum was also observed when wild-type mice were orally administered bovine-derived purified IgG for 4 weeks. On the other hand, in the mice lacking the CGRP gene, even if colostrum was orally administered, no effect as seen in the wild type was observed.

  IGF-I contributes to improvement of 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 Fcγ, which stimulates the gastric sensory nerve and is released from the sensory nerve (CGRP). It is thought that the memory learning ability is improved by inducing angiogenesis and nerve regeneration in the hippocampus by enhancing the amount of IGF-I in the brain as a result.

  According to the present invention, 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 In addition to being able to treat or prevent lesion formation, cardiovascular disorders, diabetes, diseases related to apoptosis, Alzheimer's disease, and the like, improvement or prevention of skin aging and hair restoration effects can be expected.

Claims (27)

  A nerve cell stimulator comprising an effective amount of IgG and / or an Fc fragment of IgG.   The nerve cell stimulating agent according to claim 1, wherein IgG is derived from whey protein.   The nerve cell stimulating agent according to claim 1 or 2, which induces release of CGRP from nerve cells.   1 or 2 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 and learning ability 4. The nerve cell stimulator according to any one of claims 1 to 3, for treatment or prevention of the above diseases, improvement or prevention of skin aging, and / or hair growth.   The nerve cell stimulant according to claim 4 for improving memory and learning ability.   A pharmaceutical or food composition comprising the nerve cell stimulator according to any one of claims 1 to 5.   The composition according to claim 6, wherein the medicament is in an oral dosage form.   The composition according to claim 6 or 7, wherein the content of IgG and / or the Fc fragment of IgG is 0.02 to 90% (w / w).   The composition according to claim 8, wherein the content of IgG and / or Fc fragment of IgG is 8 to 25% (w / w).   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 method according to claim 10, wherein the IgG is derived from whey protein.   12. The method according to claim 10 or 11, wherein the method induces the release of CGRP from nerve cells.   One or more diseases selected from the group consisting of ischemia-reperfusion liver injury, stress gastric mucosal lesion formation, cardiovascular disorder, diabetes, apoptosis-related diseases and Alzheimer's disease for improving memory and learning ability The method according to any one of claims 10 to 12, for the treatment or prevention of skin, for improvement or prevention of skin aging, and / or for hair growth.   14. The method according to claim 13, for improving memory and learning ability.   The pharmaceutical or food composition comprises IgG in the range of 1 mg to 5 g / kg body weight and / or an Fc fragment of IgG in the range of 0.1 mg to 0.5 g / kg body weight. The method of crab.   16. The method of claim 15, 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 method according to any of claims 10 to 16, wherein the medicament is administered orally.   A memory / learning ability improving agent comprising an effective amount of IgG and / or an Fc fragment of IgG.   The memory / learning ability improving agent according to claim 18, wherein IgG is derived from whey protein.   The memory / learning ability improving agent according to claim 18 or 19, wherein the content of IgG and / or Fc fragment of IgG is 0.02 to 90% (w / w).   The memory / learning ability improving agent according to claim 20, wherein the content of IgG and / or the Fc fragment of IgG is 8 to 25% (w / w).   A pharmaceutical or food composition comprising the memory / learning ability improving agent according to any one of claims 18 to 21.   23. The composition of claim 22, wherein the medicament is an oral dosage form.   A method for improving memory / learning ability, comprising administering or ingesting a pharmaceutical or food composition comprising an effective amount of IgG and / or an Fc fragment of IgG.   25. The method of claim 24, wherein the IgG is derived from whey protein.   26. A pharmaceutical or food composition comprising IgG in the range of 1 mg to 5 g / kg body weight and / or an Fc fragment of IgG in the range of 0.1 mg to 0.5 g / kg body weight. the method of.   27. A method according to any of claims 24-26, wherein the medicament is administered orally.