JP4451218B2 - Learning memory improver - Google Patents

Description

The present invention relates to a peptide having an action of improving learning and memory ability.
The peptide according to the present invention is used as a learning memory improver for pharmaceutical applications, and special purpose foods for people who want to improve learning memory ability, nutritional foods, functional foods, foods for specified health use, learning memory improving action Is used as a food and drink that can be advocated, and can be widely used for prevention of decline in learning memory ability.

In recent years, with the arrival of an aging society, it has been required to treat or prevent learning memory decline due to senile dementia and the like. Conventionally, peptides having opioid activity such as analgesia and anesthesia (Patent Document 1), prolyl proline derivatives (Patent Document 2), and Streptomyces organisms having prolyl endopeptidase inhibitory activity as substances that suppress learning memory decline. Fermentation products BU-4164EA and B (patent document 3), enduracidin A having a prolyl endopeptidase inhibitory activity (patent document 4), acetylcholinesterase inhibitory activity, and activity against scopolamine-induced amnesia model Known quinoline derivatives (Patent Document 5), peptide SNA-115 (Patent Document 6), which has a prolyl endopeptidase inhibitory action and is a fermentation product of a microbisbora microorganism.
On the other hand, there have been many reports on functional peptides useful for the prevention or treatment of various diseases in recent years, and the present inventors have also shown by Gly-Tyr-Pro-Met-Tyr-Pro-Leu-Pro-Arg. It has been reported that orizatensin, a functional peptide contained in rice protein, has anti-opioid activity, phagocytosis activity, and interleukin 1 production promoting activity (Patent Document 7). In addition, the present inventors obtained a tryptic digest of milk casein (κ-casein) and are known as anti-opioid peptides that exhibit ileal contractile activity and immunostimulatory activity via complement C3a receptor. -Inhibition of opioid analgesia by caspoxin C administration represented by -Ile-Pro-Ile-Gln-Tyr-Val-Leu-Ser-Arg, as well as scopolamine induction and cerebral ischemia It has been reported to show an improvement effect on amnesia caused by (Non-patent Document 1).
JP-A-9-227590 JP-A-8-3132 JP-A-6-279413 JP-A-5-301826 JP-A-5-279355 Japanese Patent Application Laid-Open No. 5-262895 JP 7-258288 A Opioid Symposium 17, Supplement, 96-100

  In spite of these findings, it is meaningful to obtain more substances that have an effect of improving learning memory, considering that there are large differences among individuals in the pathology and manifestation of learning memory decline. In addition, it is desirable that oral administration is possible, and it is an object of the present invention to provide a functional peptide having such characteristics.

  As a result of investigations from various directions in order to solve the above-mentioned problems, the present inventors have focused on peptides, particularly oligopeptides, isolated from many peptide materials, and screened the obtained peptides. As a result, we found a tetrapeptide HIRL that has ileal contraction and smooth muscle contraction and conducted in vivo tests. As a result, we confirmed that this peptide has an excellent learning memory improvement action and can be used as a learning memory improvement agent. Thus, the present invention has been completed.

The present invention
(1) a learning memory improving agent comprising as an active ingredient a peptide represented by the amino acid sequence of SEQ ID NO: 1 in the sequence listing;
It is related to.

  According to the peptide of the present invention, a high learning memory improvement effect can be exhibited.

Peptide HIRL according to the present invention consists of the amino acid sequence shown in SEQ ID NO: 1 in the sequence listing, and is shown below, and usually includes hydrochloride, acetate, sulfate, succinate, phosphate, and tartrate. It may be a peptide to which a salt used in industry is added.
Tetrapeptide HIRL: (Single letter notation); His-Ile-Arg-Leu (Three letter notation)
This peptide can be used alone or in a mixture with other learning memory enhancers.

The peptide of the present invention can be prepared not only by a known peptide synthesis method but also by enzymatic or chemical hydrolysis of a milk protein such as β-lactoglobulin using chymotrypsin or the like.
The peptide of this invention can be utilized with any form of a pharmaceutical or food-drinks. For example, it is expected to treat and / or prevent various learning memory declines by directly administering as a pharmaceutical or by directly ingesting as a special-purpose food such as a food for specified health use or a nutritional functional food. Further, it may be added to various foods (milk, soft drinks, fermented milk, yogurt, cheese, bread, biscuits, crackers, pizza crusts, etc.) and ingested.

  For food containing the peptide of the present invention, water, protein, carbohydrates, lipids, vitamins, minerals, organic acids, organic bases, fruit juices, flavors and the like can be used as main components. 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, β-lactoglobulin, α-lacto Animal and plant proteins such as albumin, lactoferrin, soy protein, egg protein, meat protein, etc., and their hydrolysates; various milks such as butter, milk minerals, cream, whey, non-protein nitrogen, sialic acid, phospholipid, lactose Ingredients and the like. Examples of lipids include sugars, processed starch (soluble in textrin, soluble starch, British starch, oxidized starch, starch ester, starch ether, etc.), dietary fiber, etc. Examples of lipids include animal fats such as lard and fish oil; palm Examples thereof include vegetable oils such as oil, safflower oil, corn oil, rapeseed oil, coconut oil, fractionated oils thereof, hydrogenated oils and transesterified oils. Examples of vitamins include vitamin A, 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, folic acid, etc. 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. These components can be used in combination of two or more, and synthetic products and / or foods containing a large amount thereof may be used.

  Next, the case where it uses as a pharmaceutical is demonstrated. The administration route of the peptide used in the present invention may be any of oral administration, parenteral administration, and rectal administration. The anti-hair loss agent of the present invention can be administered orally or parenterally. The dosage of this peptide varies depending on the type of compound, administration method, patient symptoms, age, etc., but is usually 0.1 mg / kg to 1000 mg / kg, preferably 1 mg / kg to 100 mg / kg per day. The peptide of the present invention is usually administered in the form of a preparation prepared by mixing with a pharmaceutical carrier. As a pharmaceutical carrier, a substance that is commonly used in the pharmaceutical field and does not react with the peptide of the present invention is used.

  Specifically, examples of such substances are lactose, glucose, mannitol, dextrin, cyclodextrin, starch, sucrose, magnesium aluminate metasilicate, synthetic aluminum silicate, sodium carboxymethylcellulose, hydroxypropyl starch, carboxymethylcellulose calcium. , Ion exchange resin, methyl cellulose, gelatin, gum arabic, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl pyrrolidone, polyvinyl alcohol, light anhydrous silicic acid, magnesium stearate, talc, tragacanth, bentonite, bee gum, titanium oxide, sorbitan fatty acid ester, Sodium lauryl sulfate, glycerin, fatty acid glycerin ester, purified lanolin, glycerogelatin, polyso Bate, macrogol, vegetable oils, waxes, liquid paraffin, white petrolatum, fluorocarbons, nonionic surfactants, propylene glycol, water and the like.

  Examples of the dosage form include tablets, capsules, granules, powders, syrups, suspensions, suppositories, ointments, creams, gels, patches, inhalants, injections, and the like. These preparations are prepared according to a conventional method. The liquid preparation may be dissolved or suspended in water or other appropriate solvent at the time of use. Tablets and granules may be coated by a known method. In the case of injection, it is prepared by dissolving the peptide of the present invention in water, but it may be dissolved in physiological saline or glucose solution as necessary, and a buffer or preservative may be added. Good.

  These preparations can contain the peptide of the present invention in a proportion of 0.01% to 100% by weight, preferably 1 to 90% by weight. These formulations may also contain other therapeutically valuable ingredients.

  In order to produce a solid preparation for oral administration, an active ingredient and excipient components such as lactose, starch, crystalline cellulose, calcium lactate, anhydrous silicic acid and the like are mixed into a powder, or if necessary, sucrose, Add a binder such as hydroxypropylcellulose and polyvinylpyrrolidone, a disintegrant such as carboxymethylcellulose and carboxymethylcellulose calcium, and wet or dry granulate to form granules. In order to produce tablets, these powders and granules may be tableted as they are or after adding a lubricant such as magnesium stearate or talc. These granules or tablets should be coated with an intestinal solvent base such as hydroxypropylmethylcellulose phthalate or methacrylic acid-methyl methacrylate polymer and coated with an enteric solvent preparation, or with ethylcellulose, carnauba wax, hardened oil, etc. You can also. In order to produce capsules, powders or granules are filled into hard capsules, or active ingredients are dissolved as they are or dissolved in glycerin, polyethylene glycol, sesame oil, olive oil, etc., and then coated with a gelatin film to form soft capsules. Can do.

  In order to produce a liquid preparation for oral administration, an active ingredient and a sweetener such as sucrose, sorbitol, and glycerin are dissolved in water to add a transparent syrup, further essential oil, ethanol, etc. to make an elixir, Gum arabic, tragacanth, polysorbate 80, sodium carboxymethyl cellulose and the like may be added to form an emulsion or suspension. These liquid preparations may contain a flavoring agent, a coloring agent, a preservative and the like as desired.

  In order to produce injections, active ingredients such as hydrochloric acid, sodium hydroxide, lactose, lactic acid, sodium, sodium monohydrogen phosphate, sodium dihydrogen phosphate, pH adjusters, sodium chloride, glucose etc. Dissolve in distilled water for injection with an isotonic agent, filter aseptically and fill into ampules, or add mannitol, dextrin, cyclodextrin, gelatin, etc. . In addition, reticin, polysorbate 80, polyoxyethylene hydrogenated castor oil and the like may be added to the active ingredient and emulsified in water to give an emulsion for injection.

  To produce a rectal dosage form, the active ingredient is moistened with a suppository base material such as cacao butter, fatty acid tri, di- and monoglycerides, polyethylene glycol, etc., dissolved, poured into a mold and cooled, or the active ingredient What is necessary is just to coat | cover with a gelatin film | membrane after melt | dissolving in glycol, soybean oil, etc.

  In order to produce an external preparation for skin, the active ingredient is added to white petrolatum, beeswax, liquid paraffin, polyethylene glycol, etc., and if necessary, moistened and kneaded to make an ointment, or rosin, alkyl acrylate polymer After being kneaded with an adhesive such as polyalkyl, it is spread on a non-woven fabric such as polyalkyl to obtain a tape.

  Examples of the present invention will be described below, but the present invention is not limited to the examples.

[Example 1] Learning-promoting action of β-lactotensin: intraventricular administration The effect of peptides on learning ability was examined by a passive avoidance experiment using a step-through apparatus. When a ddy mouse (male, weight 25 ± 1 g) is placed in a light room of a device divided into two light and dark rooms, the mouse enters the dark room because it likes dark places. When entering the dark room, an electric shock (28-29V, 5 sec duration) is given from the floor to educate that the dark room is dangerous. Immediately after education, HIRL was administered into the lateral ventricle, and the learning effect was evaluated by measuring the time when the mouse was put in the same device again 24 hours later and stayed in the light room. The significance test was performed by Mann-Whitney U test. The results are shown in FIG.
As a result, it was confirmed that administration of 60 nmol / body (about 1 mg / kg) significantly prolonged the staying time in the light room.

[Example 2] Learning promoting action of β-lactotensin: oral administration A test was conducted in the same manner as in Example 1 except that the peptide was orally administered instead of intraventricularly. The results are shown in FIG.
As a result, it was confirmed that administration of 300 mg / kg of the peptide significantly prolonged the staying time in the light room.

  Tetrapeptide HIRL has an effect of improving learning memory, and is useful as a preventive agent or symptom improving agent for lowering learning memory.

It is a figure which shows the learning promotion effect by intraventricular administration of (beta) -lactotensin. It is a figure which shows the learning promotion effect by oral administration of (beta) -lactotensin.

Claims (1)

A learning memory improving agent comprising a peptide represented by the amino acid sequence of SEQ ID NO: 1 in the sequence listing as an active ingredient.

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