WO2011080947A1 - 脳機能改善用組成物および脳機能を改善する方法 - Google Patents
脳機能改善用組成物および脳機能を改善する方法 Download PDFInfo
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- WO2011080947A1 WO2011080947A1 PCT/JP2010/065483 JP2010065483W WO2011080947A1 WO 2011080947 A1 WO2011080947 A1 WO 2011080947A1 JP 2010065483 W JP2010065483 W JP 2010065483W WO 2011080947 A1 WO2011080947 A1 WO 2011080947A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/10—Peptides having 12 to 20 amino acids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
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- 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
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- 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
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
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- 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
- A61P25/24—Antidepressants
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
Definitions
- the present invention relates to a composition for improving brain function and a method for improving brain function.
- Symptoms and diseases resulting from decreased brain function include depression, schizophrenia, delirium, dementia (such as cerebrovascular dementia and Alzheimer's disease). With the aging of modern society, the increase in the number of patients with dementia has become a major social problem. Symptoms of dementia vary from person to person, but common symptoms include memory impairment, disorientation, and poor judgment and thinking. The most common dementia cases are cerebrovascular dementia and Alzheimer's disease. For example, in cerebral vascular dementia, cognitive / memory impairment appears because cerebral cortex and hippocampal neurons are damaged by cerebral blood flow disorders. Therefore, in addition to treating basic diseases such as hypertension, diabetes, and hypercholesterolemia that may cause cerebrovascular disorders, drugs that improve cerebral blood flow and drugs that protect cranial nerve cells are applied.
- Alzheimer's disease has not yet been clearly clarified, but the patient has a decreased level of acetylcholine, a neurotransmitter in the brain, which is caused by a decline in cholinergic nerve function.
- acetylcholinesterase inhibitors such as donepezil hydrochloride are commercially available as therapeutic agents for Alzheimer's disease.
- acetylcholinesterase inhibitors such as donepezil hydrochloride have a problem that they cannot be taken for a long time because they have liver toxicity and strong side effects, and are expensive.
- XPLPR (X is L, I, M, F, W) (SEQ ID NO: 17) is 300 mg / kg for intraventricular administration or oral administration against scopolamine-induced amnesia. It has been reported to show an improvement effect, and as one of the mechanisms, the release of acetylcholine by the C3a receptor in the brain has been suggested (Japanese Patent No. 3898389).
- Scopolamine is a muscarinic receptor antagonist that causes a decrease in cholinergic nerve function and acts as a brain dysfunction-inducing agent. Therefore, scopolamine is used for the production of a model animal for the development of drugs for Alzheimer's disease.
- the effect of preventing and / or improving brain dysfunction by the action of scopolamine can be demonstrated by behavioral pharmacological tests such as a Y-shaped maze test, an eight-way maze test, and a passive avoidance test.
- behavioral pharmacological tests such as a Y-shaped maze test, an eight-way maze test, and a passive avoidance test.
- the effect of improvement and / or enhancement of brain function can be demonstrated by the same behavioral pharmacological test using normal animals.
- any peptide needs to be administered in a large amount orally, intraperitoneally, intraventricularly, or the like in order to exhibit an action, and does not exhibit a sufficient effect as a substance that can be taken orally.
- the present invention provides a composition that can be taken orally at a low dose in order to improve brain function.
- the present invention also provides a method for improving brain function.
- the present invention relates to X-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu-Y (wherein X is present) Or represents either Ile or Asn-Ile, wherein Y does not exist or represents Val-Met) (SEQ ID NO: 1 to 6) or a salt thereof for improving brain function It is a composition.
- the present invention effectively uses Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu (SEQ ID NO: 1) or a salt thereof A composition for improving brain function, which is a component.
- the present invention relates to Ile-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu (SEQ ID NO: 2) or a salt thereof Is a composition for improving brain function.
- the present invention relates to Asn-Ile-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu (SEQ ID NO: 3) or A composition for improving brain function comprising the salt as an active ingredient.
- the present invention relates to Asn-Ile-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu-Val-Met (sequence It is a composition for improving brain function, comprising number 6) or a salt thereof as an active ingredient.
- the present invention relates to X-Val-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu-Y (wherein X is absent, Thr-Gln-Thr-Pro, Pro-Leu -Thr-Gln-Thr-Pro, Leu-Thr-Gln-Thr-Pro or Pro, where Y is absent or Val-Met) (SEQ ID NO: 7 to 16) or a salt thereof A composition for improving brain function, which is an active ingredient.
- the present invention relates to a brain function comprising Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu (SEQ ID NO: 7) or a salt thereof as an active ingredient.
- the present invention comprises Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu (SEQ ID NO: 8) or a salt thereof as an active ingredient. This is a composition for improving brain function.
- the present invention comprises Leu-Thr-Gln-Thr-Pro-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu (SEQ ID NO: 9) or a salt thereof as an active ingredient. It is a composition for improving brain function.
- the present invention is a composition for improving brain function, comprising as an active ingredient Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu (SEQ ID NO: 10) or a salt thereof. .
- the present invention is a composition for improving brain function, comprising Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu (SEQ ID NO: 11) or a salt thereof as an active ingredient.
- the present invention is also the composition according to any one of (1) to (11), which is for oral consumption.
- the present invention is the composition according to any one of (1) to (12), wherein the improvement of brain function is prevention of amnesia or memory enhancement.
- the present invention relates to X-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu-Y (formula Wherein X is absent or represents either Ile or Asn-Ile, wherein Y is absent or represents Val-Met) or a salt thereof, a method of improving brain function But there is.
- the present invention administers Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu or a salt thereof to a non-human animal It is also a method for improving brain function.
- the present invention relates to Ile-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu or a salt thereof, particularly for non-human animals. It is also a method for improving brain function, comprising administering (17)
- the present invention relates to a non-human animal with Asn-Ile-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu or its It is also a method of improving brain function, including administering salt.
- the present invention relates to non-human animals with Asn-Ile-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu-Val -A method of improving brain function, including administering Met or a salt thereof.
- the present invention relates to X-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu-Y (wherein X is absent, Thr-Gln-Thr-Pro, Pro-Leu -Thr-Gln-Thr-Pro, Leu-Thr-Gln-Thr-Pro or Pro, where Y is absent or Val-Met) or a salt thereof It is also a way to improve functionality.
- the present invention relates to a brain function comprising administering to a non-human animal Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu or a salt thereof. It is also a way to improve.
- the present invention comprises administering Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu or a salt thereof to a non-human animal. It is also a method of improving brain function.
- the present invention includes administering to a non-human animal Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu or a salt thereof, It is also a way to improve brain function.
- the present invention is also a method for improving brain function, comprising administering Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu or a salt thereof to a non-human animal.
- the present invention is also a method for improving brain function, comprising administering Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu or a salt thereof to a non-human animal.
- the present invention is also the method according to any one of (14) to (24), wherein the administration is oral administration.
- the present invention is also the method according to any one of (14) to (25), wherein the improvement of brain function is prevention of amnesia or enhancement of memory.
- Figure 1 shows scopolamine-induced amnesia-preventing effect of peptide Asn-Ile-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu Indicates.
- the amnesia prevention effect was evaluated by the method described in Example 1, respectively.
- the graph is from the left to the control group, scopolamine control group, NIPPLTQTPVVVPPFLQPE 0.05 nmol / kg body weight, 0.5 nmol / kg body weight, 1.5 nmol / kg body weight, 5 nmol / kg body weight, 50 nmol / kg body weight, 500 nmol / kg body weight Indicates the rate of change in alternation behavior.
- a significant difference test between the water-administered control group and the scopolamine control group administered scopolamine alone was performed by Student's t-test. ** indicates P ⁇ 0.01 with respect to the water-administered control group.
- Figure 2 shows the peptides Asn-Ile-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu (NIPPLTQTPVVVPPFLQPE), Asn-Ile-Pro -Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu-Val-Met (NIPPLTQTPVVVPPFLQPEVM), Ile-Pro-Leu-Thr- Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu (IPPLTQTPVVVPPFLQPE), Asn-Ile-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu (IPPLTQTPVVVPPFLQPE), Asn-Ile
- NIPPLTQTPVVVPPFLQPE 50 nmol / kg body weight or NIPPLTQTPVVVPPFLQPEVM 50 nmol / kg body weight or IPPLTQTPVVVPPFLQPE 50 nmol / kg body weight or NIPPLTQTPVVVPPFLQP 50 nmol / kg body weight was used to evaluate the effect of preventing amnesia.
- the vertical axis in FIG. 2 indicates the voluntary alternation behavior change rate. In order to confirm whether forgetfulness was induced, a significant difference test between the water-administered control group and the scopolamine control group administered scopolamine alone was performed by Student's t-test.
- FIG. 4 shows the memory enhancement effect of the peptide Asn-Ile-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu (NIPPLTQTPVVVPPFLQPE) .
- the vertical axis in FIG. 4 indicates the ratio of search time.
- FIG. 5 shows the scopolamine-induced amnesia-preventing effect of the peptide Thr-Gln-Thr-Pro-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu (TQTPVVVPPFLQPE).
- Water (control), scopolamine alone, or TQTPVVVPPFLQPE 50 nmol / kg body weight was administered to mice together with scopolamine, and the effect of preventing amnesia was evaluated by the method described in Example 5, respectively.
- Figure 6 shows the peptides Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu (PLTQTPVVVPPFLQPE), Leu-Thr-Gln-Thr-Pro-Val -Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu (LTQTPVVVPPFLQPE), Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu (PVVVPPFLQPE), Val-Val 1 shows the scopolamine-induced amnesia-preventing effect of -Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu (VVPPFLQPE).
- Example 1 was used to evaluate the effect of preventing amnesia.
- the vertical axis in FIG. 6 shows the voluntary alternation behavior change rate.
- a significant difference test between the water-administered control group and the scopolamine control group administered scopolamine alone was performed by Student's t-test. ** indicates P ⁇ 0.01 with respect to the water-administered control group.
- a significant difference test between each peptide administration group and the scopolamine control group was performed by Student's t-test. # Indicates P ⁇ 0.05 with respect to the scopolamine control group, and ⁇ indicates P ⁇ 0.1 with respect to the scopolamine control group.
- composition of the present invention comprises the peptide X-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu-Y (where X is present) Or represents either Ile or Asn-Ile, where Y is absent or represents Val-Met) or peptide, X-Val-Val-Val-Pro-Pro-Phe-Leu-Gln -Pro-Glu-Y (where X is absent, or Thr-Gln-Thr-Pro, Pro-Leu-Thr-Gln-Thr-Pro, Leu-Thr-Gln-Thr-Pro or Pro In which Y is absent or represents Val-Met), in particular the peptide Asn-Ile-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu- Gln-Pro-Glu, or peptide Asn-Ile-Pro-Leu-Thr-Gln-Thr
- a general method such as a solid phase method (t-Boc method, Fmoc method) or a liquid phase method can be used.
- a peptide synthesizer PSSM manufactured by Shimadzu Corporation
- a peptide synthesizer PSSM manufactured by Shimadzu Corporation
- the synthesis method to be selected, appropriate reaction conditions, and the like can be arbitrarily set.
- Methods for purifying chemically synthesized peptides are also well known to those skilled in the art.
- the peptide X-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu-Y (wherein X does not exist) Or represents either Ile or Asn-Ile, where Y is absent or represents Val-Met) or peptide, X-Val-Val-Val-Pro-Pro-Phe-Leu-Gln- Pro-Glu-Y (where X is absent or represents Thr-Gln-Thr-Pro, Pro-Leu-Thr-Gln-Thr-Pro, Leu-Thr-Gln-Thr-Pro or Pro) Wherein Y is absent or represents Val-Met), in particular the peptide Asn-Ile-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln -Pro-Glu, or peptide Asn-Ile-Pro-Leu-Thr-Gl
- composition of the present invention includes peptide X-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu- which is an active ingredient of the composition of the present invention.
- Gln-Pro-Glu-Y (wherein X is absent or represents either Ile or Asn-Ile, where Y is absent or represents Val-Met) or peptide, X-Val- Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu-Y (where X is absent, Thr-Gln-Thr-Pro, Pro-Leu-Thr-Gln-Thr-Pro, Leu- Represents either Thr-Gln-Thr-Pro or Pro, where Y is absent or represents Val-Met), especially the peptide Asn-Ile-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val -Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu, or peptide Asn-Ile-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Val-Pro-Pro-Phe -Leu-Gln-Pro-Glu-Val-Met or peptide Ile-Pro-Pro
- Composition of the invention or peptide X-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu-Y (where X is present) Or represents either Ile or Asn-Ile, where Y is absent or represents Val-Met) or peptide, X-Val-Val-Val-Pro-Pro-Phe-Leu-Gln -Pro-Glu-Y (where X is absent, or Thr-Gln-Thr-Pro, Pro-Leu-Thr-Gln-Thr-Pro, Leu-Thr-Gln-Thr-Pro or Pro In which Y is absent or represents Val-Met), in particular the peptide Asn-Ile-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu- Gln-Pro-Glu, or peptide Asn-Ile-Pro-Leu-Thr-Thr-Thr-Thr-
- a drug that induces forgetfulness by causing a decrease in cholinergic nerve function by using a muscarinic receptor antagonist such as scopolamine in rats or mice, or by causing brain dysfunction Composition or X-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu-Y (where X is absent or Represents either Ile or Asn-Ile, where Y is absent or represents Val-Met) or X-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu-Y (In the formula, X does not exist or represents Thr-Gln-Thr-Pro, Pro-Leu-Thr-Gln-Thr-Pro, Leu-Thr-Gln-Thr-Pro or Pro, and Y in the formula Not present or represents Val-Met), especially Asn-Ile-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val
- X-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu-Y (X does not exist) for drug-induced amnesia Or represents either Ile or Asn-Ile, where Y is absent or represents Val-Met) or X-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro -Glu-Y (where X is absent or represents Thr-Gln-Thr-Pro, Pro-Leu-Thr-Gln-Thr-Pro, Leu-Thr-Gln-Thr-Pro or Pro, Y in the formula is absent or represents Val-Met), in particular Asn-Ile-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro -Glu, or Asn-Ile-Pro-Pro-Pro-
- Composition of the invention or peptide X-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu-Y (where X is present) Or represents either Ile or Asn-Ile, where Y is absent or represents Val-Met) or peptide, X-Val-Val-Val-Pro-Pro-Phe-Leu-Gln -Pro-Glu-Y (where X is absent, Thr-Gln-Thr-Pro, Pro-Leu-Thr-Gln-Thr-Pro, Leu-Thr-Gln-Thr-Pro or Pro In which Y is absent or represents Val-Met), in particular the peptide Asn-Ile-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu- Gln-Pro-Glu, or peptide Asn-Ile-Pro-Pro-Leu-Thr-Thr-Thr-Thr
- composition of the present invention or the peptide X-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu-Y (wherein X is absent or represents either Ile or Asn-Ile and Y is absent or represents Val-Met) or peptide, X-Val-Val-Val-Pro-Pro- Phe-Leu-Gln-Pro-Glu-Y (where X is absent, Thr-Gln-Thr-Pro, Pro-Leu-Thr-Gln-Thr-Pro, Leu-Thr-Gln-Thr-Pro or Pro Wherein Y is absent or represents Val-Met), in particular the peptide Asn-Ile-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro- Phe-Leu-Gln-Pro-Glu, or peptide Asn-Ile-Pro-Leu-Thr-Gln-Glu, or
- the active ingredient is peptide X-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu-Y (formula X is absent or represents either Ile or Asn-Ile, where Y is absent or represents Val-Met) or peptide, X-Val-Val-Val-Pro-Pro-Phe -Leu-Gln-Pro-Glu-Y (where X is absent, Thr-Gln-Thr-Pro, Pro-Leu-Thr-Gln-Thr-Pro, Leu-Thr-Gln-Thr-Pro or Pro Wherein Y is absent or represents Val-Met), in particular the peptide Asn-Ile-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro- Phe-Leu-Gln-Pro-Glu, or peptide Asn-Ile-Pro-Pro-Leu-Thr-Thr-Gln-
- the administration or ingestion period of the composition of the present invention can be variously adjusted in consideration of the age of the subject to be administered or ingested, for example, the age of the human or non-human animal, the health condition of the subject, and the like.
- Non-human animals include non-human higher vertebrates, particularly non-human mammals, including but not limited to pets such as dogs and cats, and domestic animals such as cows, horses, pigs and sheep.
- the effect of the composition of the present invention can be seen even after one administration, but a continuous effect can be expected by continuously ingesting once or more a day.
- the composition of the present invention When the composition of the present invention is used as a medicine, it can be in the form of a preparation for oral administration.
- Examples include tablets, pills, hard capsules, soft capsules, microcapsules, powders, granules, liquids and the like.
- a pharmaceutically acceptable carrier for example, excipient, excipient, preservative, stabilizer, binder, pH adjuster, buffer, thickener, if necessary.
- the composition of the present invention can also be used as a material for food and drink or an animal feed material.
- peptide X-Pro-Pro-Leu-Thr- which is an active ingredient of the composition of the present invention or the composition of the present invention.
- Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu-Y (where X is absent or represents either Ile or Asn-Ile, where Y is absent or represents Val-Met) or peptide, X-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu-Y (wherein X is absent or Thr- Gln-Thr-Pro, Pro-Leu-Thr-Gln-Thr-Pro, Leu-Thr-Gln-Thr-Pro or Pro, where Y is absent or Val-Met), especially Peptide Asn-Ile-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu, or peptide Asn-Ile-Pro-Leu -Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu
- composition or peptide X-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu-Y (wherein X is absent or represents either Ile or Asn-Ile and Y is absent or represents Val-Met) or peptide, X-Val-Val-Val-Pro-Pro- Phe-Leu-Gln-Pro-Glu-Y (where X is absent, Thr-Gln-Thr-Pro, Pro-Leu-Thr-Gln-Thr-Pro, Leu-Thr-Gln-Thr-Pro or Pro represents any of Pro, where Y is absent or Val-Met), in particular the peptide Asn-Ile-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro -Phe-Leu-Gln-Pro-Glu, or peptide Asn-Ile-Pro-Pro-Leu-Thr-Thr-Thr-Thr-Thr
- composition of the present invention or its active ingredient peptide X-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu-Y (wherein X is absent or represents either Ile or Asn-Ile and Y is absent or represents Val-Met) or peptide, X-Val-Val-Val-Pro-Pro- Phe-Leu-Gln-Pro-Glu-Y (where X is absent, Thr-Gln-Thr-Pro, Pro-Leu-Thr-Gln-Thr-Pro, Leu-Thr-Gln-Thr-Pro or Pro represents any of Pro, where Y is absent or Val-Met), in particular the peptide Asn-Ile-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro -Phe-Leu-Gln-Pro-Glu, or peptide Asn-Ile-Pro-Pro-Leu-Thr-
- composition of the present invention or its active ingredient peptide X-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu-Y (wherein X is absent or represents either Ile or Asn-Ile and Y is absent or represents Val-Met) or peptide, X-Val-Val-Val-Pro-Pro- Phe-Leu-Gln-Pro-Glu-Y (where X is absent, Thr-Gln-Thr-Pro, Pro-Leu-Thr-Gln-Thr-Pro, Leu-Thr-Gln-Thr-Pro or Pro represents any of Pro, where Y is absent or Val-Met), in particular the peptide Asn-Ile-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro -Phe-Leu-Gln-Pro-Glu, or peptide Asn-Ile-Pro-Pro-Leu-Thr-
- the aforementioned functional food can be in any form of a solid, a gel, and a liquid, for example, various processed foods and drinks, dry powder, tablets, capsules, granules, etc.
- the peptide X-Pro-Pro-Leu which is an active ingredient contained in the final product, depends on the addition form and product form.
- composition of the present invention or its active ingredient peptide X-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu-Y (wherein X is absent or represents either Ile or Asn-Ile and Y is absent or represents Val-Met) or peptide, X-Val-Val-Val-Pro-Pro- Phe-Leu-Gln-Pro-Glu-Y (where X is absent, Thr-Gln-Thr-Pro, Pro-Leu-Thr-Gln-Thr-Pro, Leu-Thr-Gln-Thr-Pro or Pro represents any of Pro, where Y is absent or Val-Met), in particular the peptide Asn-Ile-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro -Phe-Leu-Gln-Pro-Glu, or peptide Asn-Ile-Pro-Pro-Leu-Thr-
- composition of the present invention or the peptide that is an active ingredient thereof is depression, schizophrenia, delirium, dementia (cerebrovascular dementia, Alzheimer's disease, etc.) which are symptoms and diseases caused by a decrease in brain function. It can be used for treatment or prevention.
- depression schizophrenia, delirium, dementia (cerebrovascular dementia, Alzheimer's disease, etc.) which are symptoms and diseases caused by a decrease in brain function. It can be used for treatment or prevention.
- Asn-Ile-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu 0.05 nmol / kg body weight (0.1 ⁇ g / kg body weight), 0.5 nmol / kg body weight (1 ⁇ g / kg body weight), 1.5 nmol / kg body weight (3 ⁇ g / kg body weight), 5 nmol / kg body weight (10 ⁇ g / kg body weight), 50 nmol / kg body weight (100 ⁇ g / kg body weight), 500 nmol / kg body weight (1000 ⁇ g / kg body weight) was used.
- the test substance was orally administered to mice once 60 minutes before the Y-maze test for evaluating spontaneous alternation behavior. Further, 30 minutes before the Y-maze test, scopolamine was subcutaneously administered to the back so that the body weight was 1 mg / kg body weight in order to induce brain dysfunction (memory impairment and / or cognitive impairment) in mice.
- one arm is 40 cm long, the wall height is 12 cm, the floor width is 3 cm, the top width is 10 cm, and the three arms are connected at an angle of 120 degrees each.
- the character maze was used as an experimental device. The mouse was placed on the tip of any arm of the Y-shaped maze and allowed to freely explore the maze for 8 minutes, and the arm to which the mouse moved was recorded in order.
- select three different arms in succession for example, three arms A, B, When the order of the arms entered was ABCBACACB, it was counted as 4 including duplication), and this number was taken as the number of voluntary replacement actions.
- the number of voluntary alternations was divided by the total number of ingresses minus 2, and the value obtained by multiplying it by 100 was the voluntary alternation behavior change rate, which was used as an index of voluntary alternation behavior. The higher the index, the shorter the short-term memory.
- the measured values were expressed as mean ⁇ standard error for each group.
- the significance test between the control group and the scopolamine control group was performed by Student's t-test.
- NIPPLTQTPVVVPPFLQPE was shown to have an amnesia-preventing action in the range of 0.05 nmol / kg body weight to 500 nmol / kg body weight (0.1 ⁇ g / kg body weight to 1000 ⁇ g / kg body weight).
- NIPPLTQTPVVVPPFLQPE Asn-Ile-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu
- the test substance was orally administered to mice once 60 minutes before the Y-maze test for evaluating spontaneous alternation behavior. Further, 30 minutes before the Y-maze test, scopolamine was subcutaneously administered to the back so that the body weight was 1 mg / kg body weight in order to induce brain dysfunction (memory impairment and / or cognitive impairment) in mice.
- one arm is 40 cm long, the wall height is 12 cm, the floor width is 3 cm, the top width is 10 cm, and the three arms are connected at an angle of 120 degrees each.
- the character maze was used as an experimental device. The mouse was placed on the tip of any arm of the Y-shaped maze and allowed to freely explore the maze for 8 minutes, and the arm to which the mouse moved was recorded in order.
- select three different arms in succession for example, three arms A, B, When the order of the arms entered was ABCBACACB, it was counted as 4 including duplication), and this number was taken as the number of voluntary replacement actions.
- the number of voluntary alternations was divided by the total number of ingresses minus 2, and the value obtained by multiplying it by 100 was the voluntary alternation behavior change rate, which was used as an index of voluntary alternation behavior. The higher the index, the shorter the short-term memory.
- the measured values were expressed as mean ⁇ standard error for each group.
- the significance test between the control group and the scopolamine control group was performed by Student's t-test.
- NIPPLTQTPVVVPPFLQPE was shown to have an amnesia-preventing action at 50 nmol / kg body weight (100 ⁇ g / kg body weight)
- NIPPLTQTPVVVPPFLQPEVM was 50 nmol / kg body weight (120 ⁇ g / kg body weight)
- IPPLTQTPVVVPPFLQPE was 50 nmol / kg body weight (100 ⁇ g / kg body weight).
- NIPPLTQTPVVVPPFLQP did not show any amnesia-preventing action with respect to 50 nmol / kg body weight (100 ⁇ g / kg body weight) and TQTPVVVPPF with 50 nmol / kg body weight (50 ⁇ g / kg body weight) as compared with the scopolamine control group.
- NIPPLTQTPVVVPPFLQPE Asn-Ile-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu
- mice 30 minutes before the Y-maze test, scopolamine was subcutaneously administered to the back so that the body weight was 1 mg / kg body weight in order to induce brain dysfunction (memory impairment and / or cognitive impairment) in mice.
- one arm is 40 cm long, the wall height is 12 cm, the floor width is 3 cm, the top width is 10 cm, and the three arms are connected at an angle of 120 degrees each.
- the character maze was used as an experimental device. The mouse was placed on the tip of any arm of the Y-shaped maze and allowed to freely explore the maze for 8 minutes, and the arm to which the mouse moved was recorded in order.
- select three different arms in succession for example, three arms A, B, When the order of the arms entered was ABCBACACB, it was counted as 4 including duplication), and this number was taken as the number of voluntary replacement actions.
- the number of voluntary alternations was divided by the total number of ingresses minus 2, and the value obtained by multiplying it by 100 was the voluntary alternation behavior change rate, which was used as an index of voluntary alternation behavior. The higher the index, the shorter the short-term memory.
- the measured values were expressed as mean ⁇ standard error for each group.
- the significance test between the control group and the scopolamine control group was performed by Student's t-test.
- NIPPLTQTPVVVPPFLQPE was found to have an amnesia-preventing action at 500 nmol / kg body weight (1000 ⁇ g / kg body weight) and PPLTQTPVVVPPFLQPE at 500 nmol / kg body weight (1000 ⁇ g / kg body weight).
- a 30 ⁇ 30 ⁇ 30 cm box was used as an experimental device.
- a mouse was placed in an experimental apparatus with a floor covering for 5 minutes to freely search the apparatus.
- a training trial was conducted the day after the habituation operation.
- two of the three types of objects were selected and installed in the experimental device (the objects were placed 8 cm from the walls on both sides along the center line of the floor, and the positions were X1 and X2. Note that the object to be installed was selected at random in advance so that there was no bias between animals and groups.
- mice Sixty minutes after the oral administration of the test substance or water, the mice were placed in the experimental apparatus for 5 minutes, and the time (seconds) that the mice approached and searched within 1 cm of each object was measured.
- a retention trial was performed 48 hours after the training trial.
- two objects were installed in the experimental apparatus as in the training trial, but one of them was changed to an object (new object) different from that used in the training trial, and its position was set to Y.
- the significant difference test is the ratio of the search time to the novel object in the holding trial (the object installed in Y) and the object installed in the place where the novel object was placed in the training trial (installed in X1 or X2).
- the ratio of the search time to the object was determined by Student's t test between the control group and the peptide group.
- the results are shown in FIG. NIPPLTQTPVVVPPFLQPE was shown to have a memory enhancing effect at 500 nmol / kg body weight (1000 ⁇ g / kg body weight).
- NIPPLTQTPVVVPPFLQPE Asn-Ile-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu
- TQTPVVVPPFLQPE 50 nmol / kg body weight (80 ⁇ g / kg body weight) was used as a test substance.
- the test substance was orally administered to mice once 60 minutes before the Y-maze test for evaluating spontaneous alternation behavior. Further, 30 minutes before the Y-maze test, scopolamine was subcutaneously administered to the back so that the body weight was 1 mg / kg body weight in order to induce brain dysfunction (memory impairment and / or cognitive impairment) in mice.
- one arm is 40 cm long, the wall height is 12 cm, the floor width is 3 cm, the top width is 10 cm, and the three arms are connected at an angle of 120 degrees each.
- the character maze was used as an experimental device. The mouse was placed on the tip of any arm of the Y-shaped maze and allowed to freely explore the maze for 8 minutes, and the arm to which the mouse moved was recorded in order.
- select three different arms in succession for example, three arms A, B, When the order of the arms entered was ABCBACACB, it was counted as 4 including duplication), and this number was taken as the number of voluntary replacement actions.
- the number of voluntary alternations was divided by the total number of ingresses minus 2, and the value obtained by multiplying it by 100 was the voluntary alternation behavior change rate, which was used as an index of voluntary alternation behavior. The higher the index, the shorter the short-term memory.
- the measured values were expressed as mean ⁇ standard error for each group.
- the significance test between the control group and the scopolamine control group was performed by Student's t-test.
- TQTPVVVPPFLQPE was shown to have an amnesia-preventing action at 50 nmol / kg body weight (80 ⁇ g / kg body weight).
- NIPPLTQTPVVVPPFLQPE Asn-Ile-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu
- Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu (PLTQTPVVVPPFLQPE) 500 nmol / kg body weight (900 ⁇ g / kg body weight), or Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu (LTQTPVVVPPFLQPE) 500 nmol / kg body weight (850 ⁇ g / kg body weight), or Pro-Val-Val- Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu (PVVVPPFLQPE) 500 nmol / kg body weight (630 ⁇ g / kg body weight), or Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu ( VVVPPFLQPE) 500 nmol / kg body weight (580 ⁇ g / kg body weight) was used
- the test substance was orally administered to mice once 60 minutes before the Y-maze test for evaluating spontaneous alternation behavior. Further, 30 minutes before the Y-maze test, scopolamine was subcutaneously administered to the back so that the body weight was 1 mg / kg body weight in order to induce brain dysfunction (memory impairment and / or cognitive impairment) in mice.
- one arm is 40 cm long, the wall height is 12 cm, the floor width is 3 cm, the top width is 10 cm, and the three arms are connected at an angle of 120 degrees each.
- the character maze was used as an experimental device. The mouse was placed on the tip of any arm of the Y-shaped maze and allowed to freely explore the maze for 8 minutes, and the arm to which the mouse moved was recorded in order.
- select three different arms in succession for example, three arms A, B, When the order of the arms entered was ABCBACACB, it was counted as 4 including duplication), and this number was taken as the number of voluntary replacement actions.
- the number of voluntary alternations was divided by the total number of ingresses minus 2, and the value obtained by multiplying it by 100 was the voluntary alternation behavior change rate, which was used as an index of voluntary alternation behavior. The higher the index, the shorter the short-term memory.
- the measured values were expressed as mean ⁇ standard error for each group.
- the significance test between the control group and the scopolamine control group was performed by Student's t-test.
- PLTQTPVVVPPFLQPE is 500 nmol / kg body weight (900 ⁇ g / kg body weight)
- LTQTPVVVPPFLQPE is 500 nmol / kg body weight (850 ⁇ g / kg)
- PVVVPPFLQPE is 500 nmol / kg body weight (630 ⁇ g / kg)
- VVVPPFLQPE is 500 nmol / kg body weight (580 ⁇ g / kg). It has been shown to have a preventive action.
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Abstract
Description
現在、アルツハイマー病の治療薬として、例えば塩酸ドネペジル等のアセチルコリンエステラーゼ阻害剤が市販されている。しかし、塩酸ドネペジル等のアセチルコリンエステラーゼ阻害剤は肝臓毒性や強い副作用を有するため長期間服用できず、また高価であるという問題があった。
また、ペプチドに関して健忘改善効果を示した報告として、例えばXPLPR(XはL、I、M、F、W)(配列番号17)が300mg/kgの側脳室内投与または経口投与によりスコポラミン誘発健忘に対する改善効果を示すことが報告されており、そのメカニズムの一つとして脳内C3aレセプターによるアセチルコリンの放出が示唆されている(特許第3898389号公報)。スコポラミンはムスカリン受容体拮抗薬としてコリン作動性神経の機能低下を引き起こすとされており、脳機能障害誘発剤として働くため、アルツハイマー病治療薬開発の際のモデル動物作製に用いられている。このスコポラミンの作用による脳機能障害の予防および/または改善作用については、例えばY字迷路試験、八方向迷路試験、受動的回避試験などの行動薬理試験により効果を実証することができる。また、正常動物を用いた同様の行動薬理試験によって、脳機能の改善および/または強化の効果を実証することができる。しかし、何れのペプチドも、作用を示すために大量の経口投与、もしくは腹腔内投与、脳室内投与等の投与をする必要があり、経口摂取可能な物質として十分な効果を示すものではない。また、本発明におけるペプチドおよびその類縁体について評価した報告はなく、脳機能改善に関わる作用は不明であった。
したがって、高齢化社会の進行に伴い、脳機能の低下に起因する症状あるいは疾患を予防し、さらに改善効果を示すような医薬品、さらには食品への適用に優れたより安全な化合物の開発がますます強く要望されている。
(2)本発明は、Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu(配列番号1)またはその塩を有効成分とする、脳機能改善用組成物である。
(3)本発明は、Ile-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu(配列番号2)またはその塩を有効成分とする、脳機能改善用組成物である。
(4)本発明は、Asn-Ile-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu(配列番号3)またはその塩を有効成分とする、脳機能改善用組成物である。
(5)本発明は、Asn-Ile-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu-Val-Met(配列番号6)またはその塩を有効成分とする、脳機能改善用組成物である。
(6)本発明は、X-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu-Y(式中Xは存在しないか、Thr-Gln-Thr-Pro、Pro-Leu-Thr-Gln-Thr-Pro、Leu-Thr-Gln-Thr-ProまたはProのいずれかを表し、式中Yは存在しないかVal-Metを表す)(配列番号7~16)またはその塩を有効成分とする、脳機能改善用組成物である。
(7)本発明は、Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu(配列番号7)またはその塩を有効成分とする、脳機能改善用組成物である。
(8)本発明は、Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu(配列番号8)またはその塩を有効成分とする、脳機能改善用組成物である。
(9)本発明は、Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu(配列番号9)またはその塩を有効成分とする、脳機能改善用組成物である。
(10)本発明は、Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu(配列番号10)またはその塩を有効成分とする、脳機能改善用組成物である。
(11)本発明は、Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu(配列番号11)またはその塩を有効成分とする、脳機能改善用組成物である。
(12)本発明は、経口摂取用である、(1)~(11)のいずれかに記載の組成物でもある。
(13)特に本発明は、脳機能の改善が健忘予防または記憶力増強である、(1)~(12)のいずれかに記載の組成物である。
(14)本発明は、非ヒト動物にX-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu-Y(式中Xは存在しないか、またはIleまたはAsn-Ileのいずれかを表し、式中Yは存在しないか、またはVal-Metを表す)またはその塩を投与することを含む、脳機能を改善する方法でもある。
(15)本発明は、非ヒト動物にPro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Gluまたはその塩を投与することを含む、脳機能を改善する方法でもある。
(16)本発明は、特に非ヒト動物にIle-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Gluまたはその塩を投与することを含む、脳機能を改善する方法でもある。
(17)本発明は、非ヒト動物にAsn-Ile-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Gluまたはその塩を投与することを含む、脳機能を改善する方法でもある。
(18)本発明は、非ヒト動物にAsn-Ile-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu-Val-Metまたはその塩を投与することを含む、脳機能を改善する方法でもある。
(19)本発明は、X-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu-Y(式中Xは存在しないか、Thr-Gln-Thr-Pro、Pro-Leu-Thr-Gln-Thr-Pro、Leu-Thr-Gln-Thr-ProまたはProのいずれかを表し、式中Yは存在しないかVal-Metを表す)またはその塩を投与することを含む、脳機能を改善する方法でもある。
(20)本発明は、非ヒト動物にThr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Gluまたはその塩を投与することを含む、脳機能を改善する方法でもある。
(21)本発明は、非ヒト動物にPro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Gluまたはその塩を投与することを含む、脳機能を改善する方法でもある。
(22)本発明は、非ヒト動物にLeu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Gluまたはその塩を投与することを含む、脳機能を改善する方法でもある。
(23)本発明は、非ヒト動物にPro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Gluまたはその塩を投与することを含む、脳機能を改善する方法でもある。
(24)本発明は、非ヒト動物にVal-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Gluまたはその塩を投与することを含む、脳機能を改善する方法でもある。
(25)本発明は、投与が経口投与である、(14)~(24)のいずれかに記載の方法でもある。
(26)特に本発明は、脳機能を改善することが健忘予防または記憶力増強である(14)~(25)のいずれかに記載の方法でもある。
本明細書において、ペプチドX-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu-Y(式中Xは存在しないか、またはIleまたはAsn-Ileのいずれかを表し、式中Yは存在しないか、またはVal-Metを表す)またはペプチド、X-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu-Y(式中Xは存在しないか、Thr-Gln-Thr-Pro、Pro-Leu-Thr-Gln-Thr-Pro、Leu-Thr-Gln-Thr-ProまたはProのいずれかを表し、式中Yは存在しないかVal-Metを表す)、特にペプチドAsn-Ile-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu、またはペプチドAsn-Ile-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu-Val-Met、またはペプチドIle-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu、またはペプチドPro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-GluまたはペプチドThr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu、またはペプチドPro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu、またはペプチドLeu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu、またはペプチドPro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu、またはペプチドVal-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Gluについて言及する場合、特に明示した場合および文脈上除外されることが明らかである場合を除き、「X-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu-Y(式中Xは存在しないか、またはIleまたはAsn-Ileのいずれかを表し、式中Yは存在しないか、またはVal-Metを表す)または、X-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu-Y(式中Xは存在しないか、Thr-Gln-Thr-Pro、Pro-Leu-Thr-Gln-Thr-Pro、Leu-Thr-Gln-Thr-ProまたはProのいずれかを表し、式中Yは存在しないかVal-Metを表す)、特にAsn-Ile-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu、またはAsn-Ile-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu-Val-Met、またはIle-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu、またはPro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu、またはThr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu、またはPro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu、またはLeu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu、またはPro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu、またはVal-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu 」および「ペプチドX-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu-Y(式中Xは存在しないか、またはIleまたはAsn-Ileのいずれかを表し、式中Yは存在しないか、またはVal-Metを表す)またはペプチド、X-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu-Y(式中Xは存在しないか、Thr-Gln-Thr-Pro、Pro-Leu-Thr-Gln-Thr-Pro、Leu-Thr-Gln-Thr-ProまたはProのいずれかを表し、式中Yは存在しないかVal-Metを表す)、特にペプチドAsn-Ile-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu、またはペプチドAsn-Ile-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu-Val-Met、またはペプチドIle-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu、またはペプチドPro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-GluまたはペプチドThr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu、またはペプチドPro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu、またはペプチドLeu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu、またはペプチドPro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu、またはペプチドVal-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu」にはその塩が含まれる。そのような塩には、例えばナトリウム塩、カリウム塩、塩酸塩などの生理的条件下で存在しえる塩が含まれる。また、本発明の組成物は、本発明の組成物の有効成分であるペプチドX-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu-Y(式中Xは存在しないか、またはIleまたはAsn-Ileのいずれかを表し、式中Yは存在しないか、またはVal-Metを表す)またはペプチド、X-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu-Y(式中Xは存在しないか、Thr-Gln-Thr-Pro、Pro-Leu-Thr-Gln-Thr-Pro、Leu-Thr-Gln-Thr-ProまたはProのいずれかを表し、式中Yは存在しないかVal-Metを表す)、特にペプチドAsn-Ile-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu、またはペプチドAsn-Ile-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu-Val-Met、またはペプチドIle-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu、またはペプチドPro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu、またはペプチドThr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu、またはペプチドPro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu、またはペプチドLeu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu、またはペプチドPro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu、またはペプチドVal-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu以外に他のペプチドおよび遊離アミノ酸またはその塩を含んでいても良い。なお、本発明との関連において、アミノ酸の三文字表記および一文字表記ならびにペプチドの表記は当業者によく知られた一般的規則に従う。
これらの試験において陰性対照としてはたとえば水のみを投与した動物を用いることができる。薬剤によって誘導した健忘に対するX-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu-Y(式中Xは存在しないか、またはIleまたはAsn-Ileのいずれかを表し、式中Yは存在しないか、またはVal-Metを表す)または、X-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu-Y(式中Xは存在しないか、Thr-Gln-Thr-Pro、Pro-Leu-Thr-Gln-Thr-Pro、Leu-Thr-Gln-Thr-ProまたはProのいずれかを表し、式中Yは存在しないかVal-Metを表す)、特にAsn-Ile-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu、またはAsn-Ile-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu-Val-Met、またはIle-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu、またはPro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu、またはThr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu、またはPro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu、またはLeu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu、またはPro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu、またはVal-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Gluの予防作用を確認する実験の際には、スコポラミンのような脳機能障害を引き起こすことで健忘症を誘発する薬剤のみを投与した動物も対照として加えることができる。
本発明の組成物は飲食品用素材または動物用飼料素材として用いることもでき、例えば、本発明の組成物または本発明の組成物の有効成分であるペプチドX-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu-Y(式中Xは存在しないか、またはIleまたはAsn-Ileのいずれかを表し、式中Yは存在しないか、またはVal-Metを表す)またはペプチド、X-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu-Y(式中Xは存在しないか、Thr-Gln-Thr-Pro、Pro-Leu-Thr-Gln-Thr-Pro、Leu-Thr-Gln-Thr-ProまたはProのいずれかを表し、式中Yは存在しないかVal-Metを表す)、特にペプチドAsn-Ile-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu、またはペプチドAsn-Ile-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu-Val-Met、またはペプチドIle-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu、またはペプチドPro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu、またはペプチドThr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu、またはペプチドPro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu、またはペプチドLeu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu、またはペプチドPro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu、またはペプチドVal-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Gluを脳機能改善の効能を有する特定保健用食品等の機能性食品とすることができる。
所望の効果を得るための本組成物またはペプチドX-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu-Y(式中Xは存在しないか、またはIleまたはAsn-Ileのいずれかを表し、式中Yは存在しないか、またはVal-Metを表す)またはペプチド、X-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu-Y(式中Xは存在しないか、Thr-Gln-Thr-Pro、Pro-Leu-Thr-Gln-Thr-Pro、Leu-Thr-Gln-Thr-ProまたはProのいずれかを表し、式中Yは存在しないかVal-Metを表す)、特にペプチドAsn-Ile-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu、またはペプチドAsn-Ile-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu-Val-Met、またはペプチドIle-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu、またはペプチドPro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu、またはペプチドThr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu、またはペプチドPro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu、またはペプチドLeu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu、またはペプチドPro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu、またはペプチドVal-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Gluの投与または摂取量は、1回あたり有効成分であるペプチドX-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu-Y(式中Xは存在しないか、またはIleまたはAsn-Ileのいずれかを表し、式中Yは存在しないか、またはVal-Metを表す)またはペプチド、X-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu-Y(式中Xは存在しないか、Thr-Gln-Thr-Pro、Pro-Leu-Thr-Gln-Thr-Pro、Leu-Thr-Gln-Thr-ProまたはProのいずれかを表し、式中Yは存在しないかVal-Metを表す)、特にペプチドAsn-Ile-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu、またはペプチドAsn-Ile-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu-Val-Met、またはペプチドIle-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu、またはペプチドPro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu、またはペプチドThr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu、またはペプチドPro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu、またはペプチドLeu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu、またはペプチドPro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu、またはペプチドVal-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Gluの量として一般に0.1μg/kg体重~1mg/kg体重が好ましい。1日あたりの摂取回数に応じて、食品、例えば機能性食品における1回あたりの摂取量を前記量より更に低くすることも可能である。適切な摂取量は、上述の通り種々の要因を考慮して更に調整することができる。
例えば前述の機能性食品は、固形物、ゲル状物、液状物の何れの形態とすることができ、例えば、各種加工飲食品、乾燥粉末、錠剤、カプセル剤、顆粒剤等が挙げられ、更には各種飲料、ヨーグルト、流動食、ゼリー、キャンディ、レトルト食品、錠菓、クッキー、カステラ、パン、ビスケット、チョコレート等とすることができる。
本発明の組成物を含む特定保健用食品等の機能性食品を製造する場合、添加形態や製品形態によるが、最終製品に対して、含有される有効成分であるペプチドX-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu-Y(式中Xは存在しないか、またはIleまたはAsn-Ileのいずれかを表し、式中Yは存在しないか、またはVal-Metを表す)またはペプチド、X-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu-Y(式中Xは存在しないか、Thr-Gln-Thr-Pro、Pro-Leu-Thr-Gln-Thr-Pro、Leu-Thr-Gln-Thr-ProまたはProのいずれかを表し、式中Yは存在しないかVal-Metを表す)、特にペプチドAsn-Ile-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu、またはペプチドAsn-Ile-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu-Val-Met、またはペプチドIle-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu、またはペプチドPro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu、またはペプチドThr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu、またはペプチドPro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu、またはペプチドLeu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu、またはペプチドPro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu、またはペプチドVal-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Gluの含有量が100g当り1μg~10g、好ましくは10μg~1g、さらに好ましくは100μg~100mgとなるように調製する。
以下、実施例により本発明を具体的に説明するが、本発明の範囲は実施例に限られない。
ddY系雄性マウス(約7週齢)を用い(n=15-75)、餌及び水は自由摂取させた。被験物質として、Asn-Ile-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu 0.05nmol/kg体重(0.1μg/kg体重)、0.5nmol/kg体重(1μg/kg体重)、1.5nmol/kg体重(3μg/kg体重)、5nmol/kg体重(10μg/kg体重)、50nmol/kg体重(100μg/kg体重)、500nmol/kg体重(1000μg/kg体重)を用いた。被験物質は自発的交替行動を評価するY字迷路試験の実施60分前にマウスに単回経口投与した。また、Y字迷路試験の実施30分前には、マウスに脳機能障害(記憶障害および/または認知障害)を誘発するため、スコポラミンを1mg/kg体重となるよう背部に皮下投与した。Y字迷路試験では、一本のアームの長さが40cm、壁の高さが12cm、床の幅が3cm、上部の幅が10cmで3本のアームがそれぞれ120度の角度で接続されたY字迷路を実験装置として用いた。マウスをY字迷路のいずれかのアームの先端に置き、8分間にわたって迷路内を自由に探索させ、マウスが移動したアームを順に記録した。マウスが測定時間内に各アームに移動した回数をカウントし、これを総進入数とし、この中で連続して異なる三つのアームを選択した組み合わせ(例えば、3本のアームをそれぞれA、B、Cとした際に、進入したアームの順番がABCBACACBの場合は重複も含めて4とカウントする)を調べ、この数を自発的交替行動数とした。自発的交替行動数を総進入数から2を引いた数で割り、それに100を掛けて求めた値を自発的交替行動変化率とし、これを自発的交替行動の指標とした。本指標が高値である程、短期記憶が保持されていたことを示す。測定値は群毎に平均値±標準誤差で表した。対照群とスコポラミン対照群との有意差検定はスチューデント(Student)のt検定で行った。また、スコポラミン対照群とNIPPLTQTPVVVPPFLQPE投与群との有意差検定は、一元配置分散分析後にダネット(Dunnett)型多重比較検定で行った。結果を図1に示す。NIPPLTQTPVVVPPFLQPEは0.05nmol/kg体重~500nmol/kg体重(0.1μg/kg体重~1000μg/kg体重)の範囲で健忘予防作用を有することが示された。
ddY系雄性マウス(約7週齢)を用い(n=15-45)、餌及び水は自由摂取させた。被験物質として、Asn-Ile-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu 50nmol/kg体重(100μg/kg体重)、またはAsn-Ile-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu-Val-Met(NIPPLTQTPVVVPPFLQPEVM)50nmol/kg体重(120μg/kg体重)、またはIle-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu(IPPLTQTPVVVPPFLQPE)50nmol/kg体重(100μg/kg体重)、またはAsn-Ile-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro(NIPPLTQTPVVVPPFLQP)(配列番号18)50nmol/kg体重(100μg/kg体重)、またはThr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe(TQTPVVVPPF)(配列番号19)50nmol/kg体重(50μg/kg体重)を用いた。被験物質は自発的交替行動を評価するY字迷路試験の実施60分前にマウスに単回経口投与した。また、Y字迷路試験の実施30分前には、マウスに脳機能障害(記憶障害および/または認知障害)を誘発するため、スコポラミンを1mg/kg体重となるよう背部に皮下投与した。Y字迷路試験では、一本のアームの長さが40cm、壁の高さが12cm、床の幅が3cm、上部の幅が10cmで3本のアームがそれぞれ120度の角度で接続されたY字迷路を実験装置として用いた。マウスをY字迷路のいずれかのアームの先端に置き、8分間にわたって迷路内を自由に探索させ、マウスが移動したアームを順に記録した。マウスが測定時間内に各アームに移動した回数をカウントし、これを総進入数とし、この中で連続して異なる三つのアームを選択した組み合わせ(例えば、3本のアームをそれぞれA、B、Cとした際に、進入したアームの順番がABCBACACBの場合は重複も含めて4とカウントする)を調べ、この数を自発的交替行動数とした。自発的交替行動数を総進入数から2を引いた数で割り、それに100を掛けて求めた値を自発的交替行動変化率とし、これを自発的交替行動の指標とした。本指標が高値である程、短期記憶が保持されていたことを示す。測定値は群毎に平均値±標準誤差で表した。対照群とスコポラミン対照群との有意差検定はスチューデント(Student)のt検定で行った。また、スコポラミン対照群と各ペプチド投与群との有意差検定は、一元配置分散分析後にダネット(Dunnett)型多重比較検定で行った。結果を図2に示す。NIPPLTQTPVVVPPFLQPEは50nmol/kg体重(100μg/kg体重)、NIPPLTQTPVVVPPFLQPEVMは50nmol/kg体重(120μg/kg体重)、IPPLTQTPVVVPPFLQPEは50nmol/kg体重(100μg/kg体重)で健忘予防作用を有することが示された。NIPPLTQTPVVVPPFLQPは50nmol/kg体重(100μg/kg体重)およびTQTPVVVPPFは50nmol/kg体重(50μg/kg体重)については、スコポラミン対照群と比較して有意差が認められず、健忘予防作用を示さなかった。
ddY系雄性マウス(約7週齢)を用い(n=14-15)、餌及び水は自由摂取させた。被験物質として、Asn-Ile-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu 500nmol/kg体重(1000μg/kg体重)、またはPro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu(PPLTQTPVVVPPFLQPE) 500nmol/kg体重(1000μg/kg体重)を用いた。被験物質は自発的交替行動を評価するY字迷路試験の実施60分前にマウスに単回経口投与した。また、Y字迷路試験の実施30分前には、マウスに脳機能障害(記憶障害および/または認知障害)を誘発するため、スコポラミンを1mg/kg体重となるよう背部に皮下投与した。Y字迷路試験では、一本のアームの長さが40cm、壁の高さが12cm、床の幅が3cm、上部の幅が10cmで3本のアームがそれぞれ120度の角度で接続されたY字迷路を実験装置として用いた。マウスをY字迷路のいずれかのアームの先端に置き、8分間にわたって迷路内を自由に探索させ、マウスが移動したアームを順に記録した。マウスが測定時間内に各アームに移動した回数をカウントし、これを総進入数とし、この中で連続して異なる三つのアームを選択した組み合わせ(例えば、3本のアームをそれぞれA、B、Cとした際に、進入したアームの順番がABCBACACBの場合は重複も含めて4とカウントする)を調べ、この数を自発的交替行動数とした。自発的交替行動数を総進入数から2を引いた数で割り、それに100を掛けて求めた値を自発的交替行動変化率とし、これを自発的交替行動の指標とした。本指標が高値である程、短期記憶が保持されていたことを示す。測定値は群毎に平均値±標準誤差で表した。対照群とスコポラミン対照群との有意差検定はスチューデント(Student)のt検定で行った。また、スコポラミン対照群と各ペプチド投与群との有意差検定は、一元配置分散分析後にダネット(Dunnett)型多重比較検定で行った。結果を図3に示す。NIPPLTQTPVVVPPFLQPEは500nmol/kg体重(1000μg/kg体重)、PPLTQTPVVVPPFLQPEは500nmol/kg体重(1000μg/kg体重)で健忘予防作用を有することが示された。
ddY系雄性マウス(約7週齢)を用い(n=14-15)、餌及び水は自由摂取させた。被験物質として、Asn-Ile-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu 500nmol/kg体重(1000μg/kg体重)を用いた。被験物質は記憶保持を評価する新奇物体認識試験の実施60分前にマウスに単回経口投与した。新奇物体認識試験では、30×30×30 cmの箱を実験装置として用いた。馴化操作として、床敷きを敷いた実験装置内にマウスを5分間入れて自由に装置内を探索させた。馴化操作の翌日に訓練試行を実施した。訓練試行では実験装置内に3種類の物体のうち2個を選んで設置した(物体は床の中心線に沿って両サイドの壁からそれぞれ8 cmの位置に置き、その位置をX1及びX2とした。)なお、設置する物体の選択については、動物及び群間で偏りがないようにあらかじめランダムに選択した。被験物質または水を経口投与した60分後にマウスを実験装置に5分間入れ、マウスが各物体に対して1 cm以内に接近して探索した時間(秒)を測定した。訓練試行の48時間後に保持試行を実施した。保持試行では訓練試行と同様に実験装置内に物体を2個設置するが、そのうち1個は訓練試行で使用したものとは異なる物体(新奇物体)に替え、その位置をYとした。(例として、訓練試行で物体AをX1に物体BをX2に設置した場合、保持試行では物体Aに替えて物体Cを新奇物体として設置し、その位置をYとした。)訓練試行及び保持試行について、マウスが各物体に対して1 cm以内に接近して探索した時間(秒)を測定した。(ただし、物体の上に乗っている状態を除く。)訓練試行及び保持試行について、それぞれ2個の物体に対して探索を行った時間の比率を求めた。各物体に対する探索時間の比率 (%) は各群とも平均値±標準誤差で表した。有意差検定は、保持試行での新奇物体(Yに設置された物体)に対する探索時間の比率と、訓練試行で新奇物体が置かれていた場所に設置されていた物体(X1またはX2に設置された物体)に対する探索時間の比率について、対照群とペプチド群の間でスチューデント(Student)のt検定で行った。結果を図4に示す。NIPPLTQTPVVVPPFLQPEは500nmol/kg体重(1000μg/kg体重)で記憶力増強作用を有することが示された。
ddY系雄性マウス(約7週齢)を用い(n=27-40)、餌及び水は自由摂取させた。被験物質として、Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu(TQTPVVVPPFLQPE)50nmol/kg体重(80μg/kg体重)を用いた。被験物質は自発的交替行動を評価するY字迷路試験の実施60分前にマウスに単回経口投与した。また、Y字迷路試験の実施30分前には、マウスに脳機能障害(記憶障害および/または認知障害)を誘発するため、スコポラミンを1mg/kg体重となるよう背部に皮下投与した。Y字迷路試験では、一本のアームの長さが40cm、壁の高さが12cm、床の幅が3cm、上部の幅が10cmで3本のアームがそれぞれ120度の角度で接続されたY字迷路を実験装置として用いた。マウスをY字迷路のいずれかのアームの先端に置き、8分間にわたって迷路内を自由に探索させ、マウスが移動したアームを順に記録した。マウスが測定時間内に各アームに移動した回数をカウントし、これを総進入数とし、この中で連続して異なる三つのアームを選択した組み合わせ(例えば、3本のアームをそれぞれA、B、Cとした際に、進入したアームの順番がABCBACACBの場合は重複も含めて4とカウントする)を調べ、この数を自発的交替行動数とした。自発的交替行動数を総進入数から2を引いた数で割り、それに100を掛けて求めた値を自発的交替行動変化率とし、これを自発的交替行動の指標とした。本指標が高値である程、短期記憶が保持されていたことを示す。測定値は群毎に平均値±標準誤差で表した。対照群とスコポラミン対照群との有意差検定はスチューデント(Student)のt検定で行った。また、スコポラミン対照群とTQTPVVVPPFLQPE投与群との有意差検定はスチューデント(Student)のt検定で行った。結果を図1に示す。TQTPVVVPPFLQPEは50nmol/kg体重(80μg/kg体重)で健忘予防作用を有することが示された。
ddY系雄性マウス(約7週齢)を用い(n=11-40)、餌及び水は自由摂取させた。被験物質として、Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu(PLTQTPVVVPPFLQPE)500nmol/kg体重(900μg/kg体重)、またはLeu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu(LTQTPVVVPPFLQPE) 500nmol/kg体重(850μg/kg体重)、またはPro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu(PVVVPPFLQPE) 500nmol/kg体重(630μg/kg体重)、またはVal-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu(VVVPPFLQPE) 500nmol/kg体重(580μg/kg体重)を用いた。被験物質は自発的交替行動を評価するY字迷路試験の実施60分前にマウスに単回経口投与した。また、Y字迷路試験の実施30分前には、マウスに脳機能障害(記憶障害および/または認知障害)を誘発するため、スコポラミンを1mg/kg体重となるよう背部に皮下投与した。Y字迷路試験では、一本のアームの長さが40cm、壁の高さが12cm、床の幅が3cm、上部の幅が10cmで3本のアームがそれぞれ120度の角度で接続されたY字迷路を実験装置として用いた。マウスをY字迷路のいずれかのアームの先端に置き、8分間にわたって迷路内を自由に探索させ、マウスが移動したアームを順に記録した。マウスが測定時間内に各アームに移動した回数をカウントし、これを総進入数とし、この中で連続して異なる三つのアームを選択した組み合わせ(例えば、3本のアームをそれぞれA、B、Cとした際に、進入したアームの順番がABCBACACBの場合は重複も含めて4とカウントする)を調べ、この数を自発的交替行動数とした。自発的交替行動数を総進入数から2を引いた数で割り、それに100を掛けて求めた値を自発的交替行動変化率とし、これを自発的交替行動の指標とした。本指標が高値である程、短期記憶が保持されていたことを示す。測定値は群毎に平均値±標準誤差で表した。対照群とスコポラミン対照群との有意差検定はスチューデント(Student)のt検定で行った。また、スコポラミン対照群と各ペプチド投与群との有意差検定はスチューデント(Student)のt検定で行った。結果を図6に示す。PLTQTPVVVPPFLQPEは500nmol/kg体重(900μg/kg体重)、LTQTPVVVPPFLQPEは500nmol/kg体重(850μg/kg)、PVVVPPFLQPEは500nmol/kg体重(630μg/kg)、VVVPPFLQPEは500nmol/kg体重(580μg/kg)で健忘予防作用を有することが示された。
1.特許第3898389号公報
2.Science, 217, 408-414(1982)
Claims (26)
- X-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu-Y(式中Xは存在しないか、またはIleまたはAsn-Ileのいずれかを表し、式中Yは存在しないか、またはVal-Metを表す)またはその塩を有効成分とする、脳機能改善用組成物。
- Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Gluまたはその塩を有効成分とする、脳機能改善用組成物。
- Ile-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Gluまたはその塩を有効成分とする、脳機能改善用組成物。
- Asn-Ile-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Gluまたはその塩を有効成分とする、脳機能改善用組成物。
- Asn-Ile-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu-Val-Metまたはその塩を有効成分とする、脳機能改善用組成物。
- X-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu-Y(式中Xは存在しないか、Thr-Gln-Thr-Pro、Pro-Leu-Thr-Gln-Thr-Pro、Leu-Thr-Gln-Thr-ProまたはProのいずれかを表し、式中Yは存在しないかVal-Metを表す)またはその塩を有効成分とする、脳機能改善用組成物。
- Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Gluまたはその塩を有効成分とする、脳機能改善用組成物。
- Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Gluまたはその塩を有効成分とする、脳機能改善用組成物。
- Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Gluまたはその塩を有効成分とする、脳機能改善用組成物。
- Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Gluまたはその塩を有効成分とする、脳機能改善用組成物。
- Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Gluまたはその塩を有効成分とする、脳機能改善用組成物。
- 経口摂取用である、請求項1~11のいずれか1項記載の組成物。
- 脳機能改善が健忘予防または記憶力増強である、請求項1~12のいずれか1項記載の組成物。
- 非ヒト動物にX-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu-Y(式中Xは存在しないか、またはIleまたはAsn-Ileのいずれかを表し、式中Yは存在しないか、またはVal-Metを表す)またはその塩を投与することを含む、脳機能を改善する方法。
- 非ヒト動物にPro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Gluまたはその塩を投与することを含む、脳機能を改善する方法。
- 非ヒト動物にIle-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Gluまたはその塩を投与することを含む、脳機能を改善する方法。
- 非ヒト動物にAsn-Ile-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Gluまたはその塩を投与することを含む、脳機能を改善する方法。
- 非ヒト動物にAsn-Ile-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu-Val-Metまたはその塩を投与することを含む、脳機能を改善する方法。
- X-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu-Y(式中Xは存在しないか、Thr-Gln-Thr-Pro、Pro-Leu-Thr-Gln-Thr-Pro、Leu-Thr-Gln-Thr-ProまたはProのいずれかを表し、式中Yは存在しないかVal-Metを表す)またはその塩を投与することを含む、脳機能を改善する方法。
- 非ヒト動物にThr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Gluまたはその塩を投与することを含む、脳機能を改善する方法。
- 非ヒト動物にPro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Gluまたはその塩を投与することを含む、脳機能を改善する方法。
- 非ヒト動物にLeu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Gluまたはその塩を投与することを含む、脳機能を改善する方法。
- 非ヒト動物にPro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Gluまたはその塩を投与することを含む、脳機能を改善する方法。
- 非ヒト動物にVal-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Gluまたはその塩を投与することを含む、脳機能を改善する方法。
- 投与が経口投与である、請求項14~24のいずれか1項記載の方法。
- 脳機能を改善することが健忘予防または記憶力増強である、請求項14~25のいずれか1項記載の方法。
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JP5718741B2 (ja) * | 2011-06-24 | 2015-05-13 | カルピス株式会社 | 脳機能改善用ペプチドの酵素的製造方法 |
JPWO2017086303A1 (ja) * | 2015-11-16 | 2018-09-20 | キリン株式会社 | ペプチド組成物およびその製造方法 |
CN111801109A (zh) * | 2018-03-02 | 2020-10-20 | 一般财团法人粮食研究会 | 能够改善认知功能的肽 |
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WO2012036191A1 (ja) * | 2010-09-16 | 2012-03-22 | カルピス株式会社 | 脳機能改善用組成物および脳機能を改善する方法 |
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WO2012176659A1 (ja) * | 2011-06-24 | 2012-12-27 | カルピス株式会社 | 乳酸菌発酵によるカゼイン由来ペプチドの製造方法 |
CN104013953A (zh) * | 2014-06-24 | 2014-09-03 | 罗浩铭 | 具有治疗老年性痴呆及改善学习记忆新用途的14肽化合物 |
WO2020085179A1 (ja) | 2018-10-26 | 2020-04-30 | アサヒグループホールディングス株式会社 | 抗肥満剤、頻尿改善剤、自律神経活動調節剤 |
JPWO2020085179A1 (ja) * | 2018-10-26 | 2021-09-16 | アサヒグループホールディングス株式会社 | 抗肥満剤、頻尿改善剤、自律神経活動調節剤 |
JP7326318B2 (ja) | 2018-10-26 | 2023-08-15 | アサヒグループホールディングス株式会社 | 抗肥満剤、頻尿改善剤、自律神経活動調節剤 |
WO2020100421A1 (ja) * | 2018-11-16 | 2020-05-22 | アサヒグループホールディングス株式会社 | 言語力等を改善するための組成物および方法 |
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JP4989775B2 (ja) | 2012-08-01 |
JPWO2011080947A1 (ja) | 2013-05-09 |
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NZ601142A (en) | 2013-11-29 |
CA2784132A1 (en) | 2011-07-07 |
TWI461208B (zh) | 2014-11-21 |
ES2581242T3 (es) | 2016-09-02 |
DK2520308T3 (en) | 2016-09-26 |
US20120277160A1 (en) | 2012-11-01 |
MY165041A (en) | 2018-02-28 |
HK1171379A1 (en) | 2013-03-28 |
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CA2784132C (en) | 2015-05-05 |
MX2012007590A (es) | 2012-07-30 |
BR112012015984A2 (ja) | 2018-05-29 |
MY160372A (en) | 2017-03-15 |
JP2012031139A (ja) | 2012-02-16 |
AU2010337738A2 (en) | 2012-07-05 |
CN102686234B (zh) | 2015-06-17 |
AU2010337738B2 (en) | 2013-09-19 |
JP4824841B2 (ja) | 2011-11-30 |
AU2010337738A1 (en) | 2012-07-12 |
EP2520308A1 (en) | 2012-11-07 |
RU2501808C1 (ru) | 2013-12-20 |
US8569241B2 (en) | 2013-10-29 |
SG181982A1 (en) | 2012-08-30 |
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