COMPOSITION FOR IMPROVING MILD COGNITIVE IMPAIRMENT AND METHOD FOR IMPROVING MILD COGNITIVE IMPAIRMENT

Abstract

A method for improving mild cognitive impairment of a human patient includes providing a dose of 250 mg-500 mg of a composition once or twice a day for three months or more. The human patient has mild cognitive impairment with a score of 23 points or more and less than 27 points in the Mini-Mental State Examination, a score of 0.5 in the Clinical Dementia Rating, or a score of less than 25 points in the Montreal Cognitive Assessment. The composition includes imidazole dipeptide separated and purified from chicken extract or salmon extract. The imidazole dipeptide does not contain creatinine, and 75% or more of the imidazole dipeptide in the composition is anserine.

Claims

1. A method for improving mild cognitive impairment of a human patient with mild cognitive impairment with a score of 23 points or more and less than 27 points in the Mini-Mental State Examination, a score of 0.5 in the Clinical Dementia Rating, or a score of less than 25 points in the Montreal Cognitive Assessment, the method comprising: providing a dose of 250 mg-500 mg of a composition once or twice a day for three months or more, the composition comprising imidazole dipeptide separated and purified from chicken extract or salmon extract, wherein the imidazole dipeptide does not contain creatinine, and 75% or more of the imidazole dipeptide in the composition is anserine.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0027] The features described in this disclosure are set forth with particularity in the appended claims.

[0028] FIG. 1A is a chicken extract raw material, in which Vo indicates a high-molecular-weight protein fraction in the column void volume, IMDP indicates a peak of the imidazole dipeptide according to the present invention, and Cre indicates a creatinine peak;

[0029] FIG. 1B is a GPC-HPLC chromatogram of IMDP purified from chicken extract;

[0030] FIG. 1C is a salmon extract raw material;

[0031] FIG. 1D is a GPC-HPLC chromatogram of IMDP (anserine) purified from salmon extract;

[0032] FIG. 2A is a hydroxyl radical, in which 1 is untreated target protein, 2 is no antioxidant added, 3 is IMDP added, 4 is vitamin C added, 5 is ferulic acid added, 6 is IMDP+vitamin C+ferulic acid added; and

[0033] FIG. 2B is a proteolytic action by a peroxynitrite radical.

DETAILED DESCRIPTION

(1) IMDP Preparation

[0034] As shown in FIGS. 1A-D, the IMDP preparation relating to the present invention is obtained by subjecting a chicken extract or a salmon meat extract to a concentrated desalting treatment by ion exchange chromatograph and a nanofiltration membrane, to remove proteins, amino acids, creatinine, potassium salts, and the like. For example, the method of Japanese Patent No. 5142126 is used as the manufacturing method.

[0035] As for the components in IMDP, the content ratio of anserine:carnosine in chicken extract was 3:1 (75% of anserine), and salmon extract was entirely anserine (100% of anserine). Little protein, creatinine, other amino acids, and potassium salts were contained therein. As an IMDP containing no biological component such as creatinine, for example, the one produced by the enzymatic synthesis method disclosed in JP-A-2018-102287 can be used.

(2) IMDP Compounding Agent

[0036] IMDP shows strong antioxidative activity against hypochlorite radicals among the three types of reactive oxygen species produced in vivo (hypochlorite radicals, hydroxyl radicals, and peroxynitrite radicals). However, IMDP has an extremely weak antioxidant effect on hydroxyl radicals and peroxynitrite radicals.

[0037] On the other hand, vitamin E and astaxanthin are known to have strong antioxidant activity against hydroxyl radicals, and vitamin C has strong antioxidant activity against peroxynitrite radicals. Utilizing this fact, in order to prevent IMDP from being easily oxidized by active oxygen in vivo and to fully exert the effect thereof, granules were prepared by adding 25 mg-90 mg of vitamin C per 250 mg of IMDP, and 1-20 mg of ferulic acid and astaxanthin (10-40 mg in the case of vitamin E).

[0038] As shown in FIGS. 2A and 2B, ferulic acid has a strong antioxidant activity against hydroxyl radicals and vitamin C has a strong antioxidant activity against peroxynitrite radicals, thus preventing the degradation of target proteins, which would be degraded by these active oxygen species if IMDP was used alone. Therefore, by coexisting with these antioxidants, the antioxidant effect of IMDP is retained both for hydroxyl radicals and peroxynitrite radicals.

(3) MCI Subject Selection

[0039] From the viewpoint of reducing burden on the subjects, primary screening was performed in middle-aged and older persons aged 65 and over using MoCA, which has a relatively short test time. The MoCA score is 25 or less, the MMSE is 23 or more and less than 27, or the CDR score is 0.5. In CDR, a score of 0 is normal, and a score of 1 or more means dementia.

(4) IMDP Intake Trial

[0040] A double-blind, placebo-controlled trial was conducted in 29 middle-aged and elderly people who were determined to be at high risk for MCI. 14 subjects were given 250 mg IMDP purified from salmon extract and IMDP granules containing 15 mg of ferulic acid and 75 mg of vitamin C as antioxidants twice a day in the morning and evening (test diet group). 15 subjects in the placebo diet group also received a placebo diet containing 250 mg of dextran and an antioxidant instead of IMDP twice a day in the morning and evening. After ingestion for 3 months, MCI status was evaluated by means of MoCA, MMSE, or CDR. As shown in the results in Table 1, there was no significant difference in MoCA scores, but a significant improvement effect was seen in the MMSE score. Two patients in the placebo diet group, whose MMSE decreased to 23 or less, were suspected of having clinical dementia (CD) but no such subjects were found in the test diet group.

TABLE-US-00001 TABLE 1 MCI improvement effect by IMDP ingestion Before Ingestion After ingestion for 3 months Improvement Score Test diet group Placebo Test diet group Placebo Test diet group Placebo (14 subject) (15 subject) (14 subject) (15 subject) (14 subject) (15 subject) Test MoCA 22.4 ± 2.1 22.3 ± 2.0 24.1 ± 1.5 23.1 ± 1.5 1.8 ± 2.2 0.7 ± 2.1 NS MMSE 25.6 ± 2.3 26.2 ± 3.0 27.5 ± 1.7 26.3 ± 2.7 1.9 ± 2.0 0.1 ± 2.5 P = 0.04 CD result 0 0 0 2

(1) Manufacture of Imidapeptide Compound

[0041] 3000 L of water was added to 2000 kg of white salmon (semi-dressed) fillet, and the salmon extract obtained by heating and extracting at 80° C. for 30 minutes was filtered, adjusted to pH 5.0, passed through a cation exchange resin (Mitsubishi Chemical Corporation, DIAION SK-1B) column, and adsorbed on the cation exchange resin, and the anserine was eluted with 0.5% ammonia solution. The eluate was desalted and concentrated with an NF membrane (Daicen Membrane, Desal DL) to prepare an anserine solution from which creatinine and salts were removed.

[0042] Dextran was added to the eluate so that the anserine content was 30% and spray-dried to obtain about 40 kg of purified salmon anserine powder. Using the powder, 75 mg of vitamin C and 15 mg ferulic acid were added to 250 mg anserine content in the powder, and a citrus seasoning was further added to prepare approximately 5 kg of granules, which was divided into 2 g per one aluminum laminated bag to prepare 2500 packages.

[0043] The composition for improving mild cognitive impairment according to the present invention can be taken, for example, as a functional food.