Brain function-improving composition

Abstract

[Problem] To provide a novel composition having a brain function-improving effect. [Solution] The problem is achieved by a brain function-improving composition characterized by containing a sulfated polysaccharide. The sulfated polysaccharide is preferably rhamnan sulfate.

Description

Composition for improving brain function

[0001] The present invention relates to a composition for improving brain function.

[0002] Dementia is not a specific disease name, but refers to a condition in which brain function (cognitive function) deteriorates due to some kind of disease or disorder, causing memory loss and interfering with daily life and work. In recent years, even mild symptoms that do not interfere with daily life or work have come to be diagnosed with conditions such as Mild Cognitive Impairment (MCI). Everyone experiences memory loss and forgetting people's names as they age. This condition is caused by brain aging and is different from dementia. In contrast, memory loss due to dementia is caused by the destruction of brain nerve cells and is different from aging. As dementia progresses, people forget entire experiences and are unable to recall them, even when given hints.

[0003] In Japan, the number of dementia patients is increasing year by year, and it is estimated that there are currently more than 3 million dementia patients. As a therapeutic agent for dementia, anticholinesterase inhibitors are used to treat Alzheimer's dementia, but they only somewhat suppress the progression of symptoms, and no definitive therapeutic agent is available. Recent research has revealed that foods and food-derived components are effective in maintaining, developing, and improving brain function. For example, an oral composition containing chlorogenic acid extracted from coffee beans (Patent Document 1) and a substance extracted from garlic skin (Patent Document 2) have been shown to be effective in improving brain function.

[0004] JP 2018-39797 A JP 2021-153571 A

[0005] As the increase in dementia patients has become a major social problem, there has been a demand for new compositions that are effective in improving brain function. The present invention has been made in view of the above circumstances, and its object is to provide a novel composition that has the effect of improving brain function.

[0006] After extensive research, the present inventors discovered that sulfated polysaccharides have the effect of improving brain function, which led to the basic completion of the present invention. Thus, the composition of the present invention is characterized by containing sulfated polysaccharides and exhibiting the effect of improving brain function. In the above invention, the sulfated polysaccharide is preferably rhamnan sulfate. The composition of the present invention is preferably for oral administration. The daily dose of rhamnan sulfate is preferably 10 mg to 1000 mg, more preferably 30 mg to 500 mg, and even more preferably 50 mg to 300 mg. Furthermore, the composition of the present invention can be provided as a food composition for improving brain function. Here, brain function primarily refers to cognitive function, and preferably includes neurocognitive index (NCI), reaction time, overall attention, cognitive flexibility, executive function, and logical thinking. Diseases associated with impaired brain function include, for example, depression, schizophrenia, and autism.

[0007] The composition is provided by blending an effective amount of rhamnan sulfate for improving brain function with pharmaceutically acceptable carriers and additives. This composition is provided as a pharmaceutical or quasi-drug. The pharmaceutical composition is used internally or externally. This pharmaceutical composition can be used in the form of an oral preparation, an injection such as an intravenous injection, a subcutaneous injection, an intradermal injection, an intramuscular injection, and / or an intraperitoneal injection, a transmucosal preparation, a transdermal preparation, or the like. In particular, since rhamnan sulfate is effective via oral or transdermal administration, it is preferably used as an oral preparation, a transmucosal preparation, or a transdermal preparation. The dosage form of the pharmaceutical composition can be appropriately determined, and examples thereof include solid preparations such as tablets, granules, capsules, powders, and dusts; liquid preparations such as solutions and suspensions; and semi-solid preparations such as ointments and gels. While many factors are known to cause brain function decline, the present invention is particularly effective against brain function decline caused by diabetes. Therefore, the composition for improving brain function of the present invention is preferably used when the decline in brain function is due to diabetes. In this case, it is preferable that the improvement of brain function is due to increasing blood nicotinamide concentration.In addition, it is preferable that the composition for improving pancreatic function according to another invention contains rhamnan sulfate and protects the pancreas by increasing blood nicotinamide concentration.The present inventor has found that taking rhamnan sulfate increases blood nicotinamide concentration.Therefore, it has been found that rhamnan sulfate can protect the pancreas.

[0008] In the food industry, rhamnan sulfate can be used as a food ingredient in various foods to provide food compositions. In this way, food compositions labeled for improving brain function can be provided. Examples of food compositions include general foods, as well as foods for specified health uses, foods with nutrient functions, foods with functional claims, foods for hospital patients, and supplements. Additionally, rhamnan sulfate can be used as a food additive. Examples of food compositions include beverages (soft drinks, alcoholic beverages, carbonated beverages, dairy drinks, fruit juice drinks, tea, coffee, energy drinks, concentrated beverages, etc.), powdered beverages (powdered juice, powdered soup, etc.), confectioneries (candy (throat lozenges), cookies, biscuits, gum, gummy candies, chocolate, etc.), bread, cereal, seasonings, etc.

[0009] In the case of foods for specified health uses, foods with nutrient functions, and foods with functional claims, they can also be provided in the form of capsules, lozenges, syrups, granules, powders, etc. Foods for specified health uses are foods containing functional health ingredients that affect physiological functions, etc., and can be labeled as suitable for specific health uses with the permission of the Commissioner of the Consumer Affairs Agency. In the present invention, the foods are sold with a label indicating a specific use, such as an effect of improving brain function. Foods with nutrient functions are foods used to supplement nutritional components (vitamins, minerals), and display the function of the nutritional components. To be sold as a food with nutrient functions, the amount of nutritional components contained in the recommended daily intake must be within the specified upper and lower limits, and not only nutritional function labeling but also warning labeling is required.

[0010] A functional food is a food that displays functionality based on scientific evidence at the responsibility of the business operator. Information on the basis of safety and functionality is submitted to the Commissioner of the Consumer Affairs Agency before sale. The present invention contains rhamnan sulfate as an active ingredient and is used as a specified health food, a nutritionally functional food, or a functional food for healthy individuals and individuals with mild cognitive impairment (MCI) (including those with mild symptoms). The present invention contains rhamnan sulfate as an active ingredient and is used as a functional food for improving brain function in humans (particularly, a functional food for improving cognitive function).

[0011] According to the present invention, a novel composition for improving brain function can be provided.

[0012] 1 is a flowchart showing the tracking of test participants in this embodiment in Test 1. FIG. 2 is a bar graph showing the results of scores where significant differences were observed between the test group and the placebo group. (A) shows a bar graph showing the mean value ± standard deviation of the actual data, and (B) shows a bar graph showing the mean value ± standard deviation of the difference data (the same applies to FIGS. 3 to 7 ). FIG. 3 is a graph showing the results of standardized score data for NCI. FIG. 4 is a graph showing the results of standardized score data for reaction time. FIG. 5 is a graph showing the results of standardized score data for overall attention. FIG. 6 is a graph showing the results of standardized score data for cognitive flexibility. FIG. 7 is a graph showing the results of standardized score data for executive function. FIG. 8 is a graph showing the results of standardized score data for logical thinking.

[0013] This is a bar graph showing the body weights of mice in Test 2. 1%MD indicates administration of 1% sugar-containing water (1% maltodextrin), RS100 indicates administration of 100 mg / kg rhamnan sulfate, RS300 indicates administration of 300 mg / kg rhamnan sulfate, and RS1000 indicates administration of 1000 mg / kg rhamnan sulfate. In the graph, "ns" indicates no significant difference, "*" indicates significance at a 5% level (p<0.05), "**" indicates significance at a 1% level (p<0.01), "***" indicates significance at a 0.1% level (p<0.001), and "****" indicates significance at a 0.01% level (p<0.0001) (the same applies to the following figures). This is a bar graph showing the results of blood glucose level measurements. This is a bar graph showing the results of locomotor activity measurements. This is a bar graph showing task completion time in the eight-arm maze test. 16 is a bar graph showing the number of errors in the eight-arm maze test. 17 is a bar graph showing the results of the rotarod test. 18 is a bar graph showing the results of comparing the thickness of the hippocampal neuronal layer CA1. 19 is a micrograph showing the results of immunostaining brain pathological tissue sections using an anti-AGE antibody. 19 is a representative example of the control group and 1% MD group from the upper left to the right, and of the 1% MD + RS100 group, 1% MD + RS300 group, and 1% MD + RS1000 group from the lower left to the right (the order of the photographs is the same in Figure 16). 20 is a micrograph showing the results of immunostaining brain pathological tissue sections using an anti-Iba1 antibody.

[0014] Next, embodiments of the present invention will be described with reference to the accompanying drawings. However, the technical scope of the present invention is not limited to these embodiments, and various embodiments can be implemented without departing from the spirit of the invention. <Preparation of Rhamnan Sulfate> Any naturally occurring rhamnan sulfate can be used. In this embodiment, rhamnan sulfate obtained by hot water extraction from Single-Stem Algae was used. Dried seaweed was washed with water and extracted with hot water. The resulting hot water extract was filtered to obtain an extract (Rhamnox 100) containing rhamnan sulfate as the main component (60% to 90% (average approximately 70%)). This extract was used as the sample for the present invention. Note that sulfated polysaccharides (e.g., rhamnan sulfate) that can be used in the present invention can also be prepared by various methods other than the above. Furthermore, the raw material is not limited to Single-Stem Algae, but other species such as Ulva pertusa and Ulva ribbon can also be used.

[0015] <Study 1: Study on healthy subjects> <Study method> 1. Subjects (1) Eligibility criteria The enrollment criteria for subjects were Japanese (both males and females) healthy subjects aged 40 to 65 years. The exclusion criteria were as follows: those currently undergoing treatment for or with a history of malignant tumors, heart failure, or myocardial infarction; those with an implanted pacemaker or implantable cardioverter defibrillator; those undergoing treatment for arrhythmia, liver damage, kidney damage, cerebrovascular disease, rheumatism, diabetes, dyslipidemia, hypertension, or other chronic diseases; those who regularly consume foods for specified health uses, foods with functional claims, or other foods or beverages thought to be functional; those who regularly consume seaweed or products containing ingredients derived from seaweed; those who regularly use medicines (including herbal medicines) or supplements; those with allergies (to medicines or foods related to the test food); those who are pregnant, breastfeeding, or intend to become pregnant during the study period; those who have participated in other clinical trials in the 28 days prior to the date of consent acquisition or those who plan to participate during the study period; those who smoke; and those who the principal investigator deemed to be unsuitable for this study.

[0016] (2) Management of subjects When subjects visited the hospital, their physical condition was ascertained through interviews. During the study period, they recorded daily in a diary designated by the contract clinical trial organization whether they had taken the test food and whether they had their period (women only). The diaries were submitted by mail every week, and if there was a diary that had not been submitted at the time of the final examination, they brought it with them and submitted it at the time of the visit. The diary from the final examination was submitted at the time of the visit. If it could not be submitted at the time of the visit, it was filled out on the spot. Subjects were asked to strictly adhere to the following points while participating in the study. (a) consume the test food according to the prescribed usage and dosage, (b) consume the test food so that the intake rate is 80% or more, (c) avoid overeating and drinking from the date of obtaining the consent form for the study until the final test (the test 8 weeks after intake) and do not change your previous lifestyle habits, (d) refrain from drinking alcohol or engaging in excessive exercise from the day before each test until the end of the test on the day, (e) refrain from eating or drinking for 6 hours before blood sampling (this also includes the intake of test food. However, only water was permitted; functional water and tea were not permitted), (f) if any changes in your physical condition occur during the test period, immediately contact the contracted clinical trial organization and ask for instructions on how to proceed, and (g) avoid, as much as possible, consuming foods for specified health uses, foods with functional claims, or other foods / drinks that are thought to have functional properties during the test period.

[0017] (3) Dropout / Discontinuation Policy Subjects who met any of the following criteria were considered to have dropped out of the study. Safety assessments were conducted on an individual basis. (a) The study was discontinued for the subject's own convenience; (b) The subject was found not to have followed the instructions of the investigator or study organizer; (c) The subject significantly deviated from the protocol; or (d) The investigator otherwise deemed it appropriate to drop the subject. Furthermore, subjects who met any of the following criteria were considered to have been discontinued: (a) A serious adverse event occurred, and the investigator determined that the subject's participation in the study should be discontinued; (b) The investigator determined that objective symptoms made it difficult for the subject to continue the study; or (c) The investigator otherwise determined that it was difficult to continue the study. The study was also discontinued if an unexpected serious adverse event occurred, or if a serious violation or non-compliance with ethical guidelines or the protocol occurred.

[0018] 2. Test Food: The test food group used a seaweed extract (containing rhamnan sulfate), and the placebo group used a placebo without seaweed extract. 3. Test Period: The test food or placebo was administered for 8 weeks. Cognitive function was assessed twice, before and after ingestion. 4. Dosage: The dosage was as follows: Test Food Group: 1 capsule per day; Placebo Group: 1 capsule per day. The daily dose was to be taken on the same day; if a dose was missed, it was taken as soon as possible. The test food was stored at room temperature, avoiding direct sunlight, high temperatures, and humidity. The test food was manufactured by Konan Chemical Co., Ltd. The test food was indistinguishable in appearance, shape, color, odor, and taste. The composition of the test food (per capsule) is shown in Table 1. "Rhamnox 100" refers to a "Hypertrichia extract with rhamnan sulfate as the main component (approximately 70%)." Each capsule of the test food (containing 120 mg of Rhamnox 100) contains approximately 90 mg of rhamnan sulfate. "Max 1000" refers to dextrin.

[0019]

[0020] 5. Measurement Items The following cognitive function tests were measured. (1) Ten tests (verbal memory test, visual memory test, finger tapping test, SDC test, Stroop test, attention shifting test, sustained processing test, facial expression recognition test, logical reasoning test, and four-part sustained processing test) were conducted using Cognitrax. (2) Standardized scores for overall memory and standardized scores for other cognitive domains (Neurocognitive Index (NCI), verbal memory, visual memory, cognitive function speed, reaction time, overall attention, cognitive flexibility, processing speed, executive function, social cognition, logical reasoning, working memory, sustained attention, simple attention, and motor speed) were used. (3) Evaluation methods included screening and pre-intake tests and an 8-week post-intake test. (4) Physical measurements included height, weight, body fat percentage, and temperature. BMI was calculated by dividing weight (kg) by the square of height (m). These were conducted at screening and pre-intake tests and an 8-week post-intake test. However, height was measured only during the information session.

[0021] (5) In addition, as part of the physical examination, blood pressure (systolic blood pressure, diastolic blood pressure) and pulse rate were measured. In addition, urine tests (protein, glucose, urobilinogen, bilirubin, ketone bodies, pH, occult blood) and peripheral blood tests (white blood cell count, red blood cell count, hemoglobin, hematocrit value, platelet count, MCV (mean corpuscular volume), MCH (mean corpuscular hemoglobin), MCHC (mean corpuscular hemoglobin concentration), white blood cell picture (neutrophil rate, lymphocyte rate, monocyte rate, eosinophil rate, basophil rate, neutrophil count, lymphocyte count, monocyte count, eosinophil count, basophil count), AST (GOT), ALT (GPT), γ-GT (γ-GTP), ALP, LD (LDH), LAP, total bilirubin, direct bilirubin, indirect bilirubin, cholinesterase (ChE), total protein, urea nitrogen, creatinine, uric acid, CK, calcium, serum amylase, total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides (TG: Neutral lipids), glycoalbumin, serum iron (Fe), sodium (Na), potassium (K), chloride (Cl), inorganic phosphorus (IP), glucose, hemoglobin A1c (HbA1c: NGSP), and nonspecific IgE were measured.

[0022] (6) Subject Recruitment, Allocation, and Double-Blinding The number of subjects to be screened was 15, the target number 10, and the number of subjects to be tested 12. Study participants were recruited through a monitor recruitment website operated by the contract clinical trial organization. The 12 subjects were divided into two groups of six and assigned to either the test food group or the placebo group. All subjects were assigned on the same day after the target number of registered subjects set in the protocol was reached. Random numbers were generated on a computer, and an allocation list was created using a completely random method with specified variables as factors. Study participants were enrolled based on the allocation list. The allocation ratio was 1:1. The study was conducted using a double-blind method. Blinding was achieved by using indistinguishable test foods. The test food shipping staff at the contract clinical trial organization confirmed the indistinguishability of the test foods and entered and confirmed the screening test data, then communicated the identification number to the person responsible for allocation.

[0023] (7) Data collection and management Physical measurement and physical examination data were entered into paper medical records by staff at the study institution. Questionnaires were completed by the study participants themselves on questionnaire forms, which were then collected by staff at the study institution. Paper-based measurement results (medical records and questionnaire forms) were obtained by the monitoring staff. Urine test and peripheral blood test results were obtained as ".txt" data (electronic data) from m-Line (http: / / www.medience.co.jp / mline / ), operated by LSI Medience Corporation. Data management was led by the contracted clinical trial organization. The ".csv" data collected by the monitoring staff and the electronic data obtained by m-Line were imported into Access and saved at the contracted clinical trial organization. Paper-based measurement results were entered into Microsoft Access by one staff member. The entered data was checked for errors by two staff members.

[0024] The medical institutions conducting the trial, institutions with ethical review committees, contract clinical trial organizations, and the sponsor agreed to keep documents that should be kept at their respective institutions for two years after the end of the trial. When storing documents, they were to be managed appropriately to prevent the leakage, mixing, theft, or loss of personal information. Furthermore, once the storage period had expired, they were to be anonymized and discarded. Biological samples (blood and urine) collected from the trial participants were to be used for no purpose other than measurement, and after measurement they were to be discarded as medical waste while remaining anonymized. The storage and disposal of the samples was outsourced to LSI Medience Corporation.

[0025] (8) Statistical methods The full registered population set consisted of cases who provided informed consent and were enrolled in the study. The full analysis set (FAS) was a group obtained by excluding cases in the full registered population set that met one or more of the following conditions: (a) cases who did not receive the allocated intervention, (b) cases who did not meet the conditions for the target population (cases with a confirmed diagnosis of some disease or cases that met clearly defined, objectively assessable important inclusion / exclusion criteria), (c) cases who never received the intervention after allocation, and (d) cases with no post-allocation data. The per protocol analysis set (PPS) was a group obtained by excluding cases in the FAS that met one or more of the following conditions: (a) Cases in which the intake rate of the test food was less than 80%, (b) cases in which actions that significantly undermined the reliability of the test results, such as missing diary records, were found to have met the exclusion criteria after enrollment in the study, (d) cases in which violations of compliance rules were found during the study period, (e) cases in which patients consumed food or medicines during the study period that are expected to significantly affect the test results, (f) cases in which patients engaged in activities that were significantly different from their lifestyle at the time of enrollment in the study, and (g) cases in which there were other clear reasons that made it appropriate to exclude the patient.

[0026] The safety analysis population (SAF) was a subset of the entire enrollment population, excluding cases who met one or more of the following criteria: (a) cases who did not receive the assigned intervention, (b) cases who never received the intervention after allocation, and (c) cases for which safety endpoints were never measured after allocation. Demographic data for study participants was collected from the entire enrollment population set or other analysis datasets. Gender was compared between groups using the chi-squared test, and other parameters were compared using the Student's t-test. For statistical analysis of efficacy endpoints, the PPS was used as the analysis dataset for the primary outcome. Means and standard deviations were presented, and intergroup comparisons were performed using ANCOVA with baseline as a covariate. If other tests were necessary from multiple perspectives, such as unpaired t-tests, they were also used to evaluate efficacy. The PPS was then used as the analysis dataset for secondary outcomes. Means and standard deviations were presented, and actual values ​​were compared between groups using ANCOVA with baseline as a covariate. The amount of change from the screening test and the amount of change from the pre-intake test were compared between groups using unpaired t-tests.If other tests were necessary from a multifaceted perspective other than the above analytical methods, they were adopted and their effectiveness was evaluated.

[0027] For statistical analysis of safety endpoints, the SAF was used in the analysis dataset as the primary safety endpoint. Occurring side effects and adverse events were tabulated for each participant. The incidence rates of side effects and adverse events were tabulated by group, and the 95% confidence intervals for the incidence rates and differences between groups were calculated. The incidence rates of side effects and adverse events in each group were compared using chi-square tests and other methods. The SAF was used in the analysis dataset as a secondary safety endpoint. The proportion of cases in which urine and peripheral blood test values ​​within the reference range at screening and pre-intervention testing fell outside the reference range after intervention was calculated, and inter-group comparisons were performed at each time point using chi-square tests. If other tests were necessary from multiple perspectives, they were also used to evaluate safety. For other safety endpoints, a data list was created for each participant. Additionally, the principal investigator or subinvestigator reviewed the safety endpoints on an individual basis to confirm that no medically significant changes occurred due to the intake of the test food. In addition, when other tests or stratified analyses were deemed necessary from a multifaceted perspective, such as at case conferences, appropriate other tests or stratified analyses were performed. All statistical analyses were performed using two-sided tests, with a significance level of 5%. SPSS Statistics version 23 or higher was used as the software, and other statistical software was used as necessary. This study focused on the primary outcome, and multiplicity that occurs in secondary outcomes set using multiple hypotheses was not taken into consideration.

[0028] <Study Results> The following abbreviations and full names were used: ITT: Intention to treat; PPS: Per protocol set; SAF: Safety analysis population; VISIT 1: Screening and pre-intake test (baseline); VISIT 2: 8-week post-intake test; Change: Change from screening and pre-intake test to 8-week post-intake test; Mean: Mean; SD: Standard deviation; SE: Standard error; 95% CI- and 95% CI+: 95% confidence interval. Figure 1 shows the participant follow-up flowchart. This study targeted healthy Japanese men and women aged 40 to 65 years. Of the 23 participants who agreed to participate, 12 who met the eligibility criteria were enrolled in the study, with six participants assigned to the test food group and six to the placebo group. All participants completed the study, and no participants violated the compliance requirements. The analysis datasets were the PPS and SAF, which were determined at the time of study planning, and consisted of 12 participants each. Participant demographics are shown in Table 2.

[0029] The mean and SD of the cognitive function tests, the intergroup differences and their SE, 95% CI-, 95% CI+, and statistical analysis results are shown in Tables 3 and 4.

[0030]

[0031]

[0032] As shown in Tables 3 and 4, no significant differences were observed between the test food group and the placebo group in the standardized scores for overall memory, verbal memory, visual memory, cognitive function speed, social cognition, working memory, sustained attention, simple attention, motor speed, and processing speed. In contrast, significant differences (P<0.05) were observed between the test food group and the placebo group in the standardized scores for NCI, reaction time, overall attention, cognitive flexibility, executive function, and reasoning. Specifically, the differences in VISIT 2 were P=0.004, P=0.049, P=0.043, P=0.019, and P=0.042, respectively. A trend toward improvement was also observed in reasoning (P=0.070). Figures 2 to 7 show (A) bar graphs showing the mean ± standard deviation of the actual data and (B) bar graphs showing the mean ± standard deviation of the difference data for the NCI standardized scores, reaction time standardized score, overall attention standardized score, cognitive flexibility standardized score, executive function standardized score, and logical thinking standardized score. No significant differences were observed in the incidence of side effects, adverse events, or secondary safety endpoints between the subject groups. Additionally, confirmation of the results of individual anthropometric and physical examination data confirmed that no medically significant changes occurred with the intake of the test food.

[0033] <Study 2: Diabetic Mouse Model> <Test Method> C57BL / 6J mice (7 weeks old) were fasted for 24 hours and then intraperitoneally administered 240 mg / kg body weight of 1.2% w / v nicotinamide (NA) solution. 15 minutes later, 100 mg / kg body weight of 1% w / v streptozotocin (STZ) solution was administered intraperitoneally. This procedure was repeated twice, one day apart, followed by a 4-month glucose load. Five groups were used for this study: the control group was fed a normal diet and clean water; the STZ group was fed a high-fat diet and 1% sugar-containing water (1% maltodextrin); and the STZ+RS group was fed a high-fat diet and water containing rhamnan sulfate (100 mg / kg, 300 mg / kg, or 1000 mg / kg). Each group consisted of six mice. After four months of glucose loading, the rats were weighed, blood glucose levels were measured, and behavioral pharmacological tests and brain pathological autopsies were performed. The behavioral pharmacological tests included spontaneous locomotor activity tests, an eight-arm maze test, and a rotarod test. Furthermore, brain tissue sections were immunostained with anti-AGE and anti-Iba1 antibodies for pathological examination.

[0034] In the spontaneous locomotor activity test, the amount of spontaneous activity was quantified as activity. The eight-arm maze test used an elevated maze with eight lanes radiating from a central platform. A reward was placed at the end of each lane, and the time it took to reach it was measured. This test assessed memory function in cognitive function. The task completion time was measured from the start to a maximum of 600 seconds, and if the mouse was unable to complete the task, the time was set to 600 seconds. In the rotor rod test, the mouse was placed on a rotating rod, and the speed of the rod was gradually increased, measuring the time it took for the mouse to fall. This test assessed motor dysfunction in cognitive function and motor memory in behavior. Cognitive function was evaluated comprehensively based on the results of these three behavioral pharmacology tests. Statistical analysis was performed using Dunnett's test for body weight, hippocampal blood glucose levels, and behavioral pharmacology test data, and chi-square test for AGE1 and Iba1 data.

[0035] <Test Results> Figure 8 shows the results of weight measurements for each group. Compared to the control group, the 1% MD group showed a significant increase in weight. Furthermore, while no significant difference was observed in the rhamnan sulfate-administered groups, the 1% MD + RS100 group tended to show a decrease in weight compared to the 1% MD group. Figure 9 shows the results of blood glucose measurements for each group. Compared to the control group, blood glucose levels were significantly elevated in the 1% MD group. Furthermore, blood glucose levels were significantly lower in all rhamnan sulfate-administered groups compared to the 1% MD group. Figure 10 shows the results of spontaneous motor activity measurements. Although no significant difference was observed, spontaneous motor activity tended to be lower in the 1% MD group compared to the control group. Figure 11 shows the results of the task completion time in the eight-arm maze test, and Figure 12 shows the results of the number of errors in the eight-arm maze test. All animals in the 1% MD group failed to complete the task, taking 600 seconds, which was significantly longer than the control group. Although no significant difference was observed, the 1% MD + RS100 and 1% MD + RS300 groups showed a tendency for the time to complete the task to decrease compared to the 1% MD group. The number of errors in the 1% MD group increased significantly compared to the control group. Furthermore, the number of errors in the 1% MD + RS100 group decreased significantly compared to the 1% MD group, with a risk factor of 6.06%.

[0036] Figure 13 shows the results of the rotarod test. The 1% MD group showed a significantly shorter time to fall than the control group. Although no significant difference was observed, the RS group tended to show a longer time to fall than the 1% MD group. Figure 14 shows the results of comparing the thickness of the hippocampal CA1 neuronal layer. The CA1 layer was significantly thinner in the 1% MD group compared with the control group, confirming hippocampal atrophy. Furthermore, the CA1 layer was significantly thicker in the 1% MD + RS100 and 1% MD + RS300 groups compared with the 1% MD group, demonstrating an improvement in atrophy. In addition to CA1, the thickness of CA2, CA3, and dentate gyrus was also measured, and the results were similar to those for CA1.

[0037] Figure 15 shows the results of immunostaining brain histopathological sections using an anti-AGE antibody. AGEs, which stand for advanced glycation end products, have been implicated as causative agents of cognitive impairment. Inhibiting their production may potentially improve cognitive impairment. Compared to the control group, the 1% MD group showed a significant increase in AGE levels (Table 1). On the other hand, administration of RS with 1% MD appeared to inhibit the increase in AGE levels. The 1% MD RS100 group significantly inhibited the increase in AGE levels with a risk factor of 7.6% (Table 5). Thus, rhamnan sulfate is thought to improve cognitive function by inhibiting AGE production. Figure 16 shows the results of immunostaining brain histopathological sections using an anti-Iba1 antibody. Iba1 stands for "ionized calcium-binding adapter molecule 1," a protein specifically expressed in microglia in the brain, and is also used as a microglial marker. Iba1 is known to be involved in brain inflammation, and inhibiting this molecule may improve brain inflammation (cognitive dysfunction). Compared to the control group, Iba1 levels were significantly increased in the 1% MD group (Table 6). On the other hand, administration of RS with 1% MD significantly inhibited the increase in Iba1 levels in both groups (especially RS100, Table 6). Thus, rhamnan sulfate inhibits Iba1 production, thereby suppressing brain inflammation and improving cognitive function. These results suggest that administration of rhamnan sulfate (especially the RS100 group) improves cognitive function in diabetic cognitive impairment. Furthermore, rhamnan sulfate was shown to improve diabetic hippocampal atrophy.

[0038]

[0039]

[0040] <Discussion> In the above-mentioned <Study 1>, healthy Japanese adult men and women aged 40 to under 65 years were tested for the effects on dementia of 8 weeks of continuous intake of a food containing a seaweed extract containing rhamnan sulfate as an active ingredient. Cognitive function tests showed that after 8 weeks of intake, the test food group showed significantly higher scores than the placebo group on the neurocognitive index (NCI), an index of overall cognitive function. The NCI is a score composed of 11 domains: overall memory, verbal memory, visual memory, cognitive function speed, reaction time, overall attention, cognitive flexibility, processing speed, executive function, simple attention, and motor speed. In this study, after 8 weeks of intake, the test food group also showed significantly higher scores than the placebo group on reaction time, overall attention, cognitive flexibility, and executive function. Standardized scores on cognitive function tests were based on normative data for the same age group, normalized to a mean of 100 and a standard deviation of 15, with higher scores indicating better performance. Since both standardized scores in the test food group tended to exceed the average for people of the same age group after intervention compared to the placebo group, it is believed that ingestion of the test food contributed to improving cognitive function with clinical significance. There have been few previous studies examining the cognitive function-improving effects of rhamnan sulfate ingestion in healthy individuals, and its mechanism of action is unclear. Rhamnan sulfate has blood coagulation inhibitory and thrombolytic properties, so it may have the effect of improving blood flow.

[0041] Aging is a factor that leads to decreased cerebral blood flow, and previous studies have suggested a correlation between age-related decreases in cerebral blood flow and cognitive decline. Therefore, the hypothesized mechanism of action for the cognitive function-enhancing effect of this study is that ingesting rhamnan sulfate may have reduced blood flow inhibitors, thereby increasing cerebral blood flow and improving cognitive function. Other hypothesized mechanisms of action include the suggested effect of rhamnan sulfate on improving the intestinal environment, including promoting the intestinal flora-associated nicotinamide metabolic system, and the intestinal environment and nicotinamide / nicotinamide metabolites have been reported to contribute to the improvement of cognitive function. Therefore, it is possible that rhamnan sulfate may contribute to the improvement of brain and cognitive function by improving the intestinal environment and increasing blood nicotinamide levels. In <Test 2>, a mouse model was used to confirm the effect of rhamnan sulfate on diabetes-induced cognitive decline. The results showed that rhamnan sulfate improved cognitive decline due to diabetes and reduced atrophy of the hippocampal neuronal layer. By increasing blood nicotinamide levels, rhamnan sulfate also protected the pancreas. Therefore, it was found that rhamnan sulfate can also be used as a composition for improving pancreatic function. Thus, according to the present embodiment, a novel composition that is safe and has the effect of improving brain function can be provided.

Claims

1. A composition for improving brain function, comprising a sulfated polysaccharide.

2. A composition for improving brain function according to claim 1, wherein the sulfated polysaccharide is rhamnan sulfate.

3. A composition for improving brain function as described in claim 2, wherein the composition is for oral administration.

4. A food composition for improving brain function, comprising the composition for improving brain function described in claim 3.

5. A composition for improving brain function as described in claim 3, wherein the decline in brain function is due to diabetes.

6. A composition for improving brain function as described in claim 3, characterized in that it improves brain function by increasing blood nicotinamide concentration.

7. A composition for improving pancreatic function, which contains rhamnan sulfate and protects the pancreas by increasing nicotinamide concentration in the blood.

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