阅读说明：本技术 使用脂多糖的脑功能改善剂、食品和药品 (Brain function improving agent, food and pharmaceutical using lipopolysaccharide ) 是由 杣源一郎 稻川裕之 河内千惠 小林优多郎 于 2017-12-04 设计创作，主要内容包括：向阿尔茨海默病模型小鼠口服施用泛菌LPS,研究其影响,结果发现,通过口服泛菌LPS,可以显著减少脑内Aβ肽的蓄积量并改善学习功能,由此提供一种可容易获得的具有对Aβ脑内沉积的抑制效果或学习功能的改善效果的脑功能改善剂或食品组合物。(The present inventors have found that oral administration of pantoea LPS to alzheimer model mice significantly reduces the amount of accumulation of a β peptide in the brain and improves learning function, and as a result, have provided a brain function-improving agent or food composition having an inhibitory effect on a β intracerebral deposition or an improving effect on learning function, which can be easily obtained.)

1. A brain function improving agent, food or medicine contains Lipopolysaccharide (LPS) of Pantoea as effective component.

2. The brain function improving agent, food or pharmaceutical product according to claim 1, wherein the improved brain function is a cognitive function which is decreased due to aging or a brain disease accompanying aging.

3. The brain function improving agent, food or pharmaceutical product of claim 1, which comprises an effective amount of pantoea LPS.

4. The brain function improving agent, food or pharmaceutical product according to claim 1, which is used for preventing Alzheimer's disease.

5. The brain function improving agent, food or pharmaceutical product according to claim 1, which comprises Pantoea LPS in a ratio of 0.1 to 1mg/kg body weight per daily dosage unit.

Technical Field

The present invention relates to a brain function improving agent, food and pharmaceutical containing lipopolysaccharide.

Background

In recent years, the general population in japan has decreased, and the elderly population aged 65 years or older tends to increase year by year. According to data of the japan's fat-age labour province, the elderly population (2015) has exceeded 3300 ten thousand, and the percentage of elderly population is said to reach 26.7%. With respect to dementia, which is one of the senile diseases, the number of patients in japan currently exceeds 460 ten thousand, and it is expected that 700 thousand will be reached by 2025 years, with 1 in 5 elderly people. About 60% of patients with dementia have alzheimer's disease, about 20% have vascular dementia, and the rest include various dementia diseases such as lewy body dementia. The clinical symptoms of alzheimer disease include cognitive dysfunction such as memory disorder and language disorder, mental symptoms, and behavioral disorders. As a pathological feature of alzheimer's disease, there are cases where abnormal structures such as senile plaques and neurofibrillary tangles, which are also called amyloid plaques, are deposited in a large range of cerebral cortex and hippocampus. The main constituent of amyloid plaques is β -amyloid (hereinafter also referred to simply as "a β"), and particularly a β peptide consisting of 42 residues (hereinafter also referred to simply as "a β 1-42") has high aggregation properties and is known to play a key role in amyloid deposition. The latter consists of hyperphosphorylated Tau protein. Currently, the amyloid hypothesis is generally considered to support the pathological cascade of alzheimer's disease. The time sequence is as follows: formation of amyloid plaques and accumulation of Tau protein (neurofibrillary tangles) due to excessive accumulation of a β, and further, neurodegeneration and neuronal cell death are caused (non-patent document 1). Although a β appears with age even in the brain of a healthy person, accumulation of a β is thought to be promoted by a gene mutation of an enzyme involved in a β production or a decrease in the activity of a β decomposition system. As a therapeutic agent for alzheimer's disease, therapeutic agents targeting neurotransmitters or their receptors (acetylcholinesterase inhibitors and N-methyl-D-aspartate receptor antagonists) have been developed, but these are not fundamental therapeutic agents for pathological changes such as a β accumulation and tau protein aggregation, and thus are not fundamental therapeutic agents capable of preventing the development of alzheimer's disease.

On the other hand, microglia have been found to be macrophages in brain tissue and play an important role in maintaining homeostasis in the brain, such as repairing damaged tissues, phagocytizing and removing waste products in the brain, and the like. Microglia express a β receptors and take up and decompose a β by phagocytosis, and therefore, by activating the a β phagocytosis ability of microglia, prevention of alzheimer's disease caused by excessive accumulation of a β can be expected. In recent years, the search for compounds having an action capable of activating the phagocytic activity of a β of microglia has been advanced, and the effects of food ingredients such as oleamide (non-patent document 2) and peptides (patent document 1) in vitro experimental systems have been reported.

However, lipopolysaccharides are outer membrane components of the cell wall of gram-negative bacteria. The term "endotoxin" was assigned to toxic substances derived from Vibrio cholerae in 1892, and it was reported in 1954 that lipopolysaccharide is the main component of endotoxin (non-patent document 3). However, in recent years, it has been reported that intracranial injection of lipopolysaccharide into an alzheimer disease model mouse induces microglial activation and suppresses intracerebral deposition of a β (non-patent document 4). Similarly, it has been reported that intraperitoneal injection of MPL (monophosphoryl lipid a), which is a derivative of lipid a as a constituent of lipopolysaccharide and is approved for use as an (immunostimulant), exhibits an inhibitory effect on a β intracerebral deposition and an improving effect on learning function (non-patent document 5). On the other hand, it has been reported that by taking lipopolysaccharide orally or transdermally, there is no significant toxicity, and an improvement effect on diseases such as hyperlipidemia, allergy, and the like is exhibited (non-patent document 6). et al found that one of these lipopolysaccharides is lipopolysaccharide (hereinafter, also referred to as "Pantoea agglomerans") derived from Pantoea agglomerans of wheat symbiotic bacteria, and reported a fermentation and culture method for obtaining safe Lipopolysaccharide (LPS) even when added to cosmetics, foods, functional foods, and the like (patent document 2). Pantoea LPS (Pantoea LPS) administered sublingually has been reported to be an adjuvant and to improve mucosal immunological activity in animal experiments (non-patent document 7). In addition, studies by Xiaolin et al using primary cells of microglia derived from mouse brain have reported that Pantoea LPS improves phagocytic ability of A β 1-42 (non-patent document 8). Incidentally, lipopolysaccharide administered orally is hardly absorbed from the digestive tract. For example, starch is digested by human enzymes (amylase, maltase) that digest starch (high molecular weight polysaccharides bonded by α 1-4 bonds of glucose), whereas LPS polysaccharide has a structure consisting of 3-5 kinds of 6-carbon or 5-carbon sugars (victoria, lipopolysaccharide) and is not digested because human does not have a digestive enzyme that can break down the polysaccharide structure of LPS. In addition, since the transfer into the brain is accompanied by the blood-brain barrier, etc., even if lipopolysaccharide is absorbed into the blood by oral administration, the transfer efficiency into the brain is extremely low, and it is considered that the oral lipopolysaccharide cannot reach the brain. Furthermore, the inhibitory effect of oral administration of lipopolysaccharide on intracerebral deposition of a β or the improving effect on learning function has not been reported so far, nor has it been mentioned in any literature.

Disclosure of Invention

Problems to be solved by the invention

The inhibitory effect on the deposition of a β in the brain or the improving effect on learning function is considered to be useful for preventing dementia, particularly alzheimer's disease. The present invention was made in view of the above-mentioned background, and an object thereof is to provide a brain function improving agent, a food and a pharmaceutical product having an inhibitory effect on a β intracerebral deposition or an improving effect on learning function, which are produced from lipopolysaccharides that are relatively easily obtained by the above-mentioned fermentation culture method (patent document 2).

Means for solving the problems

The present inventors have conducted intensive studies to solve the above problems. Pantoea LPS was orally administered to Alzheimer's disease model mice, and its effect was studied. As a result, they have found that oral administration of Pantoea LPS significantly reduces the accumulation of A.beta.peptide in the brain and improves learning functions, thereby completing the present invention. The brain function-improving agent of the present invention is a drug for Alzheimer's disease, and is characterized by containing a Pantoea lipopolysaccharide (Pantoea LPS) as an active ingredient.

That is, the present invention has the following configuration.

(1) A brain function improving agent, food or medicine contains Lipopolysaccharide (LPS) of Pantoea as effective component.

(2) The brain function improving agent, food or pharmaceutical product according to item (1), wherein the improved brain function is a cognitive function that decreases due to aging or a brain disease accompanying aging.

(3) The brain function improving agent, food or pharmaceutical product according to item (1), which comprises an effective amount of Pantoea LPS.

(4) The brain function improving agent, food or pharmaceutical product according to item (1), which is used for preventing Alzheimer's disease.

(5) The brain function improving agent, food or pharmaceutical product according to item (1), which comprises Pantoea LPS in a daily dose of 0.1 to 1mg/kg body weight.

Effects of the invention

The present invention provides a composition such as a drug or a food, which has an effect of preventing alzheimer's disease, particularly an effect of inhibiting the intracerebral deposition of a β and an effect of improving learning function, due to LPS of pantoea. It has been confirmed that pantoea LPS is safe for oral or transdermal administration in the form of food, cosmetics, feed, etc., and therefore a preventive effect with a low risk of side effects can be expected.

Drawings

FIG. 1 shows the results of a training test in the water maze test. The figure shows that all groups shortened the time required to reach the platform after 5 consecutive days of training. As a result, no difference was observed between the groups.

Fig. 2 shows a representative swimming trajectory in a probe test of the water maze test. The dashed circle represents the mounting position of the platform.

FIG. 3 shows the results of the residence time of mice in the quadrant region where the platform was installed in the probe test of the water maze test. The results showed that the residence time was shortened in the PC group ingested with the high-fat diet, while the residence time was prolonged by the ingestion of LPS by Pantoea bacteria.

FIG. 4 shows the amount of stored A.beta. (. beta.1-40 and A.beta.1-42) in the brain removed from the mice after 18 weeks of feeding. The results showed that the amount of A.beta.1-40 was significantly increased in the PC group ingested with the high-fat diet compared to the NC group, and the amount of A.beta.1-40 and A.beta.1-42 was significantly decreased in the Pantoea LPS ingested compared to the PC group.

Detailed Description

The brain function improving agent and the food composition of the present invention contain pantoea LPS.

Here, unless otherwise specified, "pantoea LPS" refers to lipopolysaccharide obtained by culturing pantoea agglomerans, which is a gram-negative bacterium symbiotic with wheat, with wheat flour according to the procedure described in patent document 2, extracting lipopolysaccharide from the bacterial cells with hot water, and removing the solid components.

The brain function improving agent and food of the present invention can improve brain function disorder, particularly cognitive function disorder due to aging or brain diseases accompanying aging. Examples of the brain diseases associated with cognitive dysfunction include alzheimer's disease.

The Pantoea LPS of the present invention can be applied to mammals (domestic animals such as pigs, cattle, sheep, horses, dogs, cats, etc.), birds (domestic fowls such as chickens, turkeys, ducks, etc.) and the like, both of which are humans and non-humans.

The route of administration and the dosage form of the pharmaceutical composition of the present invention may be appropriately designed according to the purpose, symptoms, age, body weight, and the like of the subject. As examples of routes of administration, oral administration, transdermal administration, buccal administration (buccal administration, also called oromucosal administration), subcutaneous injection, intradermal injection, intraperitoneal injection, intramuscular administration, and the like are included. Oral, transdermal, buccal administration are preferred. Examples of the dosage form include powder, granule, liquid, capsule, fine granule, pill, syrup, and emulsion. The pharmaceutical composition can be administered orally and is effective. Such a preparation may contain, in addition to the pantoea LPS, various pharmaceutically acceptable additives, for example, stabilizers, fillers, emulsifiers, extenders, excipients, binders, humectants, disintegrating agents, surfactants, suspending agents, coating agents, coloring agents, perfumes, flavoring agents, sweeteners, preservatives and antioxidants.

The food composition of the present invention may be used with pantoea LPS as it is, or mixed with other foods or food ingredients, etc. according to a conventional method in food compositions, for example, mixed with other foods or food ingredients. The form of the food is not particularly limited, and may be any of a solid form (powder, granule, etc.), a paste form, a liquid form, and a suspension form, for example. The food composition of the present invention can be made into nutritional functional foods, specific health foods, functional indicator foods, health foods, nutritional supplementary foods, drinkable preparations, refreshing beverages, alcoholic beverages, supplements, feeds, feed additives, and the like.

In the case of oral ingestion, the brain function improving agent or food composition of the present invention is preferably formulated to contain pantoea LPS in the range of 0.1 to 1mg/kg body weight per day for an adult, and may be administered in 1 to several times. The dosage is preferably 0.3-1 mg/kg body weight, more preferably 0.5-1 mg/kg body weight. The dosage may be appropriately adjusted depending on various factors such as age, body weight, health condition of the subject, administration method, and combination with other agents (or food ingredients). In the case of long-term ingestion for preventive purposes, the dosage may be less than the above range.