WO2024143614A1 - Composition for improving memory or cognitive ability including lactobacillus rhamnosus lr5 lactic acid bacteria as active ingredient - Google Patents

Abstract

The present invention relates to a composition for improving memory or cognitive ability including Lactobacillus rhamnosus LR5 lactic acid bacteria as an active ingredient. The Lactobacillus rhamnosus LR5 lactic acid bacteria of the present invention can be effectively useful as a composition for preventing or treating memory or cognitive ability related diseases.

Description

Composition for improving memory or cognitive ability containing Lactobacillus rhamnosus LR5 lactic acid bacteria as an active ingredient

The present invention relates to a composition containing Lactobacillus rhamnosus LR5 as an active ingredient, and more specifically, to a composition for improving memory or cognitive ability containing Lactobacillus rhamnosus LR5 lactic acid bacteria as an active ingredient, which is effective in improving memory or cognitive ability. , relates to pharmaceutical and food compositions.

As the social environment changes rapidly and diversely, modern people encounter more and more stimulation than in the past, and rapid brain activity is required to accommodate this. Long-term learning or memory activities by young people, especially test takers, can cause mental and physical fatigue as well as brain fatigue and affect the healthy development of the brain. After middle age, symptoms such as memory loss or forgetfulness may appear due to a decline in the function of the central nervous system, and in the elderly, memory ability declines due to degenerative brain diseases such as dementia, and in severe cases, social life itself becomes impossible and family life becomes impossible. However, if we consider the impact on people around us, enormous social costs may be required.

Memory refers to the ability to recall past events in a conscious or unconscious state. In particular, learning and memory are closely related and should always be considered simultaneously. Memory can be divided into unconscious nondeclarative memory, which includes the acquisition of skills and habits, and declarative memory, which can be consciously reproduced, such as facts or events that occurred in the past. However, just as complex actions such as driving or playing the piano can be performed unconsciously if they become habitual, declarative memory can be converted to non-declarative memory through repetition.

In addition, the overall function of memory is called cognitive ability, and this decline in cognitive ability has emerged as a major problem in modern society because it causes poor learning and a decrease in quality of life. Currently, diseases related to cognitive decline, such as brain damage, dementia, and Alzheimer's, are increasing due to the rapid aging of modern society. These diseases cause a decline in overall and complex intellectual functions such as memory, thinking ability, comprehension, calculation ability, learning ability, language, and judgment to the extent that they cause severe disabilities in self-maintenance and social life.

Declarative memory includes working memory, which focuses on information given in the present and stores it temporarily for only a few seconds; short-term memory, which retains memories for hours or days; and memory, which remembers events from the past over a long period of time. It is divided into long-term memory (remote memory), etc. Short-term memory includes the period during which memories of current events are converted into long-term memory. During this period, memory storage is weak and easily forgotten, but once stored as long-term memory, it is not easily forgotten even if there is serious damage to the brain.

Memory can be accomplished in three stages: the first is an input stage in which new information or knowledge is memorized and input into the brain, the second is a storage stage in which the information or knowledge input to the brain is stored in the brain, and the third is in which the stored information or knowledge is stored in the brain. This is the recall stage, where information or knowledge is reconsidered. If any one of the three steps above is abnormal, a phenomenon in which information or knowledge cannot be accurately remembered may occur, that is, memory deterioration or decline may occur.

The decline or decline in memory or cognitive ability is due to various causes such as a decrease in the amount of acetylcholine due to the action of acetylcholinesterase in nerve cells of brain tissue, neurotoxicity caused by β-amyloid (βA), etc. It is known to be caused by necrosis of brain cells.

Accordingly, both surgical and pharmacological methods are currently being used for the decline or decline of memory or cognitive ability, but surgical methods are not easy, so pharmacological methods are recommended. As the above-mentioned pharmacological method, inhibitors of the activity of acetylcholinesterase, an enzyme that decomposes acetylcholine (tacrine, Aricept, donepezil, ribastigrin, or galantamine, etc.) are commercialized, but these are used to reduce memory or cognitive ability. Rather than treating the decline, it only shows temporary improvement in symptoms by regulating neurotransmitters. Furthermore, side effects such as hepatotoxicity, gastrointestinal disorders, induction of cardiac bradycardia, weight loss, and insomnia, and toxicity or dependence due to long-term use are pointed out as problems, so new treatments are being developed and required to complement these problems.

Meanwhile, Lactobacillus rhamnosus lactic acid bacteria are known to have effects such as detoxification, antioxidant effect, wrinkle reduction, anti-aging, skin strengthening, and depigmentation of skin spots, but there is no known effect on memory or cognitive ability. does not exist.

One object of the present invention is to provide a composition for improving memory or cognitive ability containing Lactobacillus rhamnosus LR5 lactic acid bacteria as an active ingredient.

Another object of the present invention is to provide a pharmaceutical composition for improving memory or cognitive ability containing Lactobacillus rhamnosus LR5 lactic acid bacteria as an active ingredient.

Another object of the present invention is to provide a food composition for improving memory or cognitive ability containing Lactobacillus rhamnosus LR5 lactic acid bacteria as an active ingredient.

However, the technical problem to be achieved by the present invention is not limited to the problems mentioned above, and other problems not mentioned can be clearly understood by those skilled in the art from the description below.

To achieve one object of the present invention, the present invention provides a composition for improving memory or cognitive ability containing Lactobacillus rhamnosus LR5 lactic acid bacteria as an active ingredient.

“Memory ability (memory)” of the present invention is the ability to retain previous impressions or experiences in consciousness, and when memory ability deteriorates or declines, memory disorders such as forgetfulness may occur.

“Cognition” as used herein refers to relatively high levels of specific information processing, including thinking, memory, perception, motivation, skilled motor skills, and language.

“Disease related to memory ability” of the present invention is meant to include all diseases in which memory ability may be reduced or decreased as a symptom of the disease.

“Cognitive-related impairment” as used herein means a significant impairment of cognition or memory that represents a marked deterioration from a previous level of functioning.

“Improvement” in the present invention refers to any effect in which memory ability is qualitatively or quantitatively enhanced, or diseases related to memory or cognitive ability are qualitatively or quantitatively alleviated.

Lactobacillus rhamnosus LR5 lactic acid bacteria were administered to animal models with reduced memory or cognitive ability due to scopolamine administration, followed by Morris water maze test and spontaneous alternation Y-maze test. As a result of performing the -maze test and passive avoidance test, the spontaneous alteration of the animal model significantly increased. This means that the Lactobacillus rhamnosus LR5 lactic acid bacterium of the present invention has the effect of improving memory or cognitive ability.

The scopolamine is also called hyoscine and is used to treat nausea or vomiting after motion sickness or surgery. It can also be used as an antidepressant by blocking some of the effects of acetylcholine in the nervous system and can be used in research on the relationship between acetylcholine and cognition and memory.

The animal model in which memory or cognitive ability is reduced due to the administration of scopolamine can be viewed as an animal model in which memory-related diseases occur beyond the decline in memory or cognitive ability.

In the present invention, the Lactobacillus rhamnosus LR5 lactic acid bacterium is Lactobacillus rhamnosus LR5, (Accession number: KCTC 12202BP).

The composition for improving memory or cognitive ability may be characterized as containing skim milk.

According to another embodiment of the present invention, it relates to a pharmaceutical composition for improving memory or cognitive ability containing Lactobacillus rhamnosus LR5 lactic acid bacteria as an active ingredient.

In the present invention, the pharmaceutical composition may be in the form of a capsule, tablet, granule, injection, ointment, powder, or beverage, and the pharmaceutical composition may be intended for human subjects.

The pharmaceutical composition of the present invention is not limited to these, but can be formulated and used in the form of oral dosage forms such as powders, granules, capsules, tablets, and aqueous suspensions, external preparations, suppositories, and sterile injection solutions according to conventional methods. You can. The pharmaceutical composition of the present invention may include a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers include binders, lubricants, disintegrants, excipients, solubilizers, dispersants, stabilizers, suspending agents, colorants, flavorings, etc. for oral administration, and buffers, preservatives, and analgesics for injections. Topics, solubilizers, isotonic agents, stabilizers, etc. can be mixed and used, and for topical administration, bases, excipients, lubricants, preservatives, etc. can be used. The dosage form of the pharmaceutical composition of the present invention can be prepared in various ways by mixing it with a pharmaceutically acceptable carrier as described above. For example, for oral administration, it can be manufactured in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, etc., and in the case of injections, it can be manufactured in the form of unit dose ampoules or multiple doses. there is. In addition, it can be formulated as a solution, suspension, tablet, capsule, sustained-release preparation, etc.

Meanwhile, examples of carriers, excipients and diluents suitable for formulation include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, malditol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, or mineral oil may be used. In addition, fillers, anti-coagulants, lubricants, wetting agents, fragrances, emulsifiers, preservatives, etc. may be additionally included.

The route of administration of the pharmaceutical composition according to the present invention is not limited to these, but is oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, enteral, and topical. , sublingual or rectal. Oral or parenteral administration is preferred.

As used herein, “parenteral” includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques. The pharmaceutical composition of the present invention can also be administered in the form of a suppository for rectal administration.

The pharmaceutical composition of the present invention may vary depending on several factors, including the activity of the specific compound used, age, body weight, general health, gender, diet, administration time, administration route, excretion rate, drug formulation, and the severity of the specific disease to be prevented or treated. It may vary, and the dosage of the pharmaceutical composition may vary depending on the patient's condition, weight, degree of disease, drug form, administration route, and period, but may be appropriately selected by a person skilled in the art, and may range from 0.0001 to 200 mg/day. It can be administered in kg or 0.001 to 200 mg/kg. Administration may be administered once a day, or may be administered in several divided doses. The above dosage does not limit the scope of the present invention in any way. The pharmaceutical composition according to the present invention may be formulated as pills, dragees, capsules, solutions, gels, syrups, slurries, and suspensions.

According to another embodiment of the present invention, it relates to a food composition for improving memory or cognitive ability containing Lactobacillus rhamnosus LR5 lactic acid bacteria as an active ingredient.

The food composition of the present invention can be manufactured in the form of various foods, such as beverages, gum, tea, vitamin complexes, powders, granules, tablets, capsules, cookies, rice cakes, bread, etc. Since the food composition of the present invention is composed of ingredients with little toxicity and side effects, it can be used safely even when taken for a long period of time for preventive purposes.

When the Lactobacillus rhamnosus LR5 lactic acid bacterium of the present invention is included in a food composition, it can be added in an amount of 0.1 to 50% of the total weight.

Here, when the food composition is manufactured in the form of a beverage, there are no particular limitations other than containing the food composition in the indicated ratio, and various flavoring agents or natural carbohydrates can be contained as additional ingredients like ordinary beverages. That is, natural carbohydrates include monosaccharides such as glucose, disaccharides such as fructose, polysaccharides such as sucrose, dextrin, cyclodextrin, etc., and sugar alcohols such as xylitol, sorbitol, and erythritol. can do. Examples of the flavoring agent include natural flavoring agents (thaumatin, stevia extract (e.g., rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.).

In addition, the food composition of the present invention contains various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic and natural flavors, colorants, pectic acid and its salts, alginic acid and its salts, organic acids, and protective colloidal thickeners. , pH adjusters, stabilizers, preservatives, glycerin, alcohol, carbonating agents used in carbonated beverages, etc.

These ingredients can be used independently or in combination. The proportion of these additives is not critical, but is generally selected in the range of 0.1 to about 50 parts by weight per 100 parts by weight of the composition of the present invention.

The Lactobacillus rhamnosus LR5 lactic acid bacterium of the present invention can be effectively used as a composition for preventing or treating diseases related to memory or cognitive ability.

In addition, the pharmaceutical and food composition containing the Lactobacillus rhamnosus LR5 lactic acid bacterium provided by the present invention has an effect of improving memory or cognitive ability.

The effects of the present invention are not limited to the effects described above, but should be understood to include all effects that can be inferred from the configuration of the invention described in the detailed description or claims of the present invention.

Figure 1a is a graph showing the weight measurement results of an animal model to confirm body weight changes following oral administration of Lactobacillus plantarum Y7 lactic acid bacteria.

Figure 1b is a graph showing the weight measurement results of an animal model to confirm body weight changes following oral administration of Lactobacillus acidophilus LA1 lactic acid bacteria.

Figure 1c is a graph showing the weight measurement results of an animal model to confirm body weight changes following oral administration of Lactobacillus rhamnosus LR5 lactic acid bacteria.

Figure 2a is a graph showing the results of a Morris water maze experiment to confirm the effect of preventing memory decline following oral administration of Lactobacillus plantarum Y7 lactic acid bacteria.

Figure 2b is a graph showing the results of a Morris water maze experiment to confirm the effect of preventing memory decline following oral administration of Lactobacillus acidophilus LA1 lactic acid bacteria.

Figure 2c is a graph showing the results of a Morris water maze experiment to confirm the effect of preventing memory decline following oral administration of Lactobacillus rhamnosus LR5 lactic acid bacteria.

Figure 3a is a graph showing the results of a voluntary alternating Y-maze experiment to confirm the effect of preventing memory decline following oral administration of Lactobacillus plantarum Y7 lactic acid bacteria.

Figure 3b is a graph showing the results of a voluntary alternating Y-maze experiment to confirm the effect of preventing memory decline following oral administration of Lactobacillus acidophilus LA1 lactic acid bacteria.

Figure 3c is a graph showing the results of a voluntary alternating Y-maze experiment to confirm the effect of preventing memory decline following oral administration of Lactobacillus rhamnosus LR5 lactic acid bacteria.

Figure 4a is a graph showing the results of a passive avoidance experiment to confirm the effect of preventing memory decline following oral administration of Lactobacillus plantarum Y7 lactic acid bacteria.

Figure 4b is a graph showing the results of a passive avoidance experiment to confirm the effect of preventing memory decline following oral administration of Lactobacillus acidophilus LA1 lactic acid bacteria.

Figure 4c is a graph showing the results of a passive avoidance experiment to confirm the effect of preventing memory decline following oral administration of Lactobacillus rhamnosus LR5 lactic acid bacteria.

The characteristics and functions of this composition will be described in more detail through examples and experimental examples below. However, these examples are only for illustrating the present invention in detail, and the scope of the present invention is not limited by these examples.

Preparation example: Preparation of scopolamine-induced memory decline model mice

In order to confirm the effect of improving memory or cognitive ability of a composition containing Lactobacillus rhamnosus LR5 lactic acid bacteria as an active ingredient, mice with impaired memory were created, and it was confirmed whether memory loss symptoms were improved by treatment with lactic acid bacteria.

96 C57BL/6JmsSlc male mice (7 weeks old) were divided into groups of 4, temperature 22±2°C, relative humidity 50±10%, ventilation frequency 10-20 times/hr, lighting time 12 hours (lights on at 9:00 AM). to 9 p.m. (lights off) and an illumination level of 150 to 300 Lux for 7 days in an animal breeding area to acclimatize to the laboratory.

Afterwards, 96 mice were divided into 6 groups of 16 each, with one group being the normal group (Comparative Example 1) and the remaining 5 groups being the experimental groups (Comparative Examples 2 and 3 and Examples 1 to 3). The experimental group was administered scopolamine intraperitoneally at a dose of 1 mg/kg/day for 4 weeks 30 minutes before the start of the behavioral experiment. 30 minutes after the intraperitoneal administration, lactic acid bacteria (1 × 10 ¹⁰ CFU/head) and additional ingredients according to Table 1 below were orally administered in Examples 1 to 3.

army Scopolamine
Processing Lactobacillus Additional ingredients Comparative Example 1 X - X Comparative Example 2 O - X Comparative Example 3 O - Donepezil (2mg/kg) Example 1 O Lactobacillus plantarum Y7 MSG (0.057mg/kg) Pyridoxal 5′-phosphate hydrate (0.005mg/kg) Example 2 O Lactobacillus acidophilus LA1 Whey protein (500 mg/kg) Example 3 O Lactobacillus rhamnosus LR5 Skim milk (1,500 mg/kg)

Experimental Example 1: General symptom recording

During the experiment, the types and degrees of general symptoms in the scopolamine-induced memory loss animal model were observed, moribund and dead animals were excluded from the test group, and any special information was recorded.

As a result, there were no unusual issues in Examples 1 to 3 in which lactic acid bacteria were administered orally.

Experimental Example 2: Weight measurement

Body weight was measured a total of six times using an electronic scale before and during administration of the test substance in the scopolamine-induced memory loss animal model, before the start of the behavioral test, and at the end of the test.

As a result, as shown in FIGS. 1A to 1C, there was no specific change in body weight in Examples 1 to 3 in which lactic acid bacteria were orally administered.

Experimental Example 3: Morris water maze test

To confirm the effectiveness of lactic acid bacteria in preventing memory decline in an animal model of scopolamine-induced memory loss, a Morris water maze experiment was performed and the time spent in the area where the platform was located was measured.

The experimental equipment consisted of a circular water tank and three signs attached to the wall that could remember the location of the escape zone. The water tank was filled with water at a temperature of approximately 25 ± 1°C, and the escape platform was placed 1 cm above the water to suit the purpose of the experiment. The experiment was conducted for 10 days by making the water opaque with white water-based paint so that the escape zone was not visible to the naked eye when located below the water surface. On the first day, cued learning was performed by making the escape platform visible and giving clues, and from the second day, hidden platform was performed by placing the escape platform under the water and hiding it. On the last day of the test, the escape latency, which is the time it takes for the experimental animal to find an escape zone, and the path length it takes until it finds the escape zone were measured and recorded, and the path length was divided by the escape latency to determine swimming speed. was calculated, and the time the animal stayed in the quadrant where the escape zone was previously located during the probe trial (Time spent in the platform quadrant, TSPQ) was recorded.

As a result, as shown in Figure 2a, when Lactobacillus Plantarum Y7 lactic acid bacteria were orally administered (Example 1), compared to the case where lactic acid bacteria were not orally administered (Comparative Example 2), no significant improvement could be confirmed, and the Even when comparing the results of four probes, no clear improvement was identified.

As a result, as shown in Figure 2b, when Lactobacillus acidophilus LA1 lactic acid bacteria were orally administered (Example 2), compared to the case where lactic acid bacteria were not orally administered (Comparative Example 2), no significant improvement was confirmed; Even when comparing the results of probing four times a day, no clear improvement was identified.

As a result, as shown in Figure 2c, when Lactobacillus rhamnosus LR5 lactic acid bacteria were orally administered (Example 3), compared to when lactic acid bacteria were not orally administered (Comparative Example 2), memory tended to improve on Reversal day 3. You can check that Day 1 stays in the quadrant where the target platform is for a longer time. This means that Lactobacillus rhamnosus LR5 lactic acid bacteria are effective in improving short-term memory or working memory.

Experimental Example 4: Spontaneous alternation Y-maze test

A Y-maze test was performed to confirm the effectiveness of lactic acid bacteria in preventing memory decline in an animal model of scopolamine-induced memory loss.

The experimental equipment used was a Y-shaped maze with walls and three passages, each divided by 120°. The animal was placed in the center zone of the Y-maze and allowed to freely explore the three passages. When all four feet entering a passage was defined as one time, the frequency was calculated by recording the total number of passages explored and the order and number of times each passage was entered.

As a result, as shown in Figure 3a, when Lactobacillus plantarum Y7 lactic acid bacteria were orally administered (Example 1), compared to when lactic acid bacteria were not orally administered (Comparative Example 2), recovery from the effects of scopolamine It was confirmed that there was no statistical significance as the trend was minimal.

As a result, as shown in Figure 3b, when Lactobacillus acidophilus LA1 lactic acid bacteria were orally administered (Example 2), compared to the case where lactic acid bacteria were not orally administered (Comparative Example 2), from the effect of scopolamine It was confirmed that there was no statistical significance as the recovery tendency was minimal.

As a result, as shown in Figure 3c, when Lactobacillus rhamnosus LR5 lactic acid bacteria were orally administered (Example 3), compared to the case where lactic acid bacteria were not orally administered (Comparative Example 2), recovery from the effects of scopolamine was observed. It was confirmed that the tendency increased statistically significantly. This means that Lactobacillus rhamnosus LR5 lactic acid bacteria have an improving effect on short-term and working memory.

Although the embodiments of the present invention have been described in detail above, the scope of the present invention is not limited thereto, and various modifications and variations are possible without departing from the technical spirit of the present invention as set forth in the claims. This will be self-evident to those with ordinary knowledge in the field.

Claims (5)

A composition for improving memory or cognitive ability containing Lactobacillus rhamnosus LR5 lactic acid bacteria as an active ingredient. According to paragraph 1, A composition for improving memory or cognitive ability, wherein the Lactobacillus rhamnosus LR5 lactic acid bacterium is Lactobacillus rhamnosus LR5, (Accession number: KCTC 12202BP). According to paragraph 1, The composition for improving memory or cognitive ability is A composition for improving memory or cognitive ability, comprising skim milk. A pharmaceutical composition for improving memory or cognitive ability containing the Lactobacillus rhamnosus LR5 lactic acid bacterium according to claim 1 as an active ingredient. A food composition for improving memory or cognitive ability containing the Lactobacillus rhamnosus LR5 lactic acid bacterium according to claim 1 as an active ingredient.

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