KR20190134130A - Novel composition useful for prevention or treatment of dementia by inhibiting synthesis of β-amyloid - Google Patents

Abstract

The present invention relates to a novel therapeutic composition for alleviating dementia symptoms by inhibiting β-amyloid (Aβ) synthesis. Since the novel therapeutic composition inhibits the synthesis of Aβ protein, a causing material of dementia, facilitates neurotransmission, and also exhibits an effect of improving motor ability, the novel therapeutic composition can be usefully used for preventing, alleviating or treating senile dementia, Alzheimer′s disease, or vascular dementia and the like.

Description

Novel composition useful for prevention or treatment of dementia by inhibiting synthesis of β-amyloid

The present invention relates to a novel therapeutic composition for improving dementia symptoms by inhibiting beta-amyloid (Aβ) synthesis. More specifically, lincomycin having an effect of inhibiting the synthesis of toxic beta-amyloid (Aβ). , Azaserrine or It relates to a composition for preventing or treating dementia, which contains belladonna extract as an active ingredient.

Dementia is a representative old age disease that has emerged as a serious social problem with the rapid aging of the population. The dementia suffers from intellectual impairment, cognitive impairment, behavior and It is a degenerative disease that causes cognitive function to be continuously and deteriorated by the progressive gradual deterioration of personality, which causes significant obstacles in daily life. Here, cognitive function refers to various intellectual abilities such as memory, language ability, space-time grasping ability, judgment ability, learning ability, storage ability, and abstract thinking ability.

In particular, Alzheimer's disease (AD) is characterized by characteristic lesions such as neuritic plaque and neurofibrillary tangle, and when visually observed, they show general brain atrophy due to neuronal loss. Known. These pathological findings are limited to the hippocampus and the olfactory olfactory cortex, which are the major brain areas that are primarily responsible for memory, but gradually spread throughout the brain through the parietal lobe and frontal lobe. Beta amyloid (β-amyloid, Aβ) is a major component of the senile plaque and is considered to be an important cause of Alzheimer's disease, and oxidative stress due to the generation of reactive oxygen species (ROS). Is known to cause necrosis and apoptosis of neuronal cells. Some cases of neurodegenerative disease caused by aging and slow progression are called senile dementia. Alzheimer's disease is progressive and progresses faster than senile dementia.

Anti-dementia drugs known to date are used to prevent and improve cognitive decline in dementia patients, including cholinesterase blockers, vasodilators, donepezil, revastigmine, and galantamine. There are also pharmacotherapy such as nootropics, and psychotropic drug therapy such as antidepressants and sedatives for the treatment of behavioral psychological symptoms, and non-pharmaceutical therapy of psychology, cognition, behavior, work, and rehabilitation.

As a composition exhibiting the effect of preventing and improving dementia, the Republic of Korea Patent No. 10-1807953 uses the coriander extract to reduce the toxicity of Aβ42, a causative agent of dementia, inhibit the death of nerve cells and improve the exercise ability. It is starting. In addition, the Republic of Korea Patent No. 10-1801478 is a composition for the prevention or treatment of degenerative brain disease, including biocanine A as an active ingredient inhibits the activity of BACE1 (beta-secretase 1) to produce beta-amyloid plaques Disclosed is a method for preventing or treating degenerative brain disease.

As described above, the development of an effective herbal extract for dementia has been of major interest, and research on this has been made, but it is still inadequate.

Accordingly, the present inventors have tried to identify the mechanism of action of dementia treatment and use it in the treatment of dementia, as well as to solve the above problems and to identify a composition for preventing or treating dementia that can be effectively applied to the treatment of dementia and the present invention Completed.

KR 10-1807953 B1, December 05, 2017 KR 10-1801478 B1, November 20, 2017

Therefore, the technical problem to be solved in the present invention is to provide a composition for preventing or treating dementia excellent in dementia treatment effect utilizing the dementia treatment mechanism.

In addition, another object of the present invention is lincomycin (azaserine) or azaserine (lincomycin) having the effect of inhibiting the synthesis of toxic beta-amyloid (Aβ) or It is to provide a composition for preventing or treating dementia containing belladonna extract (belladonna) as an active ingredient.

However, the technical problem to be achieved by the present invention is not limited to the above-mentioned problem, another task that is not mentioned will be clearly understood by those skilled in the art from the following description.

In order to solve the above technical problem, the present invention provides a composition for preventing or treating dementia containing lincomycin as an active ingredient, characterized by inhibiting beta-amyloid (Aβ) synthesis.

The present invention also provides a composition for preventing or treating dementia, which contains azaserrine as an active ingredient, characterized by inhibiting beta-amyloid (Aβ) synthesis.

In another aspect, the present invention provides a composition for preventing or treating dementia, containing a belladonna extract (belladonna) as an active ingredient, characterized by inhibiting beta-amyloid (Aβ) synthesis.

In the present invention, the main component of the senile plaque characteristic of the brain of the elderly is beta-amyloid protein (aka Aβ) which is a toxic substance. In other words, amyloid precursor protein (APP) gene is located on chromosome 21 and is expressed in most tissues, and there are mainly three polymolecular species. These are APP695, APP751, and APP770 depending on the number of amino acids. Protein.

Herein, the presenilin 1 (PS 1) gene located on chromosome 14 and the presenilin 2 (PS 2) gene located on chromosome 1 are secreted proteins that are used to pass the cell membranes (sensor receptors + signal peptides). It has a function as a transmembrane protein.

At this time, peptide synthesis of these genes is generated by the synthesis of ribosome 23SrRNA into pre-sanelin 1 (present as carboxyl terminal peptidyl tRNA) and presenilin 2 in the amanosanyl acid chamber. And these genes, after beta-secretase (β-secretase) action, by gamma-secretase action (γ-secretase) all over-producing beta-amyloid protein (Aβ) to be deposited on the cerebral blood vessel wall is deposited in the senile plaque ( senile plaque).

In the present invention, senile dementia refers to a condition in which normal metabolism of neurotransmitters and signal peptides is unable to bind due to changes in amyloid precursor protein to beta-amyloid protein (Aβ). In other words, it must maintain its function as a neurotransmitter and a signal peptide. It is excessively produced by the toxic beta-amyloid protein (Aβ) and combined with the neurotransmitter, which is an original function, and cannot pass through the membrane through ion channel permeation. Due to the imbalance of metabolism, senile dementia is lacking as a normal person, resulting in senile dementia.

Here, the signal peptide is A specific type of secretory protein synthesized from a precursor polypeptide, which is a cell membrane protein composed of 15 to 25 amino acids in amino acid sequence that is signaled when passing through a membrane included on the N-terminal side and having a basic amino acid near the N-terminal. Other mainly hydrophobic amino acids. In particular, no charged amino acids can be found in the center. This arrangement causes the precursor polypeptide to bind to the endoplasmic reticulum membrane during synthesis. Then, membrane-bound polysomes are formed, and the polypeptide chains pass through the membrane as they are synthesized. Simultaneously through the membrane, the signal peptide hydrolase in the membrane cleaves and removes the signal peptide. Signal hypothesis has been suggested to explain the mechanism by which secretory proteins of animal cells cross the cell membrane. Later, it was found that it is found in the precursors of membrane proteins and also in eukaryotic and prokaryotic cells, presumably involved in the localization of proteins.

Here, the peptide transferase (peptidyl transferase) As an enzyme catalyzing the formation of peptide bonds in a polypeptide chain reaction. Inherent in major and minor units of ribosomes. Peptide bonds are formed by the transfer of the carboxyl terminus of the peptide chain (present as a peptidyl tRNA) on the extension of the ribosome P site to the amino group of the aminoacyl tRNA newly entering the ribosome A site. Bacteria exist within 50S subunits and are known to be involved in the activity of L6, L11, L16 of ribosomal proteins, but the main body of catalytic activity is reported to be ribozyme activity represented by 23SrRNA.

Here, the peptidyl transferase catalyzes the reaction of hydrolysis of the ester bond between the peptide chain of the peptidyl tRNA and the tRNA present in the ribosome P region, which is also involved in the termination of protein biosynthesis, and binds to the signal peptide to produce toxic beta-amyloid protein Try to produce Aβ). At this time, bacterial peptidyl transferase activity was injected with chloramphenicol, lincomycin, carbomycin, etc., and eukaryotic cells were inhibited by cycloheximide, that is, 23SrRNA could not bind to signal peptide and thus toxic beta-amyloid. It prevents it from becoming a protein (Aβ) and combines it with a neurotransmitter to ensure normal and balanced metabolism through the membrane.

In the present invention, lincomycin (C ₁₈ H ₃₄ N ₂ O ₆ S) applied to the treatment of dementia is an inhibitor, its mechanism of action is the amino group of aminoacyltRNA at the carboxyl terminus by ribozyme activity represented by gene 23SrRNA. It can be effective in treating or improving dementia by inhibiting the process of forming a peptide bond itself by transferring to.

At this time, the lincomycin is an antibiotic produced by Strep-tomyces lincolnensis, the mechanism of action is the inhibition of protein synthesis, binds to the 50S subunit of bacterial ribosomes, inhibits the peptide transfer reaction, and has a stronger antimicrobial activity against anaerobic bacteria. Have

In addition, in the present invention, the azaserrine composition may be effective in treating or improving dementia by inhibiting the beta-amyloid protein (Aβ) synthesis by inhibiting the activity of γ-glutamyltranspeptidase. .

Structural Formula 1 Azaserine

In the present invention, the gene 23SrRNA cleaves the signal peptide by the signal peptide hydrolase on the membrane at the same time as it passes through the membrane, simultaneously ester-links the signal peptide and becomes a toxic beta-amyloid protein (Aβ) by the action of γ-secretas. . At this time, an important role in the detox metabolism is glutathione, and γ-glutamyltranspeptidase (γ-GTPase), which acts on gamma-secretase, is gamma-glutamyl in glutathione. It is an enzyme that catalyzes the reaction of the ( γ- glutamyl) group to bind amino acids. It can be inhibited by azaserrine and prevented from becoming toxic beta-amyloid protein (Aβ).

In the present invention, Belladonna extract is an ester compound of Tropaic acid and Tropin contained in Veradonna, a plant belonging to the branch family, and binds to the anhydrous carline acetylcholine receptor to inhibit the muscarinic action of acetylcholine.

At this time, acetylcholine receptor is a type of glycoprotein that acts as a nasal passage to receive acetylcholine, a neurotransmitter. It exists in the form of burying in the synaptic membrane and contains ion channels. When acetylcholine is combined, nerve cell is changed by changing the ion permeability of membrane. Acetylcholine is caused by binding to the muscarinic acetylcholine receptor by delivering the excitability of to the next cell, and is blocked by the receptor inhibitor atropine. Acetylcholine is a carrier of parasympathetic nerve endings, so atropine acts on many parasympathetic organs and tissues.

The composition of the present invention may be prepared as a pharmaceutical composition and a food (health functional food) composition.

When the composition of the present invention is prepared as a pharmaceutical composition, the pharmaceutical composition of the present invention includes a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers included in the pharmaceutical composition of the present invention are those commonly used in the preparation, lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, alginate, gelatin, silicic acid Calcium, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oils, and the like. It is not. In addition to the above components, the pharmaceutical composition of the present invention may further include a lubricant, a humectant, a sweetener, a flavoring agent, an emulsifier, a suspending agent, a preservative, and the like. Suitable pharmaceutically acceptable carriers and formulations are described in detail in Remington's Pharmaceutical Sciences (19th ed., 1995).

The pharmaceutical compositions of the present invention may be applied orally or parenterally, and suitable dosages of the pharmaceutical compositions of the present invention may be formulated, methods of administration, age, weight, sex, morbidity, food, time of administration, administration of the patient. Various prescriptions can be made by factors such as pathway, excretion rate and response sensitivity.

The pharmaceutical compositions of the present invention may be prepared in unit dosage form by formulating with a pharmaceutically acceptable carrier and / or excipient, according to methods which can be easily carried out by those skilled in the art. Or by incorporating into a multi-dose container. The formulations may be in the form of solutions, suspensions, syrups or emulsions in oils or aqueous media, or may be in the form of extracts, powders, powders, granules, tablets or capsules, and may further comprise dispersants or stabilizers.

When the composition of the present invention is made of a food composition or a nutraceutical composition, it includes ingredients that are commonly added during food preparation, and include, for example, proteins, carbohydrates, fats, nutrients, seasonings and flavoring agents. . Examples of the above carbohydrates include monosaccharides such as glucose, fructose and the like; Disaccharides such as maltose, sucrose, oligosaccharides and the like; And sugars such as conventional sugars such as polysaccharides such as dextrin, cyclodextrin and the like and xylitol, sorbitol, erythritol. As flavoring agents, natural flavoring agents (tauumatin, stevia extract, for example rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.) can be used.

 For example, when the food composition of the present invention is prepared with a drink, citric acid, liquid fructose, sugar, glucose, acetic acid, malic acid, fruit juice, and the like may be further included.

The composition according to the present invention inhibits the synthesis of beta-amyloid protein (Aβ), which is a causative agent of dementia, facilitates neurotransmission and improves motor performance, and prevents, improves, or improves dementia, Alzheimer's disease, or vascular dementia. It can be usefully used for treatment.

Hereinafter, the present invention will be described in more detail with reference to the following examples. These examples are only for illustrating the present invention in more detail, it will be apparent to those skilled in the art that the scope of the present invention is not limited by these examples in accordance with the gist of the present invention. .

Experimental Example 1. Activity of lincomycin for the treatment of dementia

(1) Mechanism of action of dementia treatment

The presenilin (PS 1) gene on the chromosome 14 and the PS 2 gene on the chromosome 1 are synthesized with the amino acid tRNA serine amino acid, which is waiting around the synaptic membrane as a signal peptide, and then binds to a neurotransmitter. It functions to pass through biological membranes (membrane ion channel permeability tool). Presenilin / signal peptides are homologues in which membrane-bound polysomes are formed, and the polypeptide chains pass through the membrane as they are synthesized.

As the secretory protein of the cell passes through the cell membrane, the signal peptide hydrolase on the membrane cleaves and removes the signal peptide with presenilin 1 (PS1) and presenilin 2 (PS2). In this way, metabolic metabolism is required, resulting in pathological polypeptide binding to 23SrRNA (present as a carboxyl terminal peptidyl tRNA) in ribosomes.

That is, signal transduction peptides are combined with pathological genes to bind to neurotransmitters and thus do not have a membrane-permeable function, and are toxic by beta-secretase and β-secretase. It becomes a substance called toxic beta-amyloid (Aβ) and is deposited on the cerebral blood vessel walls to become senile plaques.

Amyloid precursor protein (APP) is a type I membrane protein. When it is cleaved with beta-secretase and gamma-secretase, it produces 38-43 amino acid residues of beta-amyloid (Aβ). Secrete extracellularly. The production of normal amyloid precursor protein (APP) into toxic beta-amyloid (Aβ) is due to the action of beta-secretase and gamma-secretase, presenilin 1 (PS1). ) And presenilin 2 (PS2) are substrates such as gamma-secretase.

Pathological mutations in these truncated genes result in amyloid precursor protein (APP), presenilin 1 (PS1), and presenilin 2 (PS2) as beta-secretase and gamma-secretase (γ-). Under the action of secretase, it becomes toxic beta-amyloidro (Aβ) and beta-amyloidro (Aβ) is deposited on the blood vessel wall. It is combined with pathological genes and mainly signaling peptides (APP, PS1, PS2) to become toxic beta-amyloid (Aβ), which is deposited on the cerebrovascular wall to become senile plaques.

Experimental Example 2 Activity of Azaserine for Dementia Treatment

(1) Mechanism of action of dementia treatment

As the 23SrRNA gene passes through the membrane, it cleaves the signal peptide by the signal peptide hydrolase on the membrane, simultaneously ester-links the signal peptide, and acts as a toxic beta-amyloid by the action of gamma-secretase. It becomes

This γ- glutamyl trans-peptidase (γ-glutamyltranspeptidase, γ-GTPase ) the gamma in the glutathione as glutathione (glutathione) which play an important role in the detoxification metabolism - the reaction were removed to an glutamyl (γ -glutamyl) in combination with amino acids Is the catalytic enzyme γ- GTPase. It is inhibited by azaserine, preventing it from becoming toxic beta-amyloid (Aβ). Thus, by combining with neurotransmitters, which are inherently functional as signal peptides, they perform a job as a membrane ion permeation tool, thereby promoting balanced metabolism to the normal person.

Example 1 Belladonna Extract for Treatment of Dementia

(1) Mechanism of action of dementia treatment

Acetylcholine receptor is a glycoprotein that acts as a nasal passage to receive acetylcholine, a neurotransmitter. It exists in the form of burying in the synaptic membrane and contains ion channels. When acetylcholine is combined, it changes the ion permeability of the membrane to excite nerve cells. Is delivered to the next cell, whereby acetylcholine binds to the muscarinic acetylcholine receptor and is blocked by the receptor inhibitor atropine.

It is an ester compound of Tropaic acid and Tropin in Belladonna, a plant belonging to the branch family. Acetylcholine is a carrier of parasympathetic nerve endings, so atropine acts on many parasympathetic organs and tissues.

(2) How to take

Belladonna Extract In the form of root powder, the maximum daily dose is 300 mg and the average single dose of belladonna extract is 10 mg. At this time, the maximum daily dose is 50 mg, and the maximum daily dose is 150 mg.

Having described the specific part of the present invention in detail, it is apparent to those skilled in the art that the specific technology is merely a preferred embodiment, and the scope of the present invention is not limited thereto. Thus, the substantial scope of the present invention will be defined by the appended claims and equivalents thereof.

Claims (3)

A composition for preventing or treating dementia comprising lincomycin as an active ingredient, characterized by inhibiting beta-amyloid (Aβ) synthesis.
A composition for preventing or treating dementia comprising azaserrine as an active ingredient, characterized by inhibiting beta-amyloid (Aβ) synthesis.
A composition for preventing or treating dementia, comprising a belladonna extract as an active ingredient, characterized by inhibiting beta-amyloid (Aβ) synthesis.