KR20200144538A - A pharmaceutical composition for preventing or treating neurological diseases comprising zinc and NAC - Google Patents

Abstract

The present application relates to a composition for promoting neurogenesis, a composition for promoting proliferation and differentiation of neural progenitor cells or neural stem cells, a pharmaceutical composition for preventing or treating nervous system diseases, and a health functional food composition for preventing or alleviating nervous system diseases, all of which contain zinc and N-acetyl-L-cysteine (NAC) as active components.

Description

A pharmaceutical composition for preventing or treating neurological diseases comprising zinc and NAC}

The present application, comprising zinc and NAC (N-acetyl-L-cysteine) as an active ingredient, a composition for promoting neurogenesis; A composition for promoting proliferation and differentiation of neural progenitor cells or neural stem cells; A pharmaceutical composition for preventing or treating nervous system diseases; And it relates to a health functional food composition for preventing or improving nervous system diseases.

Neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease mainly affect the elderly, and the number of patients is increasing exponentially with the aging of society. In addition, early-onset neurodegenerative diseases are not uncommonly reported in the younger population. Accordingly, a lot of attention is focused on the development of various treatments for stopping the progression of the disease or recovering damaged brain tissue.

The definite causes of these neurodegenerative diseases have not been identified yet, but according to the findings to date, it is caused by the destruction of nerve cells present in a specific part of the brain (Hippocampus; hippocampus or Substantia nigra; black matter, etc.). It is known that the network between nerve cells is broken, resulting in various symptoms of neurodegenerative diseases.

To treat this, research is being conducted in various fields. Until now, drugs associated with symptom relief (Memantine: NMDA receptor antagonist, L-DOPA: dopamine mimic drug, etc.) are mostly, and other drug treatments also have short-term effects. However, it is difficult to apply it to treatment because side effects are found only or by continuous administration, and it is difficult to expect a therapeutic effect beyond temporarily alleviating symptoms. Therefore, there is an absolutely need for a treatment that can treat the cause of neurodegenerative diseases.

In the adult brain, there are neural stem cells (NSC) and neural progenitor cells (NPCs) that have the ability to differentiate into nervous system cells. In particular, neural stem cells exist in the subventricular zone of the lateral ventricle and the dentate gyrus of the hippocampus, and through the differentiation and proliferation of neural stem cells in this area, nerves throughout life It is known that neurogenesis takes place (Cell 132:645-660).

In neurodegenerative diseases, brain neurons are damaged and killed, so stimulation of NSC and NPC to replace damaged and dead neurons with normal functioning neurons can be a fundamental treatment for neurodegenerative diseases. . These approaches include separating NSCs and NPCs from the patient's body and stimulating them in vitro to differentiate into neurons and transplanting them into the patient (stem cell therapy). However, it is difficult to obtain NSCs and NPCs in vivo and transplant them into patients, and because NSCs or NPCs transplanted into the brain lose their function in a short time in the brain, they must be transplanted frequently. As an alternative, a method of regenerating nerve cells by inducing differentiation by stimulating NSC or NPC existing in the patient's brain by administering a drug to the patient instead of transplanting neural stem cells to the patient has been recently proposed (J. Med. Chem. 58:2863-2894).

In addition, many recent studies have shown that zinc plays an important role in the differentiation and development of cranial nerve cells, and through animal experiments, the lack of zinc intake is closely related to the function of memory and cognitive ability. And it has been reported to inhibit regeneration.

Up to now, it has not been reported that NAC (N-acetyl-L-cysteine) and Zn-NAC, a combination of NAC and zinc, can induce neurogenesis by increasing the amount of zinc in the hippocampus of the brain. Therefore, the composition comprising zinc and NAC of the present application not only promotes neurogenesis, but also has the potential to be used for treatment or prevention of various brain diseases related thereto.

The present application, comprising zinc and NAC (N-acetyl-L-cysteine) as an active ingredient, a composition for promoting neurogenesis; A composition for promoting proliferation and differentiation of neural progenitor cells or neural stem cells; A pharmaceutical composition for preventing or treating nervous system diseases; And it relates to a health functional food composition for preventing or improving nervous system diseases.

However, the problem to be solved by the present application is not limited to the problem mentioned above, and other problems that are not mentioned will be clearly understood by those skilled in the art from the following description.

The first aspect of the present application provides a composition for promoting neurogenesis, comprising zinc and NAC (N-acetyl-L-cysteine) as active ingredients.

The second aspect of the present application provides a composition for promoting proliferation and differentiation of neural progenitor cells or neural stem cells, comprising zinc and NAC (N-acetyl-L-cysteine) as active ingredients.

The third aspect of the present application provides a pharmaceutical composition for preventing or treating neurological diseases, including zinc and NAC (N-acetyl-L-cysteine) as active ingredients.

The fourth aspect of the present application provides a health functional food composition for preventing or improving nervous system diseases, comprising zinc and NAC (N-acetyl-L-cysteine) as active ingredients.

According to the embodiments of the present application, a composition comprising zinc and NAC (N-acetyl-L-cysteine) as an active ingredient improves the concentration of zinc in the hippocampus of the brain, and based on this, proliferation and differentiation of neural progenitor cells or neural stem cells As it has a promoting effect, the composition can be used for promoting neurogenesis, for promoting proliferation and differentiation of neural precursor cells or neural stem cells, and for treating neurological diseases.

1 is a diagram showing the expression of neural progenitor cells and neuroblastic markers in wild-type mice and ZnT3 KO mice from which the ZnT3 gene has been removed. A is a diagram showing the administration plan of BrdU, known as a marker of proliferative cells, B to D are diagrams showing the level of BrdU expression in wild-type mice and ZnT3 KO mice, and E to G are Ki67 expression levels in wild-type mice and ZnT3 KO mice. And H to J are diagrams showing the DCX expression level of wild-type mice and ZnT3 KO mice.
FIG. 2 is a diagram showing the expression of neurons and astrocyte markers in wild-type mice and ZnT3 KO mice from which the ZnT3 gene has been removed. A is a diagram showing the administration plan of BrdU known as a marker of proliferative cells, B to D are diagrams showing the level of BrdU expression in wild-type mice and ZnT3 KO mice, and E to L are the expression levels of BrdU, NeuN and GFAP in wild-type mice. Is a diagram showing the expression levels of BrdU, NeuN and GFAP in ZnT3 KO mice, and U and V are diagrams comparing the number of BrdU+ NeuN+ cells and BrdU+ GFAP+ cells of wild-type mice and ZnT3 KO mice. to be.
3 is a diagram showing the expression of neuronal progenitor cells and neuroblast markers in mice administered with Zn-NAC, ZnCl2 or vehicle. A to E are diagrams showing the expression level of BrdU in mice administered with Zn-NAC, ZnCl2 or vehicle, F to J are diagrams showing the expression level of Ki67 in mice administered with Zn-NAC, ZnCl2, or vehicle, K to S is a diagram showing the level of DCX expression in mice administered with Zn-NAC, ZnCl2 or vehicle.
4 is a diagram showing the expression of neural progenitor cells and neuroblastic markers in wild-type mice and ZnT3 KO mice administered with Zn-NAC. A to C are diagrams showing the level of BrdU expression in Zn-NAC-administered wild-type mice and ZnT3 KO mice, and D to F are diagrams showing Ki67 expression levels in Zn-NAC-administered wild-type mice and ZnT3 KO mice G to I are diagrams showing the DCX expression levels of wild-type mice and ZnT3 KO mice administered with Zn-NAC.
5 is a diagram showing whether or not ERK/CREB cell signaling is activated in wild-type mice and ZnT3 KO mice administered with Zn-NAC. A to E are diagrams showing the phosphorylated ERK levels of Zn-NAC or vehicle-administered wild-type mice and ZnT3 KO mice, and F to Y are phosphorylated CREB of Zn-NAC or vehicle-administered wild-type mice and ZnT3 KO mice. It is a diagram showing the level.

In the entire specification of the present application, when a certain part “includes” a certain constituent element, it means that other constituent elements may be further included rather than excluding other constituent elements unless otherwise indicated. The terms "about", "substantially", etc. of the degree used throughout the present specification are used at or close to the numerical value when manufacturing and material tolerances specific to the stated meaning are presented. To assist, accurate or absolute figures are used to prevent unfair use of the stated disclosure by unscrupulous infringers.

Throughout the present specification, the term “combination(s) thereof” included in the expression of the Makushi format refers to one or more mixtures or combinations selected from the group consisting of components described in the expression of the Makushi format, It means to include at least one selected from the group consisting of the above components.

Throughout this specification, the description of “A and/or B” means “A or B, or A and B”.

Hereinafter, embodiments and examples of the present application will be described in detail with reference to the accompanying drawings. However, the present application may not be limited to these embodiments and examples and drawings.

The first aspect of the present application provides a composition for promoting neurogenesis, comprising zinc and NAC (N-acetyl-L-cysteine) as active ingredients.

As used throughout this specification, the term "Neurogenesis" generally refers to the production of new neurons. In the past, neurogenesis only occurs during embryonic and early postnatal periods, and has been thought to have no important role in the adult brain, but recently, neurogenesis can also occur in selected areas of the adult mammalian brain. In addition, it is being studied that other areas can be stimulated in response to damage.

With regard to neurogenesis, during the development of the central and peripheral nervous systems, neural stem cells proliferate, divide into neural precursor cells, and finally differentiate into cell types that make up the adult brain. Cells derived from the neural tube give rise to neurons and glial cells of the central nervous system, while cells derived from neural crest give rise to cells of the peripheral nervous system.

The term "Neuroregeneration" used throughout the specification of the present application means that a nerve is newly generated again, and in the present specification, nerve regeneration and neurogenesis may be used interchangeably.

It was confirmed that the composition for promoting neurogenesis according to an embodiment of the present application increases the concentration of zinc in the hippocampus of the brain, thereby promoting the proliferation of neural precursor cells and differentiation into nerve cells. And it can be seen that the composition comprising NAC can promote neurogenesis.

The term "zinc" as used throughout the specification of the present application is an element of atomic number 30, reacts with acids, alkalis, and metals, and generally represents an oxidation state of +2. In the human body, zinc is one of the representative minerals that make up cells and deal with physiological functions. Specifically, growth and brain development, skin protection, maintenance of proper immune system activity, digestion, recovery, taste, smell and many other metabolisms Is absolutely necessary. In addition, it is known that when zinc is deficient, symptoms such as deterioration of taste and smell, skin problems, lethargy, and decrease in fertility are known.

The term "NAC (N-acetyl-L-cysteine, N-acetyl-L-cysteine)" used throughout the present specification is one of the derivatives of cysteine, an amino acid, in which an acetyl group is attached to the nitrogen atom of cysteine. The NAC is generally used to improve sputum excretion difficulties in respiratory diseases such as bronchitis or asthma, and is known to be additionally used for detoxification of acetaminophen.

In one embodiment of the present application, zinc and NAC contained in the composition for promoting neurogenesis may be connected, and may be combined to form a conjugate. The zinc-NAC conjugate may be that zinc is directly connected to NAC, and zinc and NAC may be connected by chelate, but is not limited thereto. In addition, the zinc-NAC conjugate may be indirectly linked through a linker. The linker is not particularly limited as long as it exhibits an effect of maintaining or improving the activity of the conjugate.

In one embodiment of the present application, the composition for promoting neurogenesis may include zinc and NAC in a ratio of 1:2, but may be specifically expressed by the following formula, but is not limited thereto.

[Formula 1]

Since the cysteine derivative NAC has a -SH group, and the divalent cation metal can bind to the -SH group in a ratio of metal:NAC of 1:2, zinc, which is a divalent cation, can be present by bonding with NAC in a ratio of 1:2. have.

In one embodiment of the present application, the composition for promoting neurogenesis may be characterized by increasing the amount of zinc in the hippocampus (Hippocampus).

In one embodiment of the present application, the composition for promoting neurogenesis may be to promote neurogenesis through an extracellular signal-regulated kinase (ERK)/cAMP response element-binding protein (CREB) pathway.

The term "ERK/CREB pathway" as used throughout the specification is one of intracellular signaling pathways and is known to regulate mechanisms related to cell proliferation.

In one embodiment of the present application, the composition for promoting neurogenesis was confirmed to phosphorylate ERK and CREB proteins of the ERK/CREB pathway, thereby activating them, and the composition activates the ERK/CREB pathway in the hippocampus of the brain. It may be to promote neurogenesis based on this.

The second aspect of the present application provides a composition for promoting proliferation and differentiation of neural progenitor cells or neural stem cells, comprising zinc and NAC (N-acetyl-L-cysteine) as active ingredients. The content overlapping with the first aspect also applies to the composition for promoting proliferation and differentiation of neural progenitor cells or neural stem cells of the second aspect.

In one embodiment of the present application, the composition for promoting proliferation and differentiation of neural progenitor cells or neural stem cells may include a substance linked to zinc and NAC, and may be combined with each other to form a conjugate. The zinc-NAC conjugate may be that zinc is directly connected to NAC, and zinc and NAC may be connected by chelate, but is not limited thereto. In addition, the zinc-NAC conjugate may be indirectly linked through a linker. The linker is not particularly limited as long as it exhibits an effect of maintaining or improving the activity of the conjugate.

In one embodiment of the present application, the composition for differentiation of neural progenitor cells may include zinc and NAC in a ratio of 1:2, but is not limited thereto. Specifically, since the cysteine derivative NAC has a -SH group, and the divalent cation metal can bind to the -SH group in a ratio of metal:NAC of 1:2, zinc, which is a divalent cation, binds NAC in a ratio of 1:2. Can exist.

The term "neural stem cell (NSC)" used throughout the specification of the present application is a cell capable of self-renewal and has the ability to differentiate into a neural system cell, and the neural stem cell is a neural cell (neuron ), astrocytes, and oligodendrocytes.

The term "neural progenitor cell or neural precursor cell" used throughout the specification refers to a progenitor cell capable of producing various cells of the nervous system, that is, a neural precursor cell with self-replicating ability is a neural line. Divides by originating from the stage cell. Therefore, in a broad sense, it is sometimes used as a synonym for neural stem cells.

Throughout the specification of the present application, "neural stem cells" or "neural progenitor cells" may be used interchangeably, and in some cases, cells derived from "neural stem cells" may be referred to as "neural progenitor cells".

Neural stem cells or neural precursor cells that can be used herein are embryonic stem cells isolated from early embryos of mammals, embryonic germ cells isolated from primitive germ cells of the embryonic period, and adult cells. It may be derived from a multipotent adult progenitor cell, and the pluripotent adult stem cell may be any multipotent adult stem cell derived from adult tissues such as umbilical cord blood, bone marrow, fat, and brain tissue, or blood. , But is not limited thereto.

The term "differentiation" as used throughout the specification refers to the development of a cell into a specific cell, and specifically, a phenomenon in which a structure or function is specialized during growth by dividing and proliferating. It means that the form or function changes in order to perform the tasks given to each of these neural stem cells "differentiation" preceded by asymmetric division in which the parent cell divides into two cells with different characteristics. Some of the cells remain as stem cells that are the same as the parent cells, and some are differentiated into specific cells. In the sense that the differentiation of neural stem cells is accompanied by this asymmetric division process, “differentiation of neural stem cells” includes the meaning of “proliferation”. can do.

The term "proliferation" as used throughout the present specification refers to a phenomenon in which cells divide and proliferate, and specifically, a phenomenon in which cells of the same type increase due to division of cells, that is, when the number of cells of the same type is reproduced. It is called.

In the composition for promoting proliferation and differentiation of neural progenitor cells or neural stem cells according to an embodiment of the present application, the neural stem cells or neural progenitor cells may be isolated or intrinsic neural stem cells or neural progenitor cells in the body, but are limited thereto. It does not become.

A third aspect of the present application provides a pharmaceutical composition for preventing or treating neurological diseases, comprising zinc and NAC (N-acetyl-L-cysteine) as active ingredients. The content overlapping with the first and second aspects also applies to the pharmaceutical composition of the third aspect.

In one embodiment of the present application, the pharmaceutical composition for preventing or treating neurological diseases may include a substance linked to zinc and NAC, and may be formed by combining with each other to form a conjugate. The zinc-NAC conjugate may be that zinc is directly connected to NAC, and zinc and NAC may be connected by chelate, but is not limited thereto. In addition, the zinc-NAC conjugate may be indirectly linked through a linker. The linker is not particularly limited as long as it exhibits an effect of maintaining or improving the activity of the conjugate.

In one embodiment of the present application, the pharmaceutical composition for preventing or treating neurological diseases may be one containing zinc and NAC in a ratio of 1:2, but is not limited thereto. Specifically, since the cysteine derivative NAC has a -SH group, and the divalent cation metal can bind to the -SH group in a ratio of metal:NAC of 1:2, zinc, which is a divalent cation, binds NAC in a ratio of 1:2. Can exist.

The term "nervous system disease" as used throughout the present specification is a disease caused by problems with the nervous system, that is, brain, spinal cord, nerve, etc., and some psychosis may also be included therein.

According to the exemplary embodiment of the present disclosure, the nervous system disease may be a degenerative brain disease, but is not limited thereto.

The term "degenerative brain disease" as used throughout this specification refers to a disease occurring in the brain among degenerative diseases that occur with age, and is a specific brain in the brain and spinal cord as a cause unknown to date. Due to the death of the cranial nerve cells, which are the most important for the transmission of information in the cranial nerve system, the formation of synapses or functional problems that transmit information between the cranial nerve cells and the cranial nerve cells, and the ideal increase or decrease in electrical activity of the cranial nerve. It is known to be caused. Neurons in the brain and spinal cord perform a wide variety of functions depending on their location.Therefore, depending on which part of the nerve cells are damaged and lose their function first, and how such a dysfunction progresses, a wide variety of clinical aspects can be seen. .

The composition according to the embodiment of the present application induces and promotes the proliferation and differentiation of neural stem cells or neural progenitor cells, so it is suitable for cell therapy for the neurological diseases caused by lack of cell number, cell damage, or cell death of nerve cells. It can be useful.

In one embodiment of the present application, the nervous system disease is dementia, Parkinson's disease, Alzheimer's disease, Peak's disease, Huntington's disease, multiple sclerosis, epilepsy, stroke, stroke, ischemic brain disease, memory loss, traumatic central nervous system disease, spinal cord injury disease , Peripheral nerve injury, amyotrophic axonal sclerosis, peripheral nerve disease, behavioral disorder, developmental disorder, mental retardation, Down syndrome or schizophrenia may be selected from the group consisting of, but is not limited thereto.

As used throughout the present specification, the term "prevention" refers to any action that suppresses or delays the occurrence of neurological diseases by administration of the composition.

As used throughout the present specification, the term "treatment" refers to any action in which symptoms caused by neurological diseases are improved or beneficially changed by administration of the composition.

In one embodiment of the present application, the pharmaceutical composition for preventing or treating neurological diseases may include zinc and N-acetyl-L-cysteine (NAC) or a pharmaceutically acceptable salt thereof.

The term "pharmaceutically acceptable salt" as used throughout the present specification means a salt that is non-toxic in a dosage, and includes commonly used salts such as inorganic acids, organic acids, or non-toxic salts.

Examples of the inorganic acid herein include hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid, but are not limited thereto, and examples of the organic acid include acetic acid, lactic acid, citric acid, malic acid, succinic acid, fumaric acid, maleic acid. Acid, tartaric acid, benzoic acid, phthalic acid, cluconic acid, saccharic acid, methane sulphonic acid, ethane disulphonic acid, aliphatic mono and dicarboxylate, phenyl-substituted eggs Canoate (phenylsubstituted alkanoate), hydroxy alkanoate (hydroxy alkanoate) and alkanedioate (alkanedioate), aromatic acid (aromatic acid), aliphatic and aromatic sulfonic acid (aliphatic and aromatic sulfonic acid), but is not limited thereto. .

The non-toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, iodide, fluoride. , Acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, Fumarate, maleate, butine-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitro benzoate, hydroxybenzoate, methoxybenzoate, Phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, beta-hydroxybutyrate, glycolate, maleate , Tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, or mandelate, but is not limited thereto.

In one embodiment of the present application, the pharmaceutical composition for preventing or treating neurological diseases may include a pharmaceutically acceptable carrier.

The term "pharmaceutically acceptable carrier" as used throughout the present specification may mean a carrier or diluent that does not stimulate an organism and does not inhibit the biological activity and properties of the compound to be injected. The type of the carrier usable herein is not particularly limited, and any carrier commonly used in the art and pharmaceutically acceptable may be used. Non-limiting examples of the carrier include saline, sterile water, Ringer's solution, buffered saline, albumin injection solution, dextrose solution, maltodextrin solution, glycerol, ethanol, and the like. These may be used alone or in combination of two or more.

In one embodiment of the present application, the pharmaceutical composition for preventing or treating neurological diseases does not increase the efficacy, but may further include an ingredient that is commonly used in pharmaceutical compositions to improve smell, taste, vision, etc. have. In addition, the pharmaceutical composition of the present application may additionally include a pharmaceutically acceptable additive. Pharmaceutically acceptable additives include, for example, starch, gelatinized starch, microcrystalline cellulose, lactose, povidone, colloidal silicon dioxide, calcium hydrogen phosphate, lactose, mannitol, syrup, gum arabic, pregelatinized starch, corn starch, powdered cellulose, Hydroxypropyl cellulose, Opadry, sodium starch glycolate, lead carnauba, synthetic aluminum silicate, stearic acid, magnesium stearate, aluminum stearate, calcium stearate, sucrose, dextrose, sorbitol and talc, and the like, but are not limited thereto.

In one embodiment of the present application, the pharmaceutical composition including a pharmaceutically acceptable carrier may be in various oral or parenteral dosage forms. In the case of formulation, it is prepared using diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, and surfactants that are usually used.

Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid preparations contain at least one excipient, for example, starch, calcium carbonate, sucrose, lactose, gelatin, etc. to the compound. It can be prepared by mixing. Further, in addition to simple excipients, lubricants such as magnesium stearate and talc may also be used. Liquid preparations for oral use include suspensions, liquid solutions, emulsions, syrups, and other excipients, such as wetting agents, sweeteners, fragrances, and preservatives, in addition to water and liquid paraffin, which are commonly used simple diluents. have.

Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized formulations and suppositories. As the non-aqueous solvent and suspending agent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used. As a base for suppositories, Witepsol, Macrogol, Tween 61, cacao butter, laurin paper, glycerogelatin, and the like can be used.

In one embodiment of the present application, the pharmaceutical composition for preventing or treating neurological diseases may be administered in a pharmaceutically effective amount.

As used throughout this specification, the term "pharmaceutically effective amount" refers to an amount sufficient to treat a disease at a reasonable benefit/risk ratio applicable to medical treatment, and the effective dose level refers to the type and severity of the subject, age, sex, It can be determined according to the type of virus infected, the activity of the drug, the sensitivity to the drug, the time of administration, the route of administration and the rate of excretion, the duration of treatment, factors including concurrent drugs and other factors well known in the medical field. For example, the composition or a pharmaceutically acceptable salt thereof may be administered at 0.0001 to 1000 mg/kg per day, preferably 0.001 to 100 mg/kg.

The administration means introducing the composition of the present invention to a patient by any suitable method, and the administration route of the composition may be administered through any general route as long as it can reach the target tissue. Specifically, it can be administered orally or parenterally according to the desired method, and when parenterally administered, select an injection method for external use or intraperitoneal injection, rectal injection, subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection. However, it is not limited thereto.

The pharmaceutical composition for preventing or treating neurological diseases of the present application may be administered daily or intermittently, and the number of administrations per day may be administered once or divided into 2 to 3 times. When the two active ingredients are a single drug, the number of administrations may be the same or different. In addition, the pharmaceutical composition of the present application may be used alone or in combination with other drug treatments for the prevention or treatment of neurological diseases. It is important to administer an amount capable of obtaining the maximum effect in a minimum amount without side effects in consideration of all the above factors, and can be easily determined by a person skilled in the art.

The individual refers to all animals including humans, monkeys, cows, horses, sheep, pigs, chickens, turkeys, quails, cats, dogs, mice, mice, rabbits, or guinea pigs who have or may develop nervous system diseases. do. By administering the pharmaceutical composition of the present application to an individual, the type of individual is included without limitation as long as the disease can be effectively prevented or treated.

In one embodiment of the present application, it provides a method for preventing or treating neurological disorders, comprising administering the composition for preventing or treating neurological disorders to an individual in need thereof.

A fourth aspect of the present application provides a health functional food composition for preventing or improving neurological diseases, including zinc and NAC (N-acetyl-L-cysteine) as active ingredients. The content overlapping with the first to third aspects also applies to the health functional food composition of the fourth aspect.

The term "functional food" used throughout the specification of the present application is the same term as food for special health use (FoSHU), and is processed so that the bioregulatory function effectively appears in addition to nutrition supply. It refers to food with high medical effect and medical effect. Here, the term "function (sex)" refers to obtaining a useful effect for health purposes such as controlling nutrients or physiological effects on the structure and function of the human body. The health functional food composition of the present application can be prepared by a method commonly used in the art, and during the production, it may be prepared by adding raw materials and ingredients commonly added in the art. In addition, the formulation of the food may be prepared without limitation as long as it is a formulation recognized as a food. The health functional food composition can be prepared in various forms, and unlike general drugs, it has the advantage of not having side effects that may occur when taking the drug for a long time by using food as a raw material, and is excellent in portability, and the food of the present invention Can be taken as an adjuvant to enhance the immune enhancing effect. Health food refers to foods that have an active health maintenance or promotion effect compared to general foods, and health supplement food refers to foods for health supplement purposes. In some cases, terms of health functional food, health food, and health supplement food may be used interchangeably.

There is no particular limitation on the type of food. Examples of foods to which the above substances can be added include drinks, meat, sausages, bread, biscuits, rice cakes, chocolates, candies, snacks, confectionery, pizza, ramen, other noodles, gum, dairy products including ice cream, various soups, There are beverages, alcoholic beverages and vitamin complexes, dairy products and dairy products, and all health functional foods in the usual sense are included.

According to the exemplary embodiment of the present disclosure, the health functional food composition may include additional ingredients that are commonly used in food compositions to improve smell, taste, vision, and the like. For example, vitamins A, C, D, E, B1, B2, B6, B12, niacin, biotin, folate, panthotenic acid, and the like may be included. In addition, minerals such as zinc (Zn), iron (Fe), calcium (Ca), chromium (Cr), magnesium (Mg), manganese (Mn), copper (Cu), and chromium (Cr) may be included. In addition, amino acids such as lysine, tryptophan, cysteine, and valine may be included, but are not limited thereto.

According to one embodiment of the present application, the health functional food composition includes preservatives (potassium sorbate, sodium benzoate, salicylic acid, sodium dehydroacetate, etc.), disinfectants (bleaching and highly bleaching, sodium hypochlorite, etc.), antioxidants (butylhydroxy Anisol (BHA), butylhydroxytoleuene (BHT), etc.), colorant (tar color, etc.), color development agent (sodium nitrite, sodium nitrite, etc.), bleach (sodium sulfite), seasoning (MSG sodium glutamate, etc.), sweetener (Dulsin, cyclamate, saccharin, sodium, etc.), fragrances (vanillin, lactones, etc.), expanding agents (alum, D-potassium hydrogen stannate, etc.), reinforcing agents, emulsifiers, thickeners (thickening agents), coating agents, gum base agents, foam Food additives such as inhibitors, solvents, and modifiers may be included, but are not limited thereto. The additive may be selected according to the type of food and used in an appropriate amount.

According to one embodiment of the present application, the health functional food composition for preventing or improving neurological diseases may be added as it is to food or used with other foods or food ingredients, and may be appropriately used according to a conventional method. The mixing amount of the active ingredient may be appropriately determined depending on the purpose of use (for prevention or improvement). In general, the amount of the composition in the health functional food may be added in an amount of 0.1 to 90 parts by weight of the total food weight. However, in the case of long-term intake for the purpose of maintaining health or for the purpose of health control, the amount may be less than the above range, and there is no problem in terms of safety, so the active ingredient may be used in an amount above the above range.

The health functional food composition according to an embodiment of the present application is not particularly limited to other ingredients other than containing the active substance as an essential ingredient in the indicated ratio, and as an additional ingredient, various flavoring agents or natural carbohydrates, etc. It may contain. Examples of the above-described natural carbohydrates include monosaccharides such as glucose, fructose, and the like; Disaccharides such as maltose, sucrose, and the like; And polysaccharides, for example, common sugars such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol. As flavoring agents other than those described above, natural flavoring agents (taumatin, stevia extract (e.g., rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used. The ratio of the natural carbohydrate is generally about 1 to 20 g, preferably about 5 to 12 g per 100 of the health functional food composition of the present application, but is not limited thereto.

The health functional food composition according to an embodiment of the present application includes various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic flavoring agents and natural flavoring agents, coloring agents and heavy ingredients (cheese, chocolate, etc.), pectic acid and its Salts, alginic acid and salts thereof, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonates used in carbonated beverages, and the like may be contained. In addition, the health functional food composition of the present application may contain flesh for the manufacture of natural fruit juice and fruit juice beverage and vegetable beverage.

These components may be used independently or in combination. The proportion of these additives is not so important, but is generally selected from 0.1 to about 20 parts by weight per 100 parts by weight of the health functional food composition of the present application.

In one embodiment of the present application, the health functional food composition for preventing or improving neurological diseases may include a substance connected to zinc and NAC, and may be formed by combining with each other to form a conjugate. The zinc-NAC conjugate may be that zinc is directly connected to NAC, and zinc and NAC may be connected by chelate, but is not limited thereto. In addition, the zinc-NAC conjugate may be indirectly linked through a linker. The linker is not particularly limited as long as it exhibits an effect of maintaining or improving the activity of the conjugate.

In one embodiment of the present application, the health functional food composition for preventing or improving neurological diseases may include zinc and NAC in a ratio of 1:2, but is not limited thereto. Specifically, since the cysteine derivative NAC has a -SH group, and the divalent cation metal can bind to the -SH group in a ratio of metal:NAC of 1:2, zinc, which is a divalent cation, binds NAC in a ratio of 1:2. Can exist.

In one embodiment of the present application, the nervous system disease may be a degenerative brain disease.

In one embodiment of the present application, the nervous system disease is dementia, Parkinson's disease, Alzheimer's disease, Peak's disease, Huntington's disease, multiple sclerosis, epilepsy, stroke, stroke, ischemic brain disease, memory loss, traumatic central nervous system disease, spinal cord injury disease , Peripheral nerve injury, amyotrophic axonal sclerosis, peripheral nerve disease, behavioral disorder, developmental disorder, mental retardation, Down syndrome or schizophrenia may be selected from the group consisting of, but is not limited thereto.

In one embodiment of the present application, the health functional food composition for preventing or improving neurological diseases may include a food acceptable salt.

In one embodiment of the present application, the health functional food composition for preventing or improving neurological diseases may be added to health functional foods such as foods and beverages for the purpose of preventing or improving neurological diseases.

Hereinafter, an embodiment of the present application will be described in detail. However, the present application may not be limited thereto.

[Example]

Example 1. Confirmation of association between zinc concentration in synaptic endoplasmic reticulum and neurogenesis

When the gene of Zinc transporter 3 (ZnT3), which is known to carry zinc in the synaptic endoplasmic reticulum of the hippocampus, was removed, the following experiment was performed to confirm whether neurogenesis in the hippocampus of the brain was suppressed.

Specifically, in order to observe changes in proliferation of neural progenitor cells in the hippocampus of the brain of wild-type mice and ZnT3 KO (knock out) mice from which the ZnT3 gene was removed, BrdU was injected twice a day for 4 days, On the fifth day, the brain tissue of the mouse was removed (Fig. 1A), and BrdU, known as a marker for proliferative cells, an antibody of Ki67, known as a marker for neuronal progenitor cells, and Doublecortin, used as a marker for neuroblast cells. DCX) was observed immunohistochemically using an antibody.

As a result of the experiment, it was observed that BrdU(+), Ki67(+), or DCX(+) cells of ZnT3 KO mice were significantly reduced compared to wild-type mice (FIGS. 1B to J).

In addition, in order to confirm the neuronal phenotype of wild-type mice and ZnT3 KO mice, BrdU was injected into each mouse twice a day for 4 days, and then brain tissue was removed at 6 weeks (Fig. 2A), as a marker of proliferative cells. Immunohistochemical observation was made using known BrdU, an antibody of NeuN known as a marker of neurons, and an antibody of GFAP (glial fibrillary acidic protein) known as a marker of astrocytes.

As a result of the experiment, it was confirmed that BrdU(+), NeuN(+) cells of ZnT3 KO mice were decreased compared to wild type, but BrdU(+) and GFAP(+) cells were increased than wild type. As a result, differentiation into neurons decreased. It can be seen that (Fig. 2E to V)

From the above experimental results, it can be seen that a decrease in the concentration of zinc in the synaptic endoplasmic reticulum by ZnT3 gene removal can suppress neurogenesis in the hippocampus of the brain.

Example 2. Confirmation of increase in neural progenitor cell proliferation and neuroblast production by Zn-NAC administration

In order to confirm whether the Zn-NAC developed herein can promote the proliferation of neural progenitor cells and generation of neuroblasts, the following experiments were performed.

Specifically, i) Zn-NAC (20 mg/kg), a novel active substance promoting neurogenesis containing both ZnCl ₂ and NAC, ii) ZnCl ₂ containing only zinc without CHP (20 mg/kg) and iii) Zinc A vehicle containing only NAC without NAC was administered intraperitoneally to the mice once a day for 2 weeks each, and BrdU (50 mg/kg) known as a marker of proliferating cells was injected into Zn-NAC, ZnCl ₂ or vehicle to identify proliferating cells. After 10 days, the mice were injected twice a day for 4 consecutive days, and on the 2nd week, the brain tissues of the mice were excised, and BrdU, known as a marker of proliferative cells, and an antibody of Ki67, known as a marker of neural progenitor cells, and It was observed immunohistochemically using a doublecortin (DCX) antibody used as a marker of neuroblastic cells.

As a result of the experiment, it was observed that the BrdU (+), Ki67 (+) or DCX (+) cells of the mice administered with Zn-NAC were increased compared to the mice administered with ZnCl ₂ or vehicle (FIG. 3 ), Zn-NAC It can be seen that administration of Zinc or NAC showed an excellent effect on proliferation of neuronal progenitor cells and generation of neuroblasts than administration of zinc or NAC, respectively.

In addition, in order to confirm the effect of Zn-NAC administration in wild-type mice and ZnT3 KO mice, Zn-NAC (20 mg/kg) was intraperitoneally administered to wild-type mice and ZnT3 KO mice as above, and antibodies of BrdU and Ki67 and It was observed immunohistochemically using DCX antibody.

As a result of the experiment, it was observed that BrdU(+), Ki67(+), or DCX(+) cells of wild-type mice were increased compared to ZnT3 KO mice (FIG. 4), and ZnT3 gene that affects zinc concentration in synaptic endoplasmic reticulum was removed. In this case, it can be seen that administration of Zn-NAC does not promote neural progenitor cell proliferation and neuroblast development.

From the above experimental results, it can be seen that the effective supply of zinc through the administration of Zn-NAC increases neurogenesis in the hippocampus of the brain.

Example 3. Confirmation of activation of ERK/CREB signaling pathway by Zn-NAC administration

In order to confirm whether the promotion of neurogenesis by Zn-NAC administration is caused by the ERK/CREB signaling pathway, the following experiment was performed.

Specifically, whether the increase in neurogenesis newly produced in the hippocampus of the brain due to Zn-NAC administration is related to the cellular signaling pathway related to phosphorylation of extracellular signal regulated kinase (ERK) and cAMP response element-binding protein (CREB)? To confirm, after administering Zn-NAC (20 mg/kg), a novel active substance for promoting neurogenesis or vehicle, to wild-type mice and ZnT3 KO mice once a day for 2 weeks, the tissues of the mice were removed. Phosphorylation of ERK and CREB was confirmed.

As a result, in the case of ZnT3 KO mice, it was confirmed that phosphorylation of ERK and CREB was significantly decreased compared to wild-type mice, and when Zn-NAC was administered, phosphorylation of ERK and CREB was increased in both wild-type and ZnT3 KO mice. I did.

Based on the above experimental results, it can be seen that promotion of neurogenesis through Zn-NAC can be caused by activation of the ERK/CREB pathway.

The foregoing description of the present application is for illustrative purposes only, and those of ordinary skill in the art to which the present application pertains will be able to understand that it is possible to easily transform it into other specific forms without changing the technical spirit or essential features of the present application. Therefore, it should be understood that the embodiments described above are illustrative in all respects and not limiting. For example, each component described as a single type may be implemented in a distributed manner, and similarly, components described as being distributed may also be implemented in a combined form.

The scope of the present application is indicated by the claims to be described later rather than the detailed description, and all changes or modifications derived from the meaning and scope of the claims and the concept of equivalents thereof should be interpreted as being included in the scope of the present application.

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Claims (2)

It contains zinc and NAC (N-acetyl-L-cysteine) as active ingredients, and the zinc and NAC are chelated at a ratio of 1:2 to increase the amount of zinc in the hippocampus, and ERK (extracellular signal- A pharmaceutical composition for preventing or treating neurological diseases through the regulated kinase) / CREB (cAMP response element-binding protein) pathway. It contains zinc and NAC (N-acetyl-L-cysteine) as an active ingredient, and the zinc and NAC are chelate-coupled in a ratio of 1:2 to proliferate and promote differentiation of neural progenitor cells or neural stem cells, and the neural stem cells Or the neural precursor cells are isolated or intrinsic neural stem cells or neural precursor cells in the body, a health functional food composition for preventing or improving nervous system diseases.

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