KR20240073798A - Composition for preventing or treating neurological diseases comprising lansoprazole, lansoprazole N-oxide, lansoprazole N-oxide metabolite, or lansoprazole N-oxide precursor - Google Patents

Abstract

The present invention relates to a composition for preventing or treating neurological diseases comprising lansoprazole, lansoprazole N-oxide, lansoprazole N-oxide metabolite, or lansoprazole N-oxide precursor, and more specifically, lansoprazole, lansoprazole N-oxide, lansoprazole Any one selected from the group consisting of schizophrenia, autism spectrum disorder, Parkinson's disease, depression, social impairment, dementia, cognitive dysfunction, and memory impairment containing N-oxide metabolite or lansoprazole N-oxide precursor as an active ingredient. It relates to a composition for preventing or treating neurological diseases.
In the present invention, it was confirmed that lansoprazole or lansoprazole N-oxide not only improves the alleviating effect on preceding stimulation, sociability, social preference, or repetitive behavior, but also improves oxidative stress and the imbalance of excitatory and inhibitory synapses. , the composition of the present invention can be usefully used as a composition for preventing or treating neurological diseases.

Description

Composition for preventing or treating neurological diseases comprising lansoprazole, lansoprazole N-oxide, lansoprazole N-oxide metabolite, or lansoprazole N-oxide precursor {Composition for preventing or treating neurological diseases comprising lansoprazole, lansoprazole N-oxide, lansoprazole N- oxide metabolite, or lansoprazole N-oxide precursor}

The present invention relates to a composition for preventing or treating neurological diseases comprising lansoprazole, lansoprazole N-oxide, lansoprazole N-oxide metabolite, or lansoprazole N-oxide precursor, and more specifically, lansoprazole, lansoprazole N-oxide, lansoprazole Any one selected from the group consisting of schizophrenia, autism spectrum disorder, Parkinson's disease, depression, social impairment, dementia, cognitive dysfunction, and memory impairment containing N-oxide metabolite or lansoprazole N-oxide precursor as an active ingredient. It relates to a composition for preventing or treating neurological diseases.

Autism Spectrum Disorder (ASD) refers to a cranial nerve development disorder whose main symptoms include limitations in the range of stereotypic behavioral interests, impaired verbal and non-verbal communication, and reduced ability to understand social interactions. There is no established method of diagnosing autism spectrum disorder through molecular biological or pathological indicators, there is no cure for the cause, and popular drug treatments are available for accompanying symptoms such as epilepsy, self-harm, aggressive behavior, anxiety, or emotional disorders. However, there is no treatment that can treat the core symptoms of lack of social skills and repetitive behaviors.

Schizophrenia is a representative psychotic disorder and is a collection of various psychotic symptoms with complex symptoms in various areas such as speech, behavior, emotion, and cognition that are related and derived from thinking disorder as the main pathology. (syndrome). Conventional antipsychotic drugs used to relieve the symptoms of schizophrenia improve the quality of life of patients to some extent, but they do not lead to complete cure and their use is limited due to side effects. Therefore, these drugs have limited therapeutic value in the management of schizophrenia, and the development of new drugs with improved efficacy and side effects is required.

Dementia is a neurological symptom caused by damage to brain nerve cells and is a type of degenerative neurological disease. It refers to a pathological condition in which mental ability is reduced to the extent that it interferes with social life and cannot lead daily life without the help of others. Alzheimer's dementia The most common cause is cerebrovascular dementia, and other causes include Parkinson's disease and brain tumors. Degenerative neurological diseases, including dementia, have a variety of causes, and cell biology is particularly important due to reduced blood supply, damage to nerve cells, inflammatory substances secreted from glial cells (microglia), which are inflammatory cells in the brain, and nerve cell death resulting from this. Regulation of glial cell activity and neuronal protection are key targets for the development of prevention, control, and treatment of neurodegenerative diseases, including stroke and dementia.

Meanwhile, lansoprazole is a benzimidazole derivative compound that suppresses gastric acid secretion by inactivating the proton pump involved in gastric acid production, showing excellent effects on gastric ulcer, duodenal ulcer, and gastroesophageal reflux disease. In the United States, it received marketing approval from the FDA in May 1995, and in Korea, it has been marketed under the product name Lanstone since December 1995 (Korean Patent Publication No. 10-2004-0080250).

Accordingly, in the present invention, as a result of diligent efforts to select effective compositions for preventing or treating neurological diseases, lansoprazole and lansoprazole N-oxide have a relieving effect on preceding stimulation, an effect of improving emotional disorders and cognitive disorders, and alleviation of motor coordination ability. It was confirmed that it was effective, and the present invention was completed.

Therefore, the purpose of the present invention is to provide a pharmaceutical composition for preventing or treating neurological diseases containing lansoprazole, lansoprazole N-oxide, lansoprazole N-oxide metabolite, or lansoprazole N-oxide precursor as an active ingredient.

Another object of the present invention is to provide a health functional food composition for preventing or improving neurological diseases containing lansoprazole, lansoprazole N-oxide, lansoprazole N-oxide metabolite, or lansoprazole N-oxide precursor as an active ingredient.

To achieve the above-mentioned purpose,

The present invention provides a pharmaceutical composition for preventing or treating neurological diseases comprising lansoprazole, lansoprazole N-oxide, lansoprazole N-oxide metabolite, lansoprazole N-oxide precursor, or a pharmaceutically acceptable salt thereof as an active ingredient. do.

In addition, the present invention provides a health functional food for preventing or improving neurological diseases containing lansoprazole, lansoprazole N-oxide, lansoprazole N-oxide metabolite, lansoprazole N-oxide precursor, or a pharmaceutically acceptable salt thereof as an active ingredient. A composition is provided.

In a preferred embodiment of the present invention, the composition can improve sensorimotor gating deficit, motor deficit, sociability, social preference, or repetitive behavior.

In another preferred embodiment of the present invention, the composition can suppress oxidative stress.

In another preferred embodiment of the present invention, the composition inhibits the expression of one or more proteins selected from the group consisting of NMDAR1, NMDAR2A, NMDAR2B, and GluR1 to promote imbalance (excitation/inhibition (E/I)) of excitatory and inhibitory synapses. ) imbalance can be improved.

In another preferred embodiment of the present invention, the neurological disease may be any one selected from the group consisting of schizophrenia, autism spectrum disorder, Parkinson's disease, depression, social disorders, emotional disorders, dementia, cognitive disorders, and memory disorders. there is.

In the present invention, it was confirmed that lansoprazole or lansoprazole N-oxide not only improves the alleviating effect on preceding stimulation, sociability, social preference, or repetitive behavior, but also improves oxidative stress and the imbalance of excitatory and inhibitory synapses. , the composition of the present invention can be usefully used as a composition for preventing or treating neurological diseases.

Figure 1 shows data confirming that the effect of lansoprazole in increasing glutathione (GSH) activity is superior to that of omeprazole or pantoprazole, which are PPI compounds.
Figure 2 shows data confirming that the oxidative stress inhibition effect of lansoprazole is superior to that of omeprazole or pantoprazole, which are PPI-based compounds.
Figure 3 shows data confirming the alleviating effect of lansoprazole on antecedent stimulation in the MK-801 schizophrenia animal model.
Figure 4 shows data confirming the effect of lansoprazole on improving sociality and social preference in the MK-801 schizophrenia animal model.
Figure 5 is data confirming the cognitive improvement effect of lansoprazole in the MK-801 schizophrenia animal model.
Figure 6 is data confirming the effect of improving social skills by lansoprazole in the VPA autism animal model. (B) represents the chamber stay period, and (A) represents the sociability index according to the chamber stay period in (B).
Figure 7 is data confirming the effect of improving social preference by lansoprazole in the VPA autism animal model. (B) represents the chamber stay period, and (A) represents the sociability index according to the chamber stay period in (B).
Figure 8 is data confirming the effect of improving repetitive behavior by lansoprazole in the VPA autism animal model.
Figure 9 is data confirming the recovery efficacy of E/I imbalance dysfunction caused by lansoprazole in the VPA autism animal model. (A) is Western blot data, and (B) to (E) are data confirming the relative expression level of each protein with respect to β-actin.
Figure 10 shows data confirming (A) glutathione (GSH) activity and (B) degree of cytotoxicity by lansoprazole N-oxide.

Hereinafter, the present invention will be described in detail.

Consistently, the present invention uses lansoprazole, lansoprazole N-oxide, lansoprazole N-oxide metabolite, lansoprazole N-oxide precursor, or a pharmaceutically acceptable salt thereof as an active ingredient. It relates to a pharmaceutical composition for preventing or treating neurological diseases, comprising:

In another consistent aspect, the present invention provides a pharmaceutical composition for preventing or improving neurological diseases comprising lansoprazole, lansoprazole N-oxide, lansoprazole N-oxide metabolite, lansoprazole N-oxide precursor, or a pharmaceutically acceptable salt thereof as an active ingredient. It relates to health functional food compositions.

In the present invention, lansoprazole is represented by the following formula (1), and lansoprazole N-oxide is represented by the following formula (2).

[Formula 1]

[Formula 2]

In the present invention, the composition may further include a benzimidazole derivative or may be administered in combination with a compound having efficacy in treating neurological diseases. When lansoprazole or lansoprazole N-oxide and benzimidazole derivatives are administered together, a synergistic effect for preventing or treating neurological diseases can be obtained.

The benzimidazole derivative may be represented by the following formula (3).

[Formula 3]

(In the above formula, R ₁ is hydrogen, a halogen atom, a hydroxyl group, or substituted or unsubstituted C ₁ -C ₆ alkyl, and R ₂ and R ₃ are each independently hydrogen, a halogen atom, hydroxyl, C ₁ -C ₆ is an alkyl group, substituted or unsubstituted C ₁ -C ₆ alkoxy, sulfonyl, sulfonic acid, or nitro, or R ₂ and R ₃ are joined together to form an aryl ring, A is C ₁ -C ₆ alkylene, NH, or (C ₁ -C ₆ alkyl)-N, X is O, N, or NH, Y is O, S, -SO-(CH ₂ ) _n -R ₄ , -S-(CH ₂ ) _n -R ₄ , -SO ₂ -(CH ₂ ) _n -R4, or -SR ₅ , n is an integer of 1 to 3, and R ₄ is C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halo. -C ₁ -C ₆ alkoxy and C ₁ -C ₆ alkoxy-C ₁ -C ₆ alkoxy, which is pyridine substituted or unsubstituted with one or more selected from the group consisting of R ₅ is hydrogen or C ₁ -C ₆ alkyl .)

Representative examples of Formula 3 include the following compounds:

1) omeprazole;

2) Omeprazole sulfide

3) omeprazole sulfone;

4) Omeprazole N-oxide

5) 5-methoxy-2-benzimidazolethiol;

6) 5-methoxy-1-methyl-1H-benzimidazole-2-thiol;

7) 5-methoxy-2-(methylthio)-1H-benzimidazole;

8) lansoprazole sulfide;

9) lansoprazole sulfone;

10) 2-mercaptobenzimidazole;

11) 1-methyl-1H-benzimidazole-2-thiol;

12) pantoprazole;

13) pantoprazole sulfide;

14) pantoprazole sulfone;

15) pantoprazole N-oxide;

16) 5-difluoromethoxy-2-mercaptobenzimidazole;

17) rabeprazole;

18) rabeprazole sulfide;

19) rabeprazole sulfone;

20) rabeprazole N-oxide;

21) chlorzoxazone;

22) 4-methyl-1H-benzimidazole-2-thiol;

23) 2-sulfanyl-1H-benzimidazole-5-sulfonic acid;

24) 5-chloro-1,3-dihydrobenzimidazol-2-one;

25) 5-hydroxyindolin-2-one;

26) 4,5,6-trichloro-3H-a,3-benzoxazol-2-one (4,5,6-trichloro-3H-a,3-benzoxazol-2-one);

27) 6-methoxybenzo[d]oxazol-2(3H)-one;

28) 2-mercapto-5-nitrobenzimidazole;

29) 6-hydroxychlorzoxazone;

30) 5-chloro-2-mercaptobenzimidazole;

31) 1,3-dihydrobenzo[f]benzimidazole-2-thione; and

32) 5,6-dimethoxy-1H-benzo[d]imidazole-2-thiol

In the present invention, lansoprazole can improve sensorimotor gating deficit, motor deficit, social impairment, emotional impairment, or cognitive impairment.

In the present invention, the neurological disease may be any one selected from the group consisting of schizophrenia, autism spectrum disorder, Parkinson's disease, depression, social disorders, emotional disorders, dementia, cognitive disorders, and memory disorders.

The pharmaceutical composition of the present invention can be formulated and used in various forms according to conventional methods. For example, it can be formulated into oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, etc., and can be formulated and used in the form of external preparations, suppositories, and sterile injection solutions. Depending on each dosage form, it may further include pharmaceutically acceptable carriers, excipients, and diluents. In addition, it can be formulated and used in the form of external preparations such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, etc., and sterile injection solutions according to conventional methods.

The carriers, excipients and diluents include lactose, dextrose, sucrose, oligosaccharides, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, These include microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxy benzoate, propylhydroxy benzoate, talc, magnesium stearate, and mineral oil. When formulating or formulating the pharmaceutical composition, it is prepared using diluents or excipients such as commonly used fillers, extenders, binders, wetting agents, disintegrants, and surfactants.

Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc. These solid preparations contain at least one excipient, such as starch, calcium carbonate, or sucrose. It is prepared by mixing , lactose, and gelatin. In addition to simple excipients, lubricants such as magnesium styrate talc are also used. Liquid preparations for oral use include suspensions, oral solutions, emulsions, and syrups. In addition to the commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, fragrances, and preservatives may be included. there is. Preparations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, suppositories, etc. Non-aqueous solvents and suspensions may include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, and injectable ester such as ethyl oleate. As a base for suppositories, witepsol, macrogol, tween 61, cacao, laurin, glycerogenatin, etc. can be used.

As used herein, the term “administration” means providing the pharmaceutical composition of the present invention to an individual by any suitable method. The present invention provides a pharmaceutical composition that provides an amount of an active ingredient or pharmaceutical composition that induces a biological or medical response in a tissue system, animal or human as considered by a researcher, veterinarian, doctor or other clinician, that is, alleviation of symptoms of the disease or disorder being treated. It can be administered in a therapeutically effective amount that induces . It is obvious to those skilled in the art that the therapeutically effective dosage and frequency of administration of the pharmaceutical composition of the present invention will vary depending on the desired effect. Therefore, the optimal dosage to be administered can be easily determined by a person skilled in the art, depending on the type of disease, the severity of the disease, the content of the active ingredient and other ingredients contained in the composition, the type of dosage form, the patient's age, weight, and general health condition. , gender and diet, administration time, administration route and secretion rate of the composition, treatment period, and various factors including concurrently used drugs. The pharmaceutical composition of the present invention can be administered to an individual through various routes. For example, it may be administered intravenously, intraperitoneally, intramuscularly, intraarterially, bucally, intracardiacally, intramedullary, intrathecally, transdermally, enterally, subcutaneously, sublingually, or topically, but is not limited thereto. The pharmaceutical composition of the present invention can be administered in an amount of 1 to 10,000 mg/kg/day, and may be administered once a day or in several divided doses.

The health functional food composition of the present invention can be used as a health functional food, food additive, or dietary supplement. When using the composition of the present invention as a food additive, it can be used appropriately according to conventional methods, such as adding it as is or mixing it with other foods or food ingredients.

Additionally, the mixing amount of the health functional food composition may be appropriately changed depending on the purpose of use (prevention, health, or therapeutic treatment). As a specific example, when manufacturing a food or beverage, the composition of the present invention is added in an amount of 15% by weight or less, preferably 10% by weight or less, based on the raw materials. However, when consumed for a long period of time for health and hygiene purposes or health control, it can be added in an amount below the above range. Since there is no problem in terms of safety, the active ingredient can be used in an amount above the above range. there is.

There is no particular limitation on the type of food, but examples of food to which the composition of the present invention can be added include meat, sausages, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gum, and ice cream. It includes dairy products, various soups, beverages, tea, drinks, alcoholic beverages, vitamin complexes, etc., and includes all health foods in the conventional sense.

When the health functional food composition of the present invention is manufactured into a beverage, it may contain additional ingredients such as various flavoring agents or natural carbohydrates, like ordinary beverages. The natural carbohydrates include monosaccharides such as glucose and fructose; Disaccharides such as maltose and sucrose; Natural sweeteners such as dextrin and cyclodextrin; Synthetic sweeteners such as saccharin and aspartame may be used. The natural carbohydrate is included in an amount of 0.01 to 10% by weight, preferably 0.01 to 0.1% by weight, based on the total weight of the food composition of the present invention.

The health functional food composition of the present invention includes various nutrients, vitamins, electrolytes, flavors, colorants, pectic acid and its salts, alginic acid and its salts, organic acids, protective colloidal thickeners, pH regulators, stabilizers, preservatives, glycerin, and alcohol. , carbonating agents used in carbonated beverages, etc., and may include pulp for the production of natural fruit juice, fruit juice drinks, and vegetable drinks, but are not limited thereto. These ingredients can be used independently or in combination. The ratio of the above additives is not greatly limited, but is preferably contained within the range of 0.01 to 0.1% by weight based on the total weight of the food composition of the present invention.

Below, preferred embodiments are presented to aid understanding of the present invention. However, the following examples are provided only to make the present invention easier to understand, and the content of the present invention is not limited by the following examples.

Confirmation of antioxidant efficacy of proton pump inhibitor (PPI) series compounds

In the present invention, in order to confirm the superiority of lansoprazole as a treatment for neurological diseases, the antioxidant effect of omeprazole and pantoprazole, which are proton pump inhibitor (PPI) series compounds, and lansoprazole were confirmed.

1-1: Measurement of GSH expression level in normal cells

Normal astrocytes were inoculated into a 48- ^well plate at 2.5 . As a control group, 0.4% DMSO was treated.

After adding the compound and culturing for 24 hours, the cells were treated with 20 mM mBCl (monochlorobimane) to measure the GSH level, and the glutathione conjugate concentration was measured at ex 394/em 490 nm. Compared to the control group, the cells were treated with 20 mM mBCl (monochlorobimane). I measured my GSH amount.

As a result, as shown in Figure 1, it was confirmed that GSH expression increased in a lansoprazole concentration-dependent manner, and the antioxidant effect of lansoprazole was found to be better than that of omeprazole and pantoprazole.

1-2: Measurement of GSH expression level in oxidative stress situation

In the present invention, in order to confirm the efficacy of lansoprazole in suppressing oxidative stress in an oxidative stress situation, each compound was treated in <Example 1-1>, cultured for 24 hours, and then treated with hydrogen peroxide (H ₂ O ₂ ) and 6. It was cultured for some time. Afterwards, to measure the GSH level, the cells were treated with 20 mM mBCl (monochlorobimane), the glutathione conjugate concentration was measured at ex 394/em 490 nm, and the amount of intracellular GSH was measured compared to the control group.

As a result, as shown in Figure 2, GSH expression was increased by lansoprazole even under oxidative stress conditions, and it was confirmed that GSH expression was further increased compared to the normal conditions of <Example 1-1>. In particular, lansoprazole at a concentration of 50 μM was found to be significantly more effective in promoting GSH expression than omeprazole and pantoprazole.

Establishment of an animal model for schizophrenia

Male C57BL/6 mice (25 g, 8 weeks old) were purchased from Orient Bio. They were divided into 6 groups, acclimatized for 1 week under standard conditions, and used in subsequent experiments (temperature 22±2°C, humidity 55±5%, 12 h-light/dark cycle, food/water free diet). All experiments were performed in accordance with the guidelines of the National Institutes of Health (NIH publication No. 85-23, revised 1985) and the Institutional Animal Care and Use Committee (IACUC) of Konkuk University. MK-801 was treated with an NMDA receptor antagonist to establish an animal model for psychiatric disorders (autism, schizophrenia, attention deficit, depression, and behavioral disorders), and aripiprazole, used as an antipsychotic, was administered as a positive control group. .

1) control (untreated group, negative control group),

2) MK-801 (dizocilpine) 0.2 mg/kg administration group

3) MK-801 (dizocilpine) 0.2 mg/kg administration + lansoprazole 0.3 mg/kg administration group

4) MK-801 (dizocilpine) 0.2 mg/kg administration + lansoprazole 1 mg/kg administration group

5) MK-801 (dizocilpine) 0.2 mg/kg administration + lansoprazole 3 mg/kg administration group

6) MK-801 (dizocilpine) 0.2 mg/kg administration + aripiprazole 1 mg/kg administration group

It was confirmed that sensorimotor gating deficit, motor deficit, social impairment, and cognitive impairment appeared in the MK-801-induced neurological disease model established above.

Confirmation of the alleviating effect of lansoprazole on antecedent stimulation in an animal model of schizophrenia

In the present invention, an Acoustic Startle Response Test was performed to confirm the alleviating effect of lansoprazole on preceding stimulation.

When NMDA receptor antagonists such as MK-801 are administered in animal models of schizophrenia, prepulse inhibition (PPI) is not achieved. Based on this fact, it is possible to determine whether a test drug is effective in an animal model of schizophrenia by stimulating a test animal with a strong sound in a startle box and then measuring its response.

The startle box consists of a box that can lightly detain a rat, a system that can consistently produce sound stimulation from 5 to 130 dB, equipment that can measure animal movements, a program that can digitize the measured stimulation, and a sound It consists of a source and a speaker that can be provided. For each test, the rats were acclimatized in the detention box for 5 minutes, during which white noise (70 dB) was added in the background. Because animals may overreact to stimulation, animals were acclimatized by stimulating them with several 120 dB sounds for 40 ms. To measure the degree of response of experimental animals to sound stimulation, sound stimulation of 80, 90, 100, 110, or 120 dB was provided, respectively, and the animal's response to each stimulus was measured.

As a result, as shown in Figure 3, the alleviating effect on preceding irritation was confirmed by the administration of lansoprazole, and it was confirmed that the lansoprazole 1 mg/kg and 3 mg/kg administration groups showed similar efficacy to the positive control group. In other words, lansoprazole has been confirmed to have a therapeutic effect on sensorimotor gating deficit in most neurological diseases, so it can be used as a treatment for various psychoneurological diseases such as schizophrenia, autism spectrum disorder, depression, and social disorders. .

Confirmation of the efficacy of lansoprazole in improving sociability and social preference in an animal model of schizophrenia

Using the animal model of Example 2, the efficacy of lansoprazole in improving sociability and social preference was confirmed.

Experimental animals were given a stimulus mouse (familiar) to explore for 10 minutes, a new stimulus mouse (novel) was added to the experimental animal, and then explored for another 10 minutes. This was done to evaluate whether more time was spent with the novel mouse than with the familiar mouse. A mouse is called familiar, and a new mouse is called novel.

If more time is spent with the novel mouse than with the familiar mouse, it is judged to be social, and the results of the experiment are measured by measuring the time the test mouse explores each mouse or the sniffing time of the test mouse for each mouse. Expressed as preference ratio (%). A higher preference ratio means that more time is spent with the novel mouse than with the familiar mouse, or that more time is spent sniffing with the novel mouse than with the familiar mouse.

As a result, as shown in Figure 4, it was confirmed that sociability and social preference were improved by lansoprazole administration, and it was confirmed that the lansoprazole 1 mg/kg and 3 mg/kg administration groups showed similar efficacy to the positive control group. In other words, since lansoprazole has been confirmed to be effective in treating most emotional and cognitive disorders, it can be used as a treatment for various mental and neurological diseases such as schizophrenia, autism spectrum disorder, depression, social disorders, dementia, and Parkinson's disease.

Confirmation of the cognitive improvement efficacy of lansoprazole in an animal model of schizophrenia

In the present invention, it was confirmed through a passive avoidance test that the cognitive function of the MK-801 treated group was reduced, and that it was significantly improved by lansoprazole treatment.

The passive avoidance experiment is a box divided into two rooms. One room is equipped with a bright light bulb, which is an environment that animals do not like, and the other room is dark, so it is an environment that animals prefer. Experimental animals have an instinctive tendency to enter a dark room, so if they are in a bright room and enter a dark room, an electric shock is given to the animal so that it remembers this. This is a method of checking cognitive function by recording the time (latency time) of entering a dark room without giving an electric shock 24 hours later and checking whether the animal remembers it.

As a result, as shown in Figure 5, it was confirmed that lansoprazole is effective in treating cognitive decline in most neurological diseases, so it can be used as a treatment for schizophrenia, autism spectrum disorder, dementia, Parkinson's disease, etc.

Confirmation of the efficacy of lansoprazole in improving social skills in an autism animal model

6-1: Establishment of an animal model for autism spectrum disorder

In the present invention, in order to confirm the effect of lansoprazole on improving autism spectrum disorder, a VPA (valproic acid) autism animal model was established.

Male C57BL/6 mice (25 g, 8 weeks old) were purchased from Orient Bio. They were divided into five groups, acclimatized for one week under standard conditions, and used in subsequent experiments (temperature 22±2°C, humidity 55±5%, 12 h-light/dark cycle, food/water free diet). All experiments were performed in accordance with the guidelines of the National Institutes of Health (NIH publication No. 85-23, revised 1985) and the Institutional Animal Care and Use Committee (IACUC) of Konkuk University. Valproic acid (VPA) was treated to establish an animal model of autism spectrum disorder.

1) control (untreated group, negative control group),

2) VPA 350 mg/kg administration group

3) VPA 350 mg/kg administration + lansoprazole 0.3 mg/kg administration group

4) VPA 350 mg/kg administration + lansoprazole 1 mg/kg administration group

5) VPA 350 mg/kg administration + lansoprazole 3 mg/kg administration group

6-2: Confirmation of effectiveness in improving social skills

The effectiveness of improving social skills was tested in a transparent box structure divided into three compartments, with round cages made of wire mesh placed in both compartments, and the test rats of <Example 6-1> above placed in the middle compartment.

Rats of the same species were placed in one cage, and the other cage was left empty, and the degree of interest shown in the empty cage was compared with the degree of interest shown in rats of the same species. Measurements were performed for 10 minutes using the EthoVision System.

As a result, as shown in Figure 6, it was confirmed that the social skills of the autism spectrum disorder animal model were improved in a lansoprazole dose-dependent manner.

Confirmation of the efficacy of lansoprazole in improving social preference in an autism animal model

After evaluating the efficacy of improving social skills in <Example 6-2>, a social preference evaluation was performed.

First, a new rat of the same species was placed in an empty cage, and the degree of interest shown by the subject rats in the existing rats and the interest shown in the new rats was compared and analyzed. Measurements were performed for 10 minutes using the EthoVision System.

As a result, as shown in Figure 7, social preference was significantly improved by lansoprazole treatment, and in particular, the effect was shown to be excellent in the lansoprazole 0.3 mg/kg and 1 mg/kg treatment groups.

Confirmation of efficacy of lansoprazole in improving repetitive behavior in autism animal model

In the present invention, in order to evaluate homology, a grooming test was performed.

The animal model of <Example 6-1> was used, and the behavior of the mouse grooming itself in the home cage or repeatedly licking or scratching its face and body using its hands was observed, and the duration and frequency were indicated.

As a result, as shown in Figure 8, it was confirmed that the repetitive behavior of the autism spectrum disorder animal model was improved in a lansoprazole dose-dependent manner.

Confirmation of the efficacy of lansoprazole in recovering E/I imbalance dysfunction in an autism animal model

In the present invention, Western blot was performed to confirm the efficacy of lansoprazole in restoring E/I imbalance function.

First, proteins were separated from the mouse brain tissue sample of <Example 6-1>, and then electrophoresis was performed using an 8 to 12% SDS-polyacrylamide gel. Next, the proteins on the membrane were electrically transferred to the nitrocellulose membrane, and the membrane was blocked and sequentially treated with primary antibodies (NMDAR1, NMDAR2A, NMDAR2B, and GluR1) and secondary antibodies. Afterwards, the membrane was washed, and the protein expression level was measured using the enhanced chemilumnescence (ECL) method.

As a result, as shown in Figure 9, the expression of NMDAR1, NMDAR2A, NMDAR2B, and GluR1 increased by VPA treatment, but when lansoprazole was administered at 0.3 mg/kg and 1 mg/kg, the expression of NMDAR1, NMDAR2A, NMDAR2B, and GluR1 It was confirmed that this decreased. In other words, it was confirmed that the imbalance between excitatory and inhibitory synapses was improved by lansoprazole.

Confirmation of improved effectiveness of lansoprazole N-oxide compared to lansoprazole

In the present invention, lansoprazole N-oxide, represented by the following formula (2), which is a compound with a better effect for treating or improving neurological diseases than lansoprazole, was further selected.

The antioxidant effect of lansoprazole N-oxide was confirmed by referring to the method of <Example 1>. Lansoprazole N-oxide was treated at a concentration of 0.1, 1, 10, 20, 50, and 100 μM, and lansoprazole was treated at a concentration of 50 μM.

In addition, the IC ₅₀ value for lansoprazole N-oxide was measured and found to be 21.03 μM, and cell viability was measured using the MTT assay.

As a result, as shown in Figure 10, it was confirmed that the antioxidant effect of lansoprazole N-oxide was better than that of lansoprazole, and no cytotoxicity was observed.

Claims (12)

Preventing neurological diseases, comprising lansoprazole, lansoprazole N-oxide, lansoprazole N-oxide metabolite, lansoprazole N-oxide precursor, or a pharmaceutically acceptable salt thereof as an active ingredient, or Pharmaceutical composition for therapeutic use.
According to paragraph 1,
The composition is a pharmaceutical composition for preventing or treating neurological diseases, characterized in that it improves sensorimotor gating deficit, motor deficit, sociability, social preference, or repetitive behavior.
According to paragraph 1,
The composition is a pharmaceutical composition for preventing or treating neurological diseases, characterized in that it inhibits oxidative stress.
According to paragraph 1,
The composition is characterized in that it improves the imbalance of excitatory and inhibitory synapses (excitation/inhibition (E/I) imbalance) by suppressing the expression of one or more proteins selected from the group consisting of NMDAR1, NMDAR2A, NMDAR2B, and GluR1. Nervous system Pharmaceutical composition for preventing or treating disease.
According to paragraph 1,
The composition includes 1) omeprazole;
2) Omeprazole sulfide
3) omeprazole sulfone;
4) Omeprazole N-oxide
5) 5-methoxy-2-benzimidazolethiol;
6) 5-methoxy-1-methyl-1H-benzimidazole-2-thiol;
7) 5-methoxy-2-(methylthio)-1H-benzimidazole;
8) lansoprazole sulfide;
9) lansoprazole sulfone;
10) 2-mercaptobenzimidazole;
11) 1-methyl-1H-benzimidazole-2-thiol;
12) pantoprazole;
13) pantoprazole sulfide;
14) pantoprazole sulfone;
15) pantoprazole N-oxide;
16) 5-difluoromethoxy-2-mercaptobenzimidazole;
17) rabeprazole;
18) rabeprazole sulfide;
19) rabeprazole sulfone;
20) rabeprazole N-oxide;
21) chlorzoxazone;
22) 4-methyl-1H-benzimidazole-2-thiol;
23) 2-sulfanyl-1H-benzimidazole-5-sulfonic acid;
24) 5-chloro-1,3-dihydrobenzimidazol-2-one;
25) 5-hydroxyindolin-2-one;
26) 4,5,6-trichloro-3H-a,3-benzoxazol-2-one (4,5,6-trichloro-3H-a,3-benzoxazol-2-one);
27) 6-methoxybenzo[d]oxazol-2(3H)-one;
28) 2-mercapto-5-nitrobenzimidazole;
29) 6-hydroxychlorzoxazone;
30) 5-chloro-2-mercaptobenzimidazole;
31) 1,3-dihydrobenzo[f]benzimidazole-2-thione; and
32) At least one benzimi selected from the group consisting of 5,6-dimethoxy-1H-benzo[d]imidazole-2-thiol A pharmaceutical composition for preventing or treating neurological diseases, characterized in that it further comprises a dazole derivative.
According to paragraph 1,
Pharmaceuticals for preventing or treating neurological diseases, wherein the neurological disease is any one selected from the group consisting of schizophrenia, autism spectrum disorder, Parkinson's disease, depression, social disorders, emotional disorders, dementia, cognitive disorders, and memory disorders. enemy composition.
Preventing neurological diseases, comprising lansoprazole, lansoprazole N-oxide, lansoprazole N-oxide metabolite, lansoprazole N-oxide precursor, or a pharmaceutically acceptable salt thereof as an active ingredient, or Health functional food composition for improvement.
In clause 7,
The composition is a health functional food composition for preventing or improving neurological diseases, characterized in that it improves sensorimotor gating deficit, motor deficit, sociability, social preference, or repetitive behavior.
In clause 7,
The composition is a health functional food composition for preventing or improving nervous system diseases, characterized in that it inhibits oxidative stress.
In clause 7,
The composition is characterized in that it improves the imbalance of excitatory and inhibitory synapses (excitation/inhibition (E/I) imbalance) by suppressing the expression of one or more proteins selected from the group consisting of NMDAR1, NMDAR2A, NMDAR2B, and GluR1. Nervous system Health functional food composition for preventing or improving disease.
In clause 7,
The composition includes 1) omeprazole;
2) Omeprazole sulfide
3) omeprazole sulfone;
4) Omeprazole N-oxide
5) 5-methoxy-2-benzimidazolethiol;
6) 5-methoxy-1-methyl-1H-benzimidazole-2-thiol;
7) 5-methoxy-2-(methylthio)-1H-benzimidazole;
8) lansoprazole sulfide;
9) lansoprazole sulfone;
10) 2-mercaptobenzimidazole;
11) 1-methyl-1H-benzimidazole-2-thiol;
12) pantoprazole;
13) pantoprazole sulfide;
14) pantoprazole sulfone;
15) pantoprazole N-oxide;
16) 5-difluoromethoxy-2-mercaptobenzimidazole;
17) rabeprazole;
18) rabeprazole sulfide;
19) rabeprazole sulfone;
20) rabeprazole N-oxide;
21) chlorzoxazone;
22) 4-methyl-1H-benzimidazole-2-thiol;
23) 2-sulfanyl-1H-benzimidazole-5-sulfonic acid;
24) 5-chloro-1,3-dihydrobenzimidazol-2-one;
25) 5-hydroxyindolin-2-one;
26) 4,5,6-trichloro-3H-a,3-benzoxazol-2-one (4,5,6-trichloro-3H-a,3-benzoxazol-2-one);
27) 6-methoxybenzo[d]oxazol-2(3H)-one;
28) 2-mercapto-5-nitrobenzimidazole;
29) 6-hydroxychlorzoxazone;
30) 5-chloro-2-mercaptobenzimidazole;
31) 1,3-dihydrobenzo[f]benzimidazole-2-thione; and
32) At least one benzimi selected from the group consisting of 5,6-dimethoxy-1H-benzo[d]imidazole-2-thiol (5,6-dimethoxy-1H-benzo[d]imidazole-2-thiol) A health functional food composition for preventing or improving neurological diseases, characterized in that it additionally contains a dazole derivative.
In clause 7,
The nervous system disease is any one selected from the group consisting of schizophrenia, autism spectrum disorder, Parkinson's disease, depression, social disorder, emotional disorder, dementia, cognitive disorder, and memory disorder. Health for preventing or improving nervous system disease. Functional food composition.