KR101895554B1 - Composition for preventing, improving or treating neurodevelopmental or obsessive compulsive disorder comprising oleanolic acid - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for preventing, alleviating, or treating neurodevelopment disorder or obsessive-compulsive disorder comprising oleanolic acid and derivatives thereof or salts thereof as active ingredients. Oleanolic acid of the present invention has excellent effects of alleviating symptoms including repetitive behavior, hyperactivity, social deprivation, cognitive impairment, emotional anxiety, attention deficit, and so on, and thus, effectively prevents, alleviates, and treats neurodevelopment disorder or obsessive-compulsive disorder including fragile X syndrome, attention deficit hyperactivity disorder (ADHD), autistic disorder, Tourette syndrome, schizophrenia, mood disorder, sleep disorder, bipolar disorder, compulsive hoarding syndrome, social phobia, and so on. In addition, oleanolic acid of the present invention is a naturally-derived compound, has no negative side effects, and thus can be variously used as a pharmaceutical composition, a health functional food, and so on.

Description

TECHNICAL FIELD The present invention relates to a composition for preventing, ameliorating or treating neurodevelopmental disorder or obsessive-compulsive disorder comprising oleanolic acid,

The present invention relates to a composition for preventing, ameliorating or treating a neurodevelopmental disorder or obsessive-compulsive disorder comprising oleanolic acid.

Specifically, the present invention relates to a pharmaceutical composition and a health functional food for preventing, ameliorating or treating neurodevelopmental disorder or obsessive-compulsive disorder comprising oleanolic acid, a derivative thereof or a salt thereof as an active ingredient.

Neurodevelopmental disorder refers to a disorder that generally involves mental disorders associated with delayed or impaired development of the central nervous system. Neurodevelopmental disorders are known to be caused by developmental disorders of the brain rather than psychological and social problems. They are mainly caused by intellectual disorder, communication disorder, learning disorder, movement disorder, attention deficit hyperactivity disorder (ADHD) Autism disorder, etc. (Lancet Psychiatry 2016 Dec 12 pii: S2215-0366 (16) 30376-5 doi: 10.1016 / S2215-0366 (16) 30376-5 Neurodevelopmental disorders. Thapara, Cooper M , Rutter M).

Obsessive compulsive disorder generally refers to a disorder in which unwanted thoughts and behaviors are repeated, reducing painful thoughts, impulses or images that repeatedly enter into consciousness, obsession and anxiety. (Compulsion), which is repetitively indicated for the treatment of the disease, is known to be the main symptom. It is known that obsessive behaviors appear in the form of cleansing behavior, confirmation behavior, repetitive behavior, restitution behavior, delayed behavior, and repeatedly performed to recover from anxiety due to obsessive thoughts, knowing that they are inadequate and excessive Clin Psychol Rev. 2017 Jan 16; 52: 137-147. Doi: 10.1016 / j.cpr.2017.01.001. Obsessions and compulsions in the lab: A meta-analysis of procedures to induce symptoms of obsessive-compulsive disorder. LM, Van Yper L, Koster EH; J Cent Nerv Syst Dis 2016 Aug 21; 8: 13-29 doi: 10.4137 / JCNSD.S38359. eCollection 2016. Evidence-Based Assessment of Obsessive-Compulsive Disorder.Rapp AM, Bergman RL, Piacentini J, McGuire JF).

Fragile X Syndrome (FXS), a type of neurodevelopmental disorder, is a genetic disorder caused by the inability of normal expression of FMRP (Fragile X mental retardation protein) (3): 145-57, doi: 10.5582 / irdr.2016.01048), which is characterized by various neurobehavioral symptoms and physical deformities such as depression, difficulty in communication, and hyperactivity. Fragile X syndrome: A review of clinical management. Lozano R, Azaranga, Wilaisakditipakorn T, Hagerman RJ; Ann NY Acad Sci. 1986; 477: 129-50. The fragile syndrome. Brown WT, Jenkins EC, Krawczun MS, Wisniewski K, Rudelli R, Cohen IL, Fisch G, Wolf-Schein E, Miezejeski C, Dobkin C. PMID: 35450). FXS tends to exhibit comorbidity and abnormal behaviors in psychiatric neurological disorders such as autism, ADHD, and asthma, a developmental disorder with an increasing worldwide prevalence, and is currently used in neurodevelopmental disorders The treatment strategy for FXS is currently undergoing, and is not a fundamental treatment for FXS (Drugs. 2016 Mar; 76 (4): 431-45. Doi: 10.1007 / s40265-016-0542-y. Pharmacotherapy for Fragile X Syndrome: Progress to Date, Davenport MH, Schaefer TL, Friedmann KJ, Fitzpatrick SE, Ericksonce). Therefore, there is a growing demand for the development of new substances applicable to the prevention and treatment of FXS itself.

The development of neurodevelopmental disorders, including FXS, is predominantly at a young age, and the symptoms continue to be seen in adults. The most common drugs for neurodevelopmental disorders are AFQ056 (mGluR5 antagonist), sertraline (SSRI), aripiprazole, and arbaclofen (GABA _B agonist), all of which slow the progression of the disease And it is necessary to develop a therapeutic agent for treating the root cause of neurodevelopmental disorder because it has limited therapeutic range at the early stage of onset.

On the other hand, oleanolic acid is a triterpenoid compound derived from natural origin and has been reported to be effective in liver protection, anticancer and antiviral mediated by a strong anti-inflammatory action. Especially, Human immunodeficiency virus (HIV) and hepatitis C virus (Hepatitis C virus). However, the therapeutic effect of oleanolic acid on neurodevelopmental disorders and obsessive-compulsive disorders is not known at all.

(Drugs 2016 Mar; 76 (4): 431, Giant Neurobiol 2016 Jul 13 doi: 10.1002 / dNeu.22419, Neuropsychopharmacology 2016 Nov 9. doi: 10.1038 / npp.2016.237, J Dev Behav Pediatr 2016 Oct; 37 (8): 619)

Davenport, Matthew H., et al. "Pharmacotherapy for Fragile X syndrome: Progress to date." Drugs 76.4 (2016): 431-445. Achuta, Venkat Swaroop, et al. "Metabotropic glutamate receptor 5 responses dictate differentiation of neural progenitors to NMDA-responsive cells in fragile X syndrome." Developmental neurobiology (2016). Veenstra-VanderWeele, Jeremy, et al. "Arbaclofen in Children and Adolescents with Autism Spectrum Disorder: A Randomized, Controlled, Phase 2 Trial." Neuropsychopharmacology (2016). Hess, Laura Greiss, et al. "A Randomized, Double-Blind, Placebo-Controlled Trial of Low-Dose Sertraline in Young Children with Fragile X Syndrome." Journal of Developmental & Behavioral Pediatrics 37.8 (2016): 619-628.

It is intended to provide a composition for preventing, ameliorating or treating neurodevelopmental or obsessive-compulsive disorder comprising oleanolic acid.

Specifically, the present invention aims to provide a pharmaceutical composition and a health functional food for preventing, ameliorating or treating a neurodevelopmental disorder or obsessive-compulsive disorder comprising oleanolic acid, a derivative thereof or a salt thereof as an active ingredient.

The present invention provides a pharmaceutical composition for preventing or treating neurodevelopmental disorder or obsessive-compulsive disorder comprising oleanolic acid, a derivative thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

The oleanolic acid of the present invention is a naturally occurring triterpenoid compound, and its specific structure is shown in the following formula (1).

[Chemical Formula 1]

The oleanolic acid of the present invention can be chemically synthesized or isolated from natural materials, and those commercially available in the market can be purchased and used. In the examples of the present invention, they were purchased from Sigma.

The present inventors have for the first time elucidated that the oleanolic acid of the present invention is superior in improving the pathologies including repetitive behavior, hyperactivity, sociability deterioration, cognitive impairment, emotional anxiety, attention deficit, etc. Thus, Or for the prevention, amelioration or treatment of obsessive compulsive disorder.

Specifically, in the examples of the present invention, animal experiments were conducted using a mouse in which a neurodevelopmental disorder was induced. As a result, in the bead hiding test, when the oleanolic acid was administered, the number of beads hidden was significantly decreased, (Table 1, Fig. 2). In the open field test, it was confirmed that when oleanolic acid was administered, the movement distance was remarkably decreased and the hyperactivity was effectively improved (Table 2, Fig. 3).

In addition, in the social interaction test, when the oleanolic acid was administered, the sociability index and the social intelligence index showed a considerable increase, indicating that the sociability deterioration was effectively improved (Table 3, Figs. 4A and 4B) (Table 4, Figs. 5A and 5B), it was confirmed that the time required for reaching the target point was significantly reduced and the time for staying at the target point was significantly increased.

As used herein, the term "neurodevelopmental disorder" refers to a disorder that generally involves a mental disorder associated with a developmental delay or impairment of the central nervous system. Neurodevelopmental disorders are known to be caused by developmental disorders of the brain rather than psychological and social problems. They are mainly caused by intellectual disorder, communication disorder, learning disorder, movement disorder, attention deficit hyperactivity disorder (ADHD) Autistic disorder, and the like.

As used herein, the term "obsessive compulsive disorder" generally refers to a disorder in which unwanted thoughts and behaviors are repeated, and is a painful thought, impulse or image that repeatedly enters consciousness, The main symptom is compulsion, which repeatedly shows to reduce obsession and anxiety. It is known that obsessive behaviors appear in the form of cleansing behaviors, confirmation behaviors, repetitive behaviors, restitution behaviors, delayed behaviors, and repeatedly performed to recover from anxiety due to obsessive thoughts while knowing that they are inappropriate and excessive.

As long as the disease to be prevented, ameliorated or treated according to the present invention is medically classified into the category of neurodevelopmental disorder or obsessive-compulsive disorder, the specific disease name is not particularly limited, but the neurodevelopmental disorder preferably includes repetitive behavior, hyperactivity, (Fragile X Syndrome), Attention Deficit Hyperactivity Disorder (ADHD), autistic disorder, Tourette's syndrome, and the like. Tourette Syndrome, asthma, mood disorder, sleep disorder, and bipolar disorder, and the obsessive-compulsive disorder may preferably be a disease selected from the group consisting of OCD or social phobia .

The term "derivative" used in the present invention refers to a compound that changes the structure and properties of the host by one or more functional groups of the oleanolic acid of the present invention by introducing, substituting, oxidizing, reducing, Means all compounds.

As used herein, the term " pharmaceutically acceptable salt " refers to a salt of the form that can be used pharmaceutically, among the salts in which the cation and anion are bound by electrostatic attraction, Salts with bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like. Examples of the metal salt include alkali metal salts (sodium salt, potassium salt, etc.), alkaline earth metal salts (calcium salt, magnesium salt, barium salt, etc.), aluminum salts and the like; Examples of salts with organic bases include salts with organic bases such as triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N, Salts with isoparaffin; Salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like; Salts with organic acids include salts with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like; Salts with basic amino acids include salts with arginine, lysine, ornithine and the like; The salt with an acidic amino acid may be a salt with aspartic acid, glutamic acid and the like.

The pharmaceutical composition of the present invention may further comprise a pharmaceutically acceptable carrier in addition to an oleanolic acid, a derivative thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

The kind of carrier which can be used in the present invention is not particularly limited and any carrier commonly used in the technical field can be used. Examples of the carrier include, but are not limited to, saline, sterilized water, Ringer's solution, buffered saline, albumin injection solution, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, maltodextrin, glycerol, . These may be used alone or in combination of two or more.

In addition, the pharmaceutical composition of the present invention may be supplemented with other pharmaceutically acceptable additives such as excipients, diluents, antioxidants, buffers or bacteriostats, and may be used as fillers, extenders, wetting agents, disintegrants, , A binder, a lubricant, and the like may be additionally used.

In the pharmaceutical composition of the present invention, the oleanolic acid, a derivative thereof, or a pharmaceutically acceptable salt thereof may be contained in an amount of 0.00001 to 99.99% by weight based on the total weight of the pharmaceutical composition, preferably 0.1 But the present invention is not limited thereto. For example, the condition of the subject to be administered, the type of the specific disease, the progress of the disease, And the like. If desired, it may also be included in the total content of the pharmaceutical composition.

The pharmaceutical composition of the present invention may be formulated into various formulations suitable for oral administration or parenteral administration.

Non-limiting examples of oral dosage forms using the pharmaceutical compositions of the present invention include troches, lozenges, tablets, aqueous suspensions, oily suspensions, prepared powders, granules, emulsions, hard capsules, soft Capsules, syrups, and elixirs.

In order to formulate the pharmaceutical composition of the present invention for oral administration, a binder such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose or gelatin; Excipients such as dicalcium phosphate and the like; Disintegrating agents such as corn starch or sweet potato starch; Magnesium stearate, calcium stearate, sodium stearyl fumarate, or polyethylene glycol wax, and the like. Sweetening agents, fragrances, syrups, and the like may also be used. Furthermore, in the case of capsules, in addition to the above-mentioned substances, liquid carriers such as fatty oils can be further used.

Non-limiting examples of the parenteral preparation using the pharmaceutical composition of the present invention include injections, suppositories, respiratory inhalation powders, aerosol preparations for spraying, ointments, powder for application, oils and creams.

In order to formulate the pharmaceutical composition of the present invention for parenteral administration, sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried preparations and external preparations may be used. Examples of the non-aqueous solutions and suspensions include propylene glycol, polyethylene Glycerol, vegetable oils such as olive oil, injectable esters such as ethyl oleate, and the like.

When the pharmaceutical composition of the present invention is formulated into an injection, the pharmaceutical composition of the present invention is mixed with a stabilizer or a buffer in water to prepare a solution or suspension, which is used for unit administration of an ampoule or a vial Can be formulated.

When the pharmaceutical composition of the present invention is formulated into an aerosol formulation, a propellant or the like may be added together with the additive such that the water-dispersed concentrate or the wet powder is dispersed.

When the pharmaceutical composition of the present invention is formulated into an ointment, a cream, a powder for application, an oil, an external preparation for skin or the like, an animal oil, a vegetable oil, a wax, a paraffin, a starch, a tracer, a cellulose derivative, a polyethylene glycol, , Silica, talc, zinc oxide or the like as a carrier.

The pharmaceutically effective amount and the effective dose of the pharmaceutical composition of the present invention can be varied depending on the formulation method, administration method, administration time and / or administration route of the pharmaceutical composition, and the kind of reaction to be achieved by administration of the pharmaceutical composition Including the age, weight, general health condition, degree and severity of the disease, sex, diet, excretion, drugs used simultaneously or simultaneously with the subject, and other compositional components, etc. May be varied according to factors well known in the art and in the pharmaceutical arts, and those of ordinary skill in the art can readily determine and prescribe dosages that are effective for the desired treatment. For example, the pharmaceutical composition of the present invention can be administered once to several times in a dose of 1 mg to 1 g, preferably 30 mg to 120 mg, on an adult basis on a day.

The administration of the pharmaceutical composition of the present invention may be administered once a day or divided into several doses. The pharmaceutical composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, and may be administered sequentially or simultaneously with conventional therapeutic agents. Taking into consideration all of the above factors, in such an amount as to obtain the maximum effect in a minimal amount without side effects, which can be easily determined by those skilled in the art.

The oleanolic acid of the present invention is a compound derived from a natural product. The oleanolic acid of the present invention, its derivatives and pharmaceutically acceptable salts thereof can be safely used for long term administration for prevention, improvement and treatment of diseases without toxicity and side effects . The fact that long-term administration of oleanolic acid does not present toxicity and side effects is supported by many studies. (Biochem Pharmacol. 2010 Jan 15; 79 (2): 198-208.Doi: 10.1016 / J.Bcp.2009.08.002. Epub 2009 Aug. 11. Beneficial actions of oleanolic acid in an experimental model of multiple sclerosis: a potential therapeutic Martin R1, Carvalho-Tavares J, Hernandez M, Arnes M, Ruiz-Gutierrez V, Nieto ML .; Chem Biol Interact 2010 Apr 15: 185 (1): 59-65 doi: 10.1016 / j.cbi. 2010.02.028. Epub 2010 Feb 24. Oleanolic acid, a natural triterpenoid improves blood glucose tolerance in normal mice and ameliorates visceral obesity in mice fed a high-fat diet de Melo CL1, Queiroz MG, Fonseca SG, Bizerra AM, Lemos TL , Melo TS, Santos FA, Rao VS.)

The route of administration and the mode of administration of the pharmaceutical composition of the present invention may be independent of each other, and may be arbitrarily selected depending on the route of administration and the mode of administration as long as the pharmaceutical composition can reach the desired site. The pharmaceutical composition may be administered orally or parenterally.

Examples of the parenteral administration method of the pharmaceutical composition of the present invention include intravenous administration, intraperitoneal administration, intramuscular administration, transdermal administration or subcutaneous administration, and the method of applying, spraying or inhalation the above composition But are not limited thereto.

The pharmaceutical composition of the present invention can be used in combination with various methods such as hormone therapy, drug therapy, etc. to prevent, ameliorate or treat neurodevelopmental disorder or obsessive-compulsive disorder.

The present invention provides a health functional food for preventing or ameliorating a neurodevelopmental disorder or obsessive-compulsive disorder comprising oleanolic acid, a derivative thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

The term " pharmaceutically acceptable salt " used in the present invention means a salt which can be used in foodstuffs among salts in which cations and anions are bound by electrostatic attraction, Specific examples include examples of the above-mentioned "pharmaceutically acceptable salts ".

The term " health food "used in the present invention refers to a food having an active health promotion effect or a health promotion effect as compared to a general food, and a health supplement food means a health food. In some cases, the terms functional food, health food, and health supplement are used. The food may be prepared in various forms such as tablets, capsules, powders, granules, liquids,

The term " functional food " as used in the present invention refers to a food for special health use (FoSHU). In addition to nutrition, the term " functional food " It means foods with high effectiveness.

The health functional food of the present invention may contain additional components that are commonly used in food compositions and can improve odor, taste, visual appearance and the like. For example, vitamins A, C, D, E, B1, B2, B6, B12, niacin, biotin, folate, panthotenic acid and the like. In addition, it may include minerals such as zinc (Zn), iron (Fe), calcium (Ca), chromium (Cr), magnesium (Mg), manganese (Mn) and copper (Cu) It may also include amino acids such as lysine, tryptophan, cysteine, valine, and the like. It is also possible to use preservatives such as potassium sorbate, sodium benzoate, salicylic acid and dihydroxyacetate, disinfectants such as bleaching powder and highly bleached sodium hypochlorite, antioxidants such as butylhydroxyanilide (BHA), butylhydroxytoluene (BHT ), Coloring agent (tar color, etc.), coloring agent (such as sodium nitrite, sodium acetylate), bleaching agent (sodium sulfite), seasoning (MSG sodium glutamate, etc.), sweetener (hypodermic, cyclamate, saccharin, (Food additive) such as flavorings (vanillin, lactones, etc.), swelling agents (alum, potassium hydrogen D-tartrate), reinforcing agents, emulsifiers, thickeners, encapsulating agents, gum bases, foam inhibitors, Can be added. The additives may be selected and used in appropriate amounts depending on the type of food.

When the health functional food of the present invention is used as a food additive, it may be added as it is or may be used together with other food or food ingredients, and may be appropriately used according to a conventional method.

In the health functional food of the present invention, the content of the oleanolic acid, its derivative or the pharmaceutically acceptable salt thereof is not particularly limited and may be variously changed according to the condition of the subject to be administered, . If necessary, it may also be included in the total content of the food.

The oleanolic acid of the present invention is excellent in improving the symptoms including repeated action, hyperactivity, sociability deterioration, cognitive impairment, emotional anxiety, attention deficit and the like, and is effective for treating Fragile X Syndrome, Efficacy of effectively preventing, ameliorating, and treating neurodevelopmental or obsessive-compulsive disorder including hyperactivity disorder (ADHD), autistic disorder, Tourette Syndrome, asthma, mood disorder, sleep disorder, bipolar disorder .

In addition, the oleanolic acid of the present invention is a naturally occurring compound and has no side effects, so that it can be utilized variously as a pharmaceutical composition, a health functional food, and the like.

1 is a chemical structural formula of the oleanolic acid of the present invention.
FIG. 2 is a graph showing the results of bead screening test of mice according to the administration of oleanolic acid according to the present invention. FIG.
FIG. 3 is a graph showing the results of an open field test of mice according to the administration of oleanolic acid according to the present invention.
FIG. 4 is a graph showing the social interaction test results of mice according to the administration of oleanolic acid according to the present invention, wherein (a) is a sociometric index, and (b) is a graph showing a social intelligence index.
FIG. 5 is a graph showing the results of the Barnes maze test of mice according to the administration of oleanolic acid according to the present invention. FIG. 5 (a) is a graph showing the time taken to reach the target point, and FIG.

Hereinafter, the present invention will be described in more detail with reference to examples. However, these examples are for illustrative purposes only, and the scope of the present invention is not limited to these examples. In addition, the reagents and solvents used below are purchased from Sigma, unless otherwise noted.

Example  1: Preparation of experimental animals for neurodevelopmental disorders

Using Fmrl KO deficient in Fragile X mental retardation protein (FMRP) as an animal model for neurodevelopmental and obsessive compulsive disorder, we confirmed the efficacy of oleanolic acid to prevent, ameliorate and treat neurodevelopmental and obsessive-compulsive disorder.

1) Preparation of experimental animals

About 26 g to 28 g of FVB-based Fmr1 KO mice (Jackson Laboratory, USA) were allowed to freely take up water and feed, and were subjected to an environment having a temperature of about 23 ± 2 ° C., a humidity of about 55 ± 10% (KHUASP (SE) 15-119), which was used for the experiment after animal breeding (animal laboratory of the College of Pharmacy, Kyung Hee University).

2) Statistical processing

All experimental results were statistically analyzed using one-way analysis of variance (ANOVA). Two-way ANOVA and post-Bonferroni post-test were used for treatment of variables between drug treatment and genetic groups.

3) Drug treatment

All animals were treated with WT and deficient KO male mice with normal FMRP expression. The dosing was carried out at the same time, and weekly weights were measured to confirm drug-induced stress and toxicity. Behavioral testing was carried out one week after dosing and continued for 4 weeks.

(OA 10, 30) and 4 to 6 groups (4 to 10 animals per group), each of which was administered with oleanolic acid in WT and KO, respectively. For the drug-administered group, oleanolic acid was dissolved in a 10% Tween 80 solution and then orally administered at a dose of 10 mg / kg and 30 mg / kg, respectively. Meanwhile, 10% Tween 80 solution was orally administered to the control group.

Example  2: Bead Hide Test ( Marble burying test )

When rodents are placed in a cage with beads aligned, rodents show a tendency to bury beads when suffering from mental illness such as obsessive compulsive disorder. At this time, when treating the treatment for obsessive compulsive disorder, the number of beads hiding in rodents is significantly decreased. Using this simple experiment (bead hiding), we can identify the obsessive-compulsive behavior, repetitive behavior, and impulsive behavior of the rodent (Cogn Affect Behav Neurosci. 2016 Jun; 16 (3): 551-60.doi: 10.3758 / s13415- 016-0413-8. Of mice and marbles: Novel perspectives on burying behavior as a screening test for psychiatric illness. Wolmarans de W, Stein DJ, Harvey BH).

The bedding was laid on the cage at a height of 5 cm, and 20 balls of 4 x 5 were arranged thereon. Then, the mice prepared in Example 1 were placed in a cage containing beads and observed for 30 minutes. After 30 minutes, the remains of each bead were photographed and the number of beads buried in the bed was recorded. At that time, only two-thirds of the beads buried in the bedding counted the number of beads.

The greater the number of beads hidden, the greater the repetitive behavior. The average number of hidden beads of mice in each group is shown in Table 1 and FIG.

[Table 1]

As shown in Table 1 and FIG. 2, the number of beads occluded in the group treated with oleanolic acid in the KO group was significantly lower than that in the control group 2 administered with vehicle, indicating that the repetitive behavior was improved do. On the other hand, in the case of the WT group as a normal animal, it was confirmed that the drug was not significantly influenced by the medication. This demonstrates that oleanolic acid can effectively prevent or treat neurodevelopmental disorders, obsessive-compulsive disorders that exhibit repetitive behavior.

Example  3: open field test ( Open field test )

The animals were placed in a black box (open field box) of 90 x 90 x 90 cm, and then the animal's movement was observed for a certain period of time. The moving distance, speed, habit of climbing the wall, , Grooming, etc. can be analyzed through the Ethovision program (analysis program). As a result, it is possible to check the general health status of the animal, mental activity, mobility, etc. (Exp Toxicol Pathol 2003 Jul; 55 (1): 69-83.) Behavioral phenotyping of mice in pharmacological and toxicological research Karl T, Pabst R , von Horsten S). The experimental method is as follows.

The mice prepared in Example 1 were placed in an open field box, video of 30 minutes of action was recorded, and general behavior of the animals was evaluated through an analysis program.

The results of the experiment are shown in Table 2 and FIG.

[Table 2]

As shown in the above Table 2 and FIG. 3, in the KO group, the distances shifted compared with the control group 2 in which the vehicle was administered showed a remarkable decrease with the drug-administered groups 3 and 4 administered with oleanolic acid. On the other hand, in the case of the WT group as a normal animal, it was confirmed that the drug was not significantly influenced by the medication. This demonstrates that oleanolic acid can effectively prevent or treat neurodevelopmental disorders such as hyperactivity, obsessive-compulsive disorder.

Example  4: Social interaction test ( Social interaction test )

Three-chamber test is a typical behavioral test measuring general sociability and social novelty. Usually rodents prefer sociability with other animals and social novelty rather than being isolated alone. This experiment is an experimental method for experimentally confirming whether an animal has problems in sociality or intelligence of the society (Nat Rev Neurosci. 2010 Jul 11 (7): 490-502 doi: 10.1038 / nrn2851 Behavioural Phenotyping assays for mouse models of autism. Silverman JL1, Yang M, Lord C, Crawley JN).

The three chamber boxes are literally made up of three rooms, each of which can be moved freely into an open space. The mouse prepared in Example 1 was placed in the center of an empty test box and was adapted to the space for 10 minutes. Then, the left and right space of the mouse are arbitrarily divided into S1 (space in which the mouse is placed) and Empty (empty space), and a stimulus animal is put into the mouse and the behavior of the test mouse is observed for 10 minutes Respectively. In other words, the time spent in the S1 and Empty space was measured to assess the behavior of the animal to sociability with other animals.

Immediately afterwards, the time to stay in the S2 space (ie, the space where the new mouse is placed) and the time to stay in the S1 space where the existing animal is placed, novelty.

The results of the above experiment are shown in Table 3 and FIG. 4, and the sociability index and the social intellectual index are calculated by the following equations.

[Table 3]

As shown in Table 3 and FIG. 4, the groups 3 and 4 administered with oleanolic acid in the KO group significantly increased the sociability and cognitive ability as compared with the control group 2 administered with Vehicle, and they were almost similar to the control group 1 Respectively. This demonstrates that oleanolic acid can effectively prevent or treat neurodevelopmental disorders, obsessive compulsive disorders such as sociability deterioration.

Example  5: Barnes  Maze test ( Barnes maze test )

Barnes Maze is a method of evaluating spatial memory that is very similar to the Morris Underwater Maze test, but it is a relatively less stressful method in that it does not train swimming in water.

Barnes maze placed a fluorescent light on a disk of 20 holes of the same size to give a strong light stimulus to the experimenter, place visual cues on every quadrant, and place an escape box on one of the holes It is constructed so that the animal enters and rests.

The experiment was carried out for a total of 6 days. On the first day, the mouse prepared in Example 1 was adapted to enter the box (target box) on the disk. From the 2nd to the 5th day, the mouse was trained to enter the target box by referring to the visual hint for 180 seconds on the disk three times a day, and the latency and error nomber for reaching this time were recorded Respectively. After removing the box on the last day, we evaluated whether the mouse remembers the space in which the target box was placed for 120 seconds. In this case, we analyze the time in target zone in the target zone of the quadrant . That is, the data during the training period is used to evaluate the learning ability of the mouse, and the amount of learning that is generated during the test day.

The results of the above experiment are shown in Table 4 and FIG.

[Table 4]

As shown in Table 4 and FIG. 5, in the case of the KO group, the drug administration groups 3 and 4 administered with oleanolic acid showed time to reach the target point during the training period of 4 days compared to the vehicle control group 2 Lt; / RTI > In addition, the time to stay at the target point significantly increased on the day of the test. On the other hand, in the case of the WT group as a normal animal, it was found that it was not significantly influenced by the drug administration. This demonstrates that oleanolic acid can effectively prevent or treat cognitive disorders such as learning and memory depression, neurodevelopmental disorders, and obsessive-compulsive disorders.

It is to be understood that both the foregoing general description and the following detailed description of the present invention are exemplary and explanatory and are intended to provide further explanation of the invention as claimed. More variations are possible within a range that does not. Accordingly, the present invention may be embodied in other forms without departing from the spirit or scope of the inventive concept as defined by the appended claims and their equivalents.

Claims (8)

A pharmaceutical composition for preventing or treating obsessive-compulsive disorder comprising oleanolic acid or a pharmaceutically acceptable salt thereof as an active ingredient. delete delete 2. The pharmaceutical composition according to claim 1, wherein the obsessive-compulsive disorder is a disease selected from storage compulsive disorder or social phobia. A health functional food for preventing or ameliorating obsessive-compulsive disorder comprising oleanolic acid or a pharmaceutically acceptable salt thereof as an active ingredient. delete delete 6. The health functional food according to claim 5, wherein the obsessive-compulsive disorder is a disease selected from storage compulsive disorder or social phobia.

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