KR20200031582A - Pharmaceutical Composition for Improving Fragile X Syndrome Comprising Agmatine or its derivatives - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for improving concentration, and preventing and treating (psychiatric) neurological behaviors such as cognitive impairment, lack of sociality and communication, hyperactivity, repetitive behavior, etc., which contains agmatine or pharmaceutically acceptable salt thereof.

Description

Pharmaceutical Composition for Improving Fragile X Syndrome Comprising Agmatine or its derivatives, including Agmatine and its pharmaceutically acceptable salts

The present invention is to prevent (psychiatric) neurological behaviors such as agmatine (agmatine) or pharmacologically acceptable salts thereof, improved concentration, cognitive dysfunction, lack of social and communication, hyperactivity, repetitive behavior, etc. It relates to a pharmaceutical composition for treatment. More specifically, the present invention, as a result of administering agmatine to a mouse knocking out Fragile X mental retardation protein (FMRP), a gene responsible for Fragile X Syndrome (FXS), was administered to the FMRP Knock-out. Agmatine-administered group can be effectively prevented or treated in mental neurological diseases including Fragile X Syndrome (FXS) by confirming improvement in repetitive behavioral problems, social and cognitive problems, etc. Was confirmed.

Fragile X Syndrome (FXS) is a genetic disease that occurs when the expression of Fragile X mental retardation protein (FMRP) does not appear. It decreases cognitive ability including learning and memory, social problems, communication difficulties, and hyperactivity. It is characterized by various neurobehavioral symptoms and physical anomalies. In particular, because it is located in the X gene, there is a large difference in the prevalence between sexes (in men, the prevalence is 2-3 times higher). The autism category of diseases (autism, Asperger's syndrome, childhood disintegrative disorder and general developmental disorder) is a mental and behavioral disorder corresponding to F of the disease classification code, while FXS is a gene X chromosome corresponding to Q of the disease classification code. Congenital anomalies, deformities, and chromosomal abnormalities caused by a break in the long arm, FXS is a completely different disease from the autistic category (autism, Asperger's syndrome, childhood disintegrative disorder, and general developmental disorder). However, FXS exhibits abnormal behaviors and comorbidities in mental neurological diseases such as autism, ADHD, and schizophrenia, which are a type of developmental disorder that is increasing worldwide. Therefore, there is an increasing demand for the development of functional substances or drugs, foods, etc., which are adaptable to the prevention and treatment of FXS.

FXS is a type of developmental disorder that occurs within 3 years of age, and various cerebral and hippocampal function disorders have been reported, such as hyperactivity, difficulty in learning and memory, impulsivity, and difficulty in social or communication. Symptoms persist from childhood to adulthood, leading to high social costs in terms of treatment and time in society as well as patients. The mechanism of development of FXS is relatively well known compared to other neurological diseases, but the approved and used therapeutics have not been developed. Since mGluR signaling and hyperactivity of functions of the central nervous system are common, treatment methods for adjusting the E / I balance of the brain by administering antagonists thereof or agonists of GABAergic signals have been widely used for the treatment. . Representative drugs include AFQ056 (mGluR5 antagonist), sertraline (SSRI), aripiprazole, and arbaclofen (GABA _B agonist). Since all of them slow the progression of the disease and have little effect on direct treatment and also have a limited treatment range in the early stages of the disease, efforts have been made to develop drugs to treat the underlying causes of FXS (Drugs. 2016 Mar; 76 ( 4): 431; Dev 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).

Agmatine of the present invention is reported as an NMDA receptor blocker and is an endogenous bio-amine formed by L-arginine decarboxylation. Agmatine has been reported to be responsible for neuroprotective functions, neurotransmitters, and neuromodulators. Accordingly, the present inventors are studying to develop an effective therapeutic agent that can prevent or treat mental neurological diseases such as FXS and improve learning ability or sociality, while effectively improving memory and cognitive ability and improving sociality, An active ingredient capable of alleviating impulsivity and hyperactivity was found and the present invention has been completed.

An object of the present invention is to provide a pharmaceutical composition for the prevention or treatment of Fragile X Syndrome (FXS) or related diseases containing agmatine or a pharmaceutically acceptable salt thereof as an active ingredient.

Another object of the present invention is to provide a health functional food composition for the prevention or improvement of Fragile X Syndrome (FXS) or related diseases containing agmatine or a pharmaceutically acceptable salt thereof as an active ingredient. .

The present invention relates to a pharmaceutical composition for the prevention or treatment of Fragile X Syndrome (FXS) or related diseases containing agmatine or a pharmaceutically acceptable salt thereof as an active ingredient.

Agmatine is a compound represented by the following formula (1).

[Formula 1]

The agmatine may include derivatives thereof represented by the following Chemical Formula 2.

[Formula 2]

R ₁ , R ₂ and R ₃ are each independently hydrogen or a halogen atom or substituted or unsubstituted alkyl, alkoxy, alkenyl, alkynyl, alkadienyl, aryl, aryloxy, heteroaryl, cycloalkyl, cycloal A kenyl, bicycloalkyl or heterocyclyl group.

 The agmatine represented by the above formula or a pharmaceutically acceptable salt thereof is a symptom of repetitive behavior, hyperactivity, and lack of sociality in Fragile X Syndrome (FXS) to Fragile X Syndrome (FXS) , Reduction of learning ability or reduction of prior stimulation suppression can prevent or treat symptoms. More specifically, agmatine represented by the above formula and a pharmaceutically acceptable salt thereof reduce repetitive behavior, suppress excessive behavior, improve social performance, learning ability, and increase antecedent stimulation suppression, resulting in fragile X syndrome (Fragile X Syndrome (FXS) or related diseases can be prevented or treated. In addition, the pharmaceutical composition comprising agmatine represented by the above formula of the present invention or a pharmaceutically acceptable salt thereof has no toxicity and side effects, and thus can be safely used even when prolonged for prophylactic or therapeutic purposes.

In the pharmaceutical composition comprising the agmatine or a pharmaceutically acceptable salt thereof of the present invention, the agmatine or a pharmaceutically acceptable salt thereof is administered once or several times per day in a dose of 1 mg to 1 g per adult. It is possible to administer, preferably a single to several doses in a dose of 30 mg to 120 mg. However, the dosage of the agmatine or a pharmaceutically acceptable salt thereof can be appropriately adjusted according to the patient's condition such as the patient's severity, age, sex, and weight, and the formulation, administration route, and administration period of the drug.

The pharmaceutical composition of the present invention may include the active material in an amount of 0.1 to 50% by weight based on the total weight of the composition. However, the content is not necessarily limited to this, and may vary depending on the patient's condition and the type and progression of the disease.

The disease related to the Fragile X Syndrome (FXS) may be autism categorical disease, and the autistic categorical disease may be autism, Asperger's syndrome, childhood disintegrative disorder and general developmental disorder (PDD-NOS).

In the pharmaceutical composition for preventing or treating diseases related to Fragile X Syndrome (FXS) containing the active ingredient of the present invention, the active substance is administered once or several times per day in a dose of 1 mg to 1 g per adult. It is possible to administer, preferably a single to several doses in a dose of 30 mg to 120 mg. However, the dosage of the drug may be appropriately adjusted according to the patient's condition such as the patient's severity, age, sex, and weight, and the drug formulation, administration route, and administration period.

The pharmaceutical composition comprising agmatine or a pharmaceutically acceptable salt thereof according to the present invention is used alone or hormonal therapy, drug treatment, etc. to prevent or treat mental neurological disorders that exhibit symptoms such as decreased concentration, impulsivity and sociality. It can be used in combination with a variety of methods.

The pharmaceutical composition comprising agmatine represented by Formula 1 of the present invention or a pharmaceutically acceptable salt thereof is a pharmaceutically acceptable diluent, binder, disintegrant, lubricant, pH within a range not impairing the effects of the present invention Additives such as regulators, antioxidants, and dissolution aids may be included. Diluents may include sugar, starch, microcrystalline cellulose, lactose (lactose hydrate), glucose, di-mannitol, alginate, alkaline earth metal salts, clay, polyethylene glycol, calcium hydrogen phosphate anhydride, or mixtures thereof; Binders are starch, microcrystalline cellulose, highly dispersible silica, mannitol, di-mannitol, sucrose, lactose hydrate, polyethylene glycol, polyvinylpyrrolidone (povidone), polyvinylpyrrolidone copolymer (copovidone), hypromellose , Hydroxypropyl cellulose, natural gums, synthetic gums, copovidone, gelatin, or mixtures thereof. Disintegrants include starch or modified starch such as sodium starch glycolate, corn starch, potato starch or pregelatinized starch; Clays such as bentonite, montmorillonite, or veegum; Cellulose such as microcrystalline cellulose, hydroxypropyl cellulose or carboxymethyl cellulose; Algins such as sodium alginate or alginic acid; Cross-linked celluloses such as croscarmellose sodium; Gums such as guar gum and xanthan gum; Crosslinked polymers such as crosslinked polyvinylpyrrolidone (crospovidone); Effervescent agents, such as sodium bicarbonate and citric acid, or mixtures thereof can be used. Lubricants are talc, stearic acid, magnesium stearate, calcium stearate, sodium lauryl sulfate, hydrogenated vegetable oil, sodium benzoate, sodium stearyl fumarate, glyceryl behenate, glyceryl monorate, glyceryl monostearate, glyceryl palmi Tostearate, colloidal silicon dioxide, or mixtures thereof can be used. pH adjusting agents include acidifying agents such as acetic acid, adipic acid, ascorbic acid, sodium ascorbate, sodium ether, malic acid, succinic acid, tartaric acid, fumaric acid, citric acid (citric acid) and precipitated calcium carbonate, ammonia water, meglumine, carbonic acid Basic agents such as sodium, magnesium oxide, magnesium carbonate, sodium citrate and tribasic calcium phosphate can be used. Antioxidants may use dibutyl hydroxy toluene, butylated hydroxyanisole, tocopherol acetate, tocopherol, propyl gallate, sodium hydrogen sulfite, sodium pyrosulfite, etc. In the prior-release compartment of the present invention, the dissolution aid is Polyoxyethylene sorbitan fatty acid esters such as sodium lauryl sulfate and polysorbate, docusate sodium, and poloxamer can be used.

The pharmaceutical composition comprising agmatine or a pharmaceutically acceptable salt thereof of the present invention may be formulated into solid preparations such as tablets, pills, powders, granules and capsules for oral administration. Martin-containing compound and at least one excipient, for example, starch, calcium carbonate (calcium carbonate), sucrose (sucrose) or lactose (lactose), may be prepared by mixing gelatin. In addition, lubricants such as magnesium stearate can be used in addition to simple excipients. In addition, the pharmaceutical composition may be formulated as a liquid formulation such as suspension, oral solution, emulsion, syrup for oral use, and various excipients, such as water and liquid paraffin, for example, wetting agents, sweeteners, fragrances, and preservatives are used. It can be formulated as a liquid formulation.

Agmatine of the present invention and its derivatives or pharmaceutical compositions containing the same may include sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, and suppositories for formulation for parenteral administration. Non-aqueous solvents and suspensions may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. As a base for suppositories, witepsol, macrogol, tween 61, cacao butter, laurin butter, and glycerogelatin may be used.

The term "administration" in the present invention means to introduce a composition for prevention and treatment in a kind of developmental disorder or mental neurological disorder, such as FXS of the present invention, to a patient in any suitable way, improving the learning ability and sociality of the present invention And the administration route of the composition for the prevention and treatment of developmental disorders or mental neurological diseases can be administered through any general route as long as the target tissue can be reached. Oral administration, intraperitoneal administration, intravenous administration, intramuscular administration, subcutaneous administration, intradermal administration, intranasal administration, intrapulmonary administration, rectal administration, intranasal administration, intraperitoneal administration, intrathecal administration, but limited thereto It does not work. For example, it can be administered by oral, rectal or intravenous, intramuscular, subcutaneous, intrauterine dura mater or intracerebroventricular injection.

The present invention can provide a health functional food composition for the prevention or improvement of Fragile X Syndrome (FXS) or related diseases containing agmatine or a pharmaceutically acceptable salt thereof as an active ingredient.

 The agmatine represented by the above formula or a pharmaceutically acceptable salt thereof is a symptom of repetitive behavior, hyperactivity, social lack of symptoms, decreased learning ability, or decreased prior stimulation suppression as indicated by Fragile X Syndrome (FXS). Can be prevented or improved. Specifically, agmatine represented by the above formula and its pharmaceutically acceptable salts reduce repetitive behavior, inhibit hyperactivity, improve social performance and learning ability, and increase antecedent stimulation suppression, resulting in fragile X syndrome (Fragile X Syndrome (FXS) or related diseases can be prevented or improved. The pharmaceutical composition comprising agmatine or a pharmaceutically acceptable salt thereof of the present invention can effectively treat and improve the abnormal behavior of the mouse without any special side effects.

The Fragile X Syndrome (FXS) related disease may be autism categorical disease, and the autistic categorical disease may be autism, Asperger's syndrome, childhood disintegrative disorder, and general developmental disorder (PDD-NOS).

The present invention relates to a food composition for preventing or improving mental neurological diseases that exhibit symptoms such as decreased concentration, impulsiveness and sociality, and a pharmaceutical composition comprising agmatine represented by the above formula or a pharmaceutically acceptable salt thereof.

The food composition according to the present invention may further include an additive, such as a food composition, a dietary supplement or a beverage. For example, the food composition of the present invention includes sweeteners such as white sugar, fructose, glucose, D-sorbitol, mannitol, isomaltoligosaccharide, stevioside, aspartame, acesulfame potassium, sucralose, citric anhydride, DL- Acidifying agents such as malic acid, succinic acid and salts thereof, preservatives such as benzoic acid and derivatives thereof, various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic flavoring agents and natural flavoring agents, coloring agents and neutralizing agents (cheese, chocolate And the like), pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickeners, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols, carbonic acid used in carbonated beverages, and the like. In addition, the food compositions of the present invention may contain flesh for the preparation of natural fruit juices and vegetable drinks. The proportion of these additives may be used in the range of about 20 parts by weight or less per 100 parts by weight of the food composition of the present invention. When the food composition of the present invention is a beverage, it may further include flavoring agents or natural carbohydrates commonly included in beverages. The natural carbohydrate may be monosaccharides such as glucose and fructose, disaccharides such as maltose and sucrose, polysaccharides such as dextrin and cyclodextrin, or sugar alcohols such as xylitol, sorbitol and erythritol. In addition, the flavoring agent may be a natural flavoring agent of taumatin or stevia extract (rebaudioside A, glycyrrhizine) or a synthetic flavoring agent such as saccharin or aspartame. When the food composition is a beverage, natural carbohydrates may be included in an amount of about 1 g to 20 g, preferably about 5 g to 12 g per 100 ml of the composition. The food composition comprising the agmatine of the present invention or a pharmaceutically acceptable salt thereof is prepared in the form of a powder, granule, tablet, capsule or beverage to be used as foods, beverages, gums, teas, vitamin complexes, and dietary supplements You can. The composition comprising agmatine or a pharmaceutically acceptable salt thereof of the present invention may be added to medicines, food and beverages for improving or improving learning ability and preventing or improving hyperactivity or social communication problems. For example, the Agmatine of the present invention and its derivatives or compositions containing the same may be added to food, beverages, gums, teas, vitamin complexes, health supplements, and the like. The composition of the present invention may be added at 1% to 5% by weight of the total weight of the food, and may be added at a rate of 0.02 g to 10 g, preferably 0.3 g to 1 g, to 100 ml of beverage.

The pharmaceutical composition comprising agmatine and its derivatives or a part of the compound according to the present invention can effectively prevent and treat (psychiatric) neurological behaviors and diseases such as concentration improvement, cognitive dysfunction, social performance communication, repetitive behavior, etc. have. Specifically, a pharmaceutical composition comprising agmatine or a pharmaceutically acceptable salt thereof according to the present invention effectively prevents fragile X syndrome (Fragile X Syndrome; FXS) by improving repetitive behavioral problems and social and cognitive problems. It can be treated.

Figure 1 shows the structural formula of the Agmatine of the present invention.
2 is a view showing the effect of alleviating the repetitive behavior or impulsivity of the pharmaceutical composition comprising agmatine according to the present invention.
3 is a view suggesting that it is effective in the hyperactivity of the pharmaceutical composition containing agmatine according to the present invention.
4 is a result showing the social and cognitive memory enhancement effect of the pharmaceutical composition containing agmatine according to the present invention, showing the search time for the animal of the same species and the empty space accordingly "social indicator" (animal / bin It is the result of calculating the time to stay in space.
Figure 5 is a result showing the social and cognitive memory enhancement effect of the pharmaceutical composition containing agmatine according to the present invention, the result of displaying the search time in familiar and unfamiliar animals, accordingly "social cognitive ability or preference index" It is the result of calculating (Search time for unfamiliar / friendly animals).
6 is a result showing the learning and memory improvement effect of the pharmaceutical composition containing agmatine according to the present invention, and the result of arranging the effect on the learning period of memory by displaying the time taken to remember the target point (Latency) .
7 is a result showing the learning and memory enhancement effect of the pharmaceutical composition containing agmatine according to the present invention, after the memory is formed, an index for evaluating the spatial memory ability of the test animal for 90 seconds, the target point in the entire quadrant It is the result of arranging the time to stay in.
8 is a view showing the pre-stimulation inhibitory effect of the pharmaceutical composition comprising agmatine according to the present invention.
9 is a view showing an improvement effect on (social) communication of a pharmaceutical composition comprising agmatine according to the present invention.

The following preparation examples and experimental examples are intended to explain the present invention in more detail. These production examples and experimental examples are only for explaining the present invention, and the scope of the present invention is not limited by the following production examples and experimental examples. In addition, the reagents and solvents mentioned below were purchased from Sigma, unless otherwise specified.

Experimental Example: Confirmation of neuropharmacological efficacy of Agmatine

The following experiments were performed using a transgenic animal (Fmr1 KO mouse) deficient in FMRP protein in order to confirm the therapeutic efficacy of psycho-inflammatory diseases including FXS of a drug containing agmatine. The results are as follows.

Preparation Example 1 Preparation of experimental animals

An environment in which approximately 26g to 28g of 6-9 week old FVB-based Fmr1 KO mouse (Jackson Laboratory, USA) is free to consume water and feed, and the temperature is about 23 ± 2 ℃, humidity is about 55 ± 10%, and the contrast cycle is 12 hours. After adaptation and breeding (animal laboratory of the College of Pharmacy, Kyung Hee University), it was used for experiments. The deliberation approval number of the animal experiment is as follows. KHUASP (SE) 15-119

Preparation Example 2 Drug Treatment

All animals used WT with normal FMRP expression and KO male mice lacking FMRP expression (inducing Fragile X Syndrome (FXS)), and long-term dosing and experiments were conducted according to age. Dosing was conducted at the same time, and weekly weight was measured to check the stress and toxicity caused by the drug. Behavioral experiments were conducted one week after dosing, and dosing continued for four weeks. A group administered 30 mg / kg (Example 1) or 100 mg / kg (Example 2) of agmatine to Knock-Out mice lacking FMRP expression, respectively, and 30 mg / kg of agmatine to Wild Type mice, respectively. (Control 1) or 100 mg / kg (Control 2), Wild Type mice treated with 0.9% physiological saline (saline solution) (Control 3) and FMRP expression-deficient Knock-Out mice It was divided into groups (Comparative Example 1) to which 0.9% physiological saline (saline solution) was administered to prepare 4-10 animals per group. For the drug administration group, agmatine was dissolved in 0.9% physiological saline (saline solution) and then administered intraperitoneally at a dose of 30 and 100 mg / kg. Meanwhile, in the control group, 0.9% physiological saline (saline solution) was administered intraperitoneally.

Experimental Example 1: Marble burying test

For the experiment, beads were arranged in a cage in which a bedding was prepared. After the mice prepared in 3) were placed in a cage containing beads, the behavior was observed for 30 minutes. After the end of the experiment, the remaining figure of each marble was photographed and the number was recorded. The more the number of hidden marbles, the greater the repetitive behavior. Table 1 and FIG. 2 show the average number of hidden beads in each group of mice.

Experimental group Number of hidden marbles (no) Control 1
(Wild Type; Agmatine 30 mg / kg) 7.50 ± 1.336 Control 2
(Wild Type; Agmatine 100 mg / kg) 7.67 ± 1.382 Example 1
(Knock-Out lacking FMRP expression
Agmatine 30 mg / kg) 12.70 ± 1.155 Example 2
(Knock-Out lacking FMRP expression
Agmatine 100 mg / kg) 10.83 ± 0.895 Control 3
(Wild Type; Vehicle) 7.13 ± 1.394 Comparative Example 1
(Knock-Out Vehicle lacking FMRP expression) 18.30 ± 0.684

As can be seen from Table 1 and Figure 2, in the case of the KO group, Example 1 and Example 2 administered agmatine significantly reduced repetitive behavior compared to Comparative Example 1 administered vehicle. On the other hand, in the case of the normal animal WT group, the control group 1 and the control group 2, the amantin administration group, did not have a significant difference compared to the control group 3, which was administered with the vehicle, so that they were not significantly affected by behavioral drug administration. Able to know. From this, it was found that agmatine can effectively prevent or treat FXS, which exhibits repetitive behaviors, and developmental disorders and mental neurological disorders related thereto.

Experimental Example 2: Open field test

The mice were divided into groups as in Preparation Example 2, and 0.9% of physiological saline (saline solution) or agmatine was administered intraperitoneally to Knock-Out mice lacking wild typ or FMRP expression. After that, an open field test was conducted. The results of the experiment are shown in Table 2 and FIG. 3 below.

Experimental group Distance traveled (cm) Control 1
(Wild Type; Agmatine 30 mg / kg) 7111 ± 1037 Control 2
(Wild Type; Agmatine 100 mg / kg) 6671 ± 2041 Example 1
(Knock-Out lacking FMRP expression
Agmatine 30 mg / kg) 8758 ± 403 Example 2
(Knock-Out lacking FMRP expression
Agmatine 100 mg / kg) 6657 ± 1414 Control 3
(Wild Type; Vehicle) 7692 ± 230 Comparative Example 1
(Knock-Out Vehicle lacking FMRP expression) 12040 ± 379

As can be seen in Table 2 and FIG. 3, in the case of the KO group, Example 1 and Example 2 in which agmatine was administered were significantly reduced in distance compared to Comparative Example 1 in which the vehicle was administered. On the other hand, in the case of the normal animal WT group, the control group 1 and the control group 2, the amantin administration group, did not have a significant difference compared to the control group 3, which was administered with the vehicle, so that they were not significantly affected by behavioral drug administration. Able to know. From this, it was found that administration of agmatine can effectively prevent or treat Fragile X Syndrome (FXS), such as hyperactivity, and developmental disorders and mental neurological disorders related thereto.

Experimental Example 3: Social interaction test (Three chamber task)

The mice were divided into groups as in Preparation Example 2, and 0.9% of physiological saline (saline solution) or agmatine was administered intraperitoneally to Knock-Out mice lacking wild typ or FMRP expression. Afterwards, a social interaction test was conducted using the Three chamber. The results of the experiment are shown in Table 3 below and FIGS. 4-5.

Experimental group Sociality Index (%) Social cognitive index (%) Control 1
(Wild Type; Agmatine 30 mg / kg) 71.59 ± 5.094 63.73 ± 4.850 Control 2
(Wild Type; Agmatine 100 mg / kg) 77.65 ± 4.975 67.43 ± 2.665 Example 1
(Knock-Out lacking FMRP expression
Agmatine 30 mg / kg) 64.03 ± 5.959 45.17 ± 1.659 Example 2
(Knock-Out lacking FMRP expression
Agmatine 100 mg / kg) 68.59 ± 4.351 58.36 ± 3.481 Control 3
(Wild Type; Vehicle) 62.60 ± 3.049 58.33 ± 3.485 Comparative Example 1
(Knock-Out Vehicle lacking FMRP expression) 31.80 ± 1.164 38.02 ± 1.432

As can be seen from Table 3 and FIGS. 4-5, in the case of the KO group, Examples 1 and 2 in which agmatine was administered significantly increased sociality and cognitive ability compared to Comparative Example 1 in which the vehicle was administered. . On the other hand, in the case of the normal animal WT group, the control group 1 and the control group 2, the agmatine administration group, did not have a significant difference compared to the control group 3, which was administered with the vehicle. You can. From this, it was found that administration of agmatine can effectively prevent or treat Fragile X Syndrome (FXS), such as social deterioration, and developmental disorders and psychoneurological disorders related thereto.

Experimental Example 4: Barnes maze test

The mice were divided into groups as in Preparation Example 2, and 0.9% of physiological saline (saline solution) or agmatine was administered intraperitoneally to Knock-Out mice lacking wild typ or FMRP expression. Then, learning and memory were evaluated using Barnes maze. The results of the experiment are shown in Table 4 below and FIGS. 6-7.

Experimental group Time it takes to reach the target point (s) Time to stay at target point (s) 1 day 2 days 3 days 4 days Control 1
(Wild Type; Agmatine 30 mg / kg)  175.8 ± 4.25 127.5 ± 15.95 48.4 ± 9.04 24.5 ± 3.60 47.75 ± 3.051 Control 2
(Wild Type; Agmatine 100 mg / kg) 172.1 ± 7.88 97.8 ± 16.42 40.0 ± 8.82 30.5 ± 5.79 45.13 ± 5.961 Example 1
(Knock-Out lacking FMRP expression
Agmatine 30 mg / kg) 179.2 ± 0.80 144.9 ± 16 112.6 ± 5.21 101.6 ± 6.95 39.47 ± 9.665 Example 2
(Knock-Out lacking FMRP expression
Agmatine 100 mg / kg) 180 123.0 ± 17.35 94.0 ± 9.14 98.1 ± 14.36  43.13 ± 2.967 Control 3
(Wild Type; Vehicle) 173.0 ± 7.00 112.8 ± 12.21 53.0 ± 4.45 27.8 ± 3.91 51.55 ± 7.140 Comparative Example 1
(Knock-Out Vehicle lacking FMRP expression) 180 166.9 ± 7.88 130.7 ± 6.33 128.2 ± 5.39  19.70 ± 4.668

As can be seen in Table 4 and Figure 6-7, in the case of the KO group, Example 1 and Example 2 in which agmatine was administered were target points during a four-day training period compared to Comparative Example 1 in which a vehicle was administered. The time to reach was significantly reduced. In addition, on the day of the test, the time to stay at the target point was significantly increased. On the other hand, in the case of the normal animal WT group, the control group 1 and the control group 2, the agmatine administration group, did not have a significant difference compared to the control group 3, which was administered with the vehicle. Can. From this, it was found that administration of agmatine can effectively prevent or treat cognitive disorders such as deterioration of learning and memory.

Experimental Example 5: Prepulse inhibition test

The mice were divided into groups as in Preparation Example 2, and 0.9% physiological saline (saline solution) or agmatine was intraperitoneally administered to Knock-Out mice lacking wild typ or FMRP expression. Subsequently, sensorimotor gating was evaluated through a preceding stimulation inhibition test. The results of the above experiments were converted by Equation 1 below, and the results are shown in Tables 5 and 8 below.

The preceding stimulus inhibiting ability converted by Equation 1 is shown in Tables 5 and 8 below.

Experimental group Advance stimulation inhibiting ability (%) 3 dB 6 dB 12 dB 16 dB Control 1
(Wild Type; Agmatine 30 mg / kg) 3.6 ± 11.95 12.5 ± 11.12 45.9 ± 4.67 66.2 ± 2.89 Control 2
(Wild Type; Agmatine 100 mg / kg)  -1.9 ± 9.54 21.5 ± 5.94 53.0 ± 5.59 71.9 ± 2.82 Example 1
(Knock-Out lacking FMRP expression
Agmatine 30 mg / kg) -12.5 ± 6.70 -21.3 ± 9.58 26.3 ± 7.22 40.3 ± 4.74 Example 2
(Knock-Out lacking FMRP expression
Agmatine 100 mg / kg) 3.0 ± 9.90 18.1 ± 11.19 30.7 ± 11.89 51.2 ± 2.57 Control 3
(Wild Type; Vehicle) 18.4 ± 8.17 29.7 ± 8.76 52.0 ± 6.11 66.1 ± 3.28 Comparative Example 1
(Knock-Out; Vehicle lacking FMRP expression) -29.9 ± 17.35 3.0 ± 9.58 8.2 ± 11.91 9.2 ± 5.59

As can be seen in Table 5 and FIG. 8, in the case of the KO group, Examples 1 and 2 in which agmatine was administered increased inhibition of the prior stimulation compared to Comparative Example 1 in which the vehicle was administered. On the other hand, in the case of the normal animal WT group, the control group 1 and the control group 2, the agmatine administration group, did not have a significant difference compared to the control group 3, which was administered with the vehicle. You can. From this, it was found that administration of agmatine can effectively prevent or treat psycho-neuropathy disorders, which are antecedent stimulatory abnormalities represented by sensorimotor gating deficit.

Experimental Example 6: Ultrasonic vocalization test

The mice were divided into groups as in Preparation Example 2, and 0.9% of physiological saline (saline solution) or agmatine was administered intraperitoneally to Knock-Out mice lacking wild typ or FMRP expression. Then, ultrasonic vocalization was evaluated using Sonotrack. The results of the experiment are shown in Table 6 and FIG. 9 below.

Experimental group Total ultrasound count Control 1
(Wild Type; Agmatine 30 mg / kg) 1495 ± 143.2 Example 1
(Knock-Out lacking FMRP expression
Agmatine 30 mg / kg) 631 ± 164.7 Control 3
(Wild Type; Vehicle) 1104 ± 152.4 Comparative Example 1
(Knock-Out; Vehicle lacking FMRP expression) 190.3 ± 100.9

As can be seen in Table 6 and FIG. 9, in the case of the KO group, Example 1 in which agmatine was administered increased the total number of ultrasonic waves generated compared to Comparative Example 1 in which the vehicle was administered. That is, it can be seen that communication between the two is active. On the other hand, it can be seen that the control group 3, which is a normal animal, was not significantly affected by drug administration. From this, it was found that administration of agmatine can effectively prevent or treat developmental disorders or psychological disorders that indicate communication or social problems.

Claims (7)

Fragile X Syndrome (FXS) containing agmatine or a pharmaceutically acceptable salt thereof as an active ingredient or a pharmaceutical composition for preventing or treating diseases related thereto. The method of claim 1, wherein the agmatine or a pharmaceutically acceptable salt thereof is a symptom of repetitive behavior, hyperactivity, social lack of symptoms, decreased learning ability, or suppression of prior stimulation in Fragile X Syndrome (FXS). A pharmaceutical composition for the prevention or treatment of Fragile X Syndrome (FXS), characterized by preventing or treating reduced symptoms. The pharmaceutical composition for prevention or treatment according to claim 1, wherein the pharmaceutical composition is formulated in a tablet, capsule, pill, granule, powder, injection or liquid form. The pharmaceutical composition for preventing or treating Fragile X Syndrome (FXS) according to claim 1, wherein the Fragile X Syndrome (FXS) -related disease is an autism categorical disease. Fragile X Syndrome (FXS) containing agmatine or a pharmaceutically acceptable salt thereof as an active ingredient or a health functional food composition for preventing or improving diseases related thereto. The method of claim 5, wherein the agmatine or a pharmaceutically acceptable salt thereof is a symptom of repetitive behavior, hyperactivity, social lack of symptoms, decreased learning ability, or suppression of prior stimulation in Fragile X Syndrome (FXS). A health functional food composition for the prevention or improvement of Fragile X Syndrome (FXS), characterized by preventing or treating symptoms of reduction. The method of claim 5, wherein the Fragile X Syndrome (FXS) -related disease is autism categorical disease, Fragile X Syndrome (FXS) or a health functional food composition for the prevention or amelioration of diseases related thereto.

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