KR20190121569A - Pharmaceutical Composition for Improving Fragile X Syndrome Comprising Agmatine or its derivatives - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for preventing and treating (mental)neurological abnormalities such as concentration degradation, cognitive dysfunction, lack of social and communication, hyperactivity, repetitive behavior and the like, comprising agmatine or a pharmaceutically acceptable salt thereof.

Description

Pharmaceutical Composition for Improving Fragile X Syndrome Comprising Agmatine or its derivatives}

The present invention relates to the prevention and prevention of (mental) neurological abnormalities such as concentration improvement, cognitive impairment, lack of social and communication, hyperactivity, repetitive behavior, and the like, including agmatine or a pharmaceutically acceptable salt thereof. It relates to a therapeutic pharmaceutical composition. More specifically, the present invention is a result of administering agmatine to mice knocked out of Fragile X mental retardation protein (FMRP), which is the cause gene of Fragile X Syndrome (FXS), to the FMRP knock-out. Agmatine group was found to improve repetitive behavioral problems and social and cognitive problems, and can effectively prevent or treat agmatine in mental neurological diseases including Fragile X Syndrome (FXS). It was confirmed.

Fragile X Syndrome (FXS) is a hereditary disease caused by the absence of the expression of Fragile X mental retardation protein (FMRP) .Fragile X Syndrome (FXS) is a disorder of cognitive ability including learning and memory, social problems, communication difficulties, and hyperactivity. It is characterized by various neurobehavioral symptoms and physical malformations. In particular, because it is located in the X gene, there is a big difference in the prevalence between genders (2-3 times higher prevalence in men). Diseases of the autism category (autism, Asperger's syndrome, childhood disruptive disorders and general developmental disorders) are mental and behavioral disorders corresponding to F of the disease classification code, whereas FXS represents the gene X chromosome corresponding to Q of the disease classification code. Congenital malformations, deformities and chromosomal aberrations caused by breaking of the long arm distal end. FXS is a completely different disease from the autistic category of disorders (autism, Asperger's syndrome, childhood decay and overall developmental disability). However, FXS shows comorbidity and abnormal behaviors that occur in mental disorders 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, drugs, and foods that are adaptable to the prevention and treatment of FXS.

FXS is a type of developmental disorder that develops within three years of life and has been reported to have various cerebral and hippocampal dysfunctions, including hyperactivity, difficulty learning and memory, impulsivity, and social or communication difficulties. Symptoms persist at an early age and continue to adulthood, resulting in high social costs not only for patients but also for the treatment and time of society as a whole. The pathogenesis of FXS is relatively well known compared to other neurological diseases, but therapies currently approved and used have not been developed. Since mGluR signaling and functional overactivity of the central nervous system are common, the treatment method that adjusts the brain's E / I balance by administering its antagonist or GABAergic signal dysfunction has been widely used. . Representative drugs include AFQ056 (mGluR5 antagonist), sertraline (SSRI), aripiprazole, arbaclofen (GABA _B agonist). All of these have slowed disease progression, have little effect on direct treatment, and have a limited range of treatment at the outset, and efforts have been made to develop drugs to treat the underlying cause 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 bioamine formed by L-arginine decarboxylation. Agmatine is reported to be responsible for neuroprotective functions, neurotransmitters and neuromodulators. Accordingly, the present inventors can effectively improve memory and cognitive ability and improve sociality while researching to develop an effective therapeutic agent that can prevent or treat mental neurological diseases such as FXS and improve learning ability or sociality. The present invention was completed by finding an active ingredient that can alleviate impulsiveness and hyperactivity.

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

Still another object of the present invention is to provide a nutraceutical 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 preventing or treating Fragile X Syndrome (FXS) or a related disease 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 a derivative thereof, such as the following 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.

 Agmatine or a pharmaceutically acceptable salt thereof represented by the above formula is a symptom of repetitive behavior, hyperactivity, and social deficiency in Fragile X Syndrome (FXS) in Fragile X Syndrome (FXS). This can prevent or treat symptoms of decreased learning ability, or decreased pre-stimulation. More specifically, Agmatine and its pharmaceutically acceptable salts represented by the above formula decreases repetitive behavior, suppresses hyperactivity, improves social and learning ability, and increases pre-stimulation inhibition, thereby fragile X syndrome (Fragile). X Syndrome (FXS) or related diseases can be prevented or treated. In addition, the pharmaceutical composition comprising agmatine or a pharmaceutically acceptable salt thereof represented by the above formula of the present invention has no toxicity and side effects, and thus can be used safely for long-term administration 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 used once or several times at a dose of 1 mg to 1 g per adult. Administration is possible, preferably from single to several dosages of 30 mg to 120 mg. However, the dosage of the agmatine or a pharmaceutically acceptable salt thereof may be appropriately adjusted according to the patient's condition such as the severity, age, sex, and weight of the patient and the formulation, route of administration, and duration of administration of the drug.

The pharmaceutical composition of the present invention may include 0.1 to 50% by weight of the active substance based on the total weight of the composition. However, the content is not necessarily limited thereto, and may vary depending on the condition of the patient and the type and extent of the disease.

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

In the pharmaceutical composition for preventing or treating Fragile X Syndrome (FXS) -related diseases comprising the active ingredient of the present invention, the active substance is used once or several times at a dose of 1 mg to 1 g per adult. Administration is possible, preferably from single to several dosages 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 formulation, route of administration, and duration of administration of the drug.

The pharmaceutical composition comprising agmatine or a pharmaceutically acceptable salt thereof according to the present invention may be used alone or in hormonal therapy, drug therapy, or the like to prevent or treat mental neurological disorders such as decreased concentration, impulsivity and social symptoms. It can be used in combination with various methods.

A pharmaceutical composition comprising agmatine or a pharmaceutically acceptable salt thereof represented by Chemical Formula 1 of the present invention is a pharmaceutically acceptable diluent, binder, disintegrant, lubricant, pH within a range that does not impair the effects of the present invention. Additives such as modifiers, antioxidants, dissolution aids, and the like. The diluent may be sugar, starch, microcrystalline cellulose, lactose (lactose monohydrate), glucose, di-mannitol, alginate, alkaline earth metal salts, clay, polyethylene glycol, anhydrous calcium hydrogen phosphate, or a mixture thereof; Binders, starch, microcrystalline cellulose, highly dispersible silica, mannitol, di-mannitol, sucrose, lactose monohydrate, polyethylene glycol, polyvinylpyrrolidone (povidone), polyvinylpyrrolidone copolymer (copovidone), hypromellose , Hydroxypropyl cellulose, natural gum, synthetic gum, copovidone, gelatin, or a mixture thereof. The disintegrating agent may be a starch or modified starch such as sodium starch glycolate, corn starch, potato starch or pregelatinized starch; Clay such as bentonite, montmorillonite, or veegum; Celluloses such as microcrystalline cellulose, hydroxypropyl cellulose or carboxymethyl cellulose; Algins such as sodium alginate or alginic acid; Crosslinked 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, citric acid, or mixtures thereof can be used. Lubricants include talc, stearic acid, magnesium stearate, calcium stearate, sodium lauryl sulfate, hydrogenated vegetable oils, sodium benzoate, sodium stearyl fumarate, glyceryl behenate, glyceryl monorate, glyceryl monostearate, glyceryl palmi Tostearate, colloidal silicon dioxide, mixtures thereof, and the like. pH adjusters 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, carbonate Basic agents, such as sodium, magnesium oxide, magnesium carbonate, sodium citrate, and calcium tribasic phosphate, etc. can be used. The antioxidant may be dibutyl hydroxy toluene, butylated hydroxyanisole, tocopherol acetate, tocopherol, propyl gallate, sodium hydrogen sulfite, sodium pyrosulfite, etc. In the pre-release compartment of the present invention, dissolution aids Polyoxyethylene sorbitan fatty acid esters such as sodium lauryl sulfate and polysorbate, sodium docusate, poloxamer and the like.

The pharmaceutical composition comprising the agmatine of the present invention or a pharmaceutically acceptable salt thereof may be formulated into solid preparations such as tablets, pills, powders, granules, capsules, or the like for oral administration, and such solid preparations may be It may be prepared by mixing a martin-containing compound with at least one excipient such as starch, calcium carbonate, sucrose or lactose, gelatin and the like. In addition to simple excipients, lubricants such as magnesium styrate talc may also be used. In addition, the pharmaceutical composition may be formulated as a liquid preparation such as oral suspensions, liquid solutions, emulsions, and syrups, and in addition to water and liquid paraffin, various excipients such as wetting agents, sweeteners, fragrances, and preservatives may be used. It may be formulated as a liquid formulation.

Agmatine and its derivatives or pharmaceutical compositions comprising the same of the present invention may contain sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories for formulation for parenteral administration. As the non-aqueous solvent and suspending agent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerogelatin and the like can be used.

In the present invention, the term "administration" means introducing a composition for prevention and treatment in a kind of developmental disorder or mental neurological disease such as FXS of the present invention to the patient by any suitable method, and improve the learning ability and sociality of the present invention. And the route of administration 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, pulmonary administration, rectal administration, intranasal administration, intraperitoneal administration, intradural administration, but not limited thereto. It doesn't work. For example, it can be administered by oral, rectal or intravenous, intramuscular, subcutaneous, intrauterine dural or intracerebroventricular injection.

The present invention can provide a nutraceutical composition for the prevention or amelioration of fragile X syndrome (Fragile X Syndrome; FXS) or related diseases containing agmatine or a pharmaceutically acceptable salt thereof as an active ingredient.

 Agmatine represented by the above formula or a pharmaceutically acceptable salt thereof is a symptom of repetitive behavior, hyperactivity, social deficiency, decreased learning ability or suppression of pro-stimulation in Fragile X Syndrome (FXS). Can be prevented or improved. Specifically, Agmatine and its pharmaceutically acceptable salts represented by the above formulas reduce fragile behavior, inhibit hyperactivity, improve social and learning ability, and increase pre-stimulation inhibition, thereby fragile X syndrome. Syndrome (FXS) or related diseases can be prevented or ameliorated. The pharmaceutical composition comprising the agmatine or a pharmaceutically acceptable salt thereof of the present invention can effectively treat and improve the abnormal behavior of mice without any special side effects.

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

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

The food composition according to the present invention may further include additives, such as food composition, health functional food or beverages. For example, the food composition of the present invention is a sweetener such as white sugar, fructose, glucose, D-sorbitol, mannitol, isomaltoligosaccharide, stevioside, aspartame, acesulfame potassium, sucralose, citric anhydride, DL- Preservatives such as malic acid, succinic acid and salts thereof, preservatives such as benzoic acid and derivatives thereof, various nutrients, vitamins, minerals (electrolytes), synthetic flavors and natural flavoring agents, such as colorants and neutralizing agents (cheese, chocolate) Etc.), and the salts of pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickeners, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols, carbonated drinks used in carbonated beverages and the like. In addition, the food compositions of the present invention may contain pulp for the production of natural fruit juices and vegetable drinks. The proportion of such 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 a flavor or natural carbohydrate that is commonly included in the beverage. The natural carbohydrate may be a monosaccharide such as glucose, fructose, a disaccharide such as maltose, sucrose, a polysaccharide such as dextrin, a cyclodexscreen or a sugar alcohol such as xylitol, sorbitol, erythritol. In addition, the flavourant may be a natural flavourant such as taumartin, stevia extract (rebaudioside A, glycyrzin, etc.) or synthetic flavors such as saccharin and aspartame. When the food composition is a beverage, natural carbohydrates may generally comprise 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 or a pharmaceutically acceptable salt thereof of the present invention is prepared in the form of a powder, granule, tablet, capsule or beverage to be used as foods, beverages, gums, teas, vitamin complexes, dietary supplements Can be. The composition containing the agmatine or a pharmaceutically acceptable salt thereof of the present invention may be added to drugs, foods and beverages for improving or improving learning ability and preventing or improving problems such as excessive behavior or social communication. For example, Agmatine of the present invention and its derivatives or compositions comprising the same may be added to foods, beverages, gums, teas, vitamin complexes, dietary supplements, and the like. The composition of the present invention may be added in an amount of 1% to 5% by weight of the total weight of the food, and may be added to 100 ml of the beverage at a ratio of 0.02 g to 10 g, preferably 0.3 g to 1 g.

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) neuropathy and diseases such as concentration improvement, cognitive impairment, social and communication, repetitive behavior, etc. have. Specifically, the pharmaceutical composition comprising agmatine or a pharmaceutically acceptable salt thereof according to the present invention effectively prevents fragile X syndrome (FXS) by improving repetitive behavior abnormalities and social and cognitive problems. It can be cured.

Figure 1 shows the structural formula of Agmatine of the present invention.
Figure 2 is a view showing the effect of reducing the repetitive behavior to impulse of the pharmaceutical composition comprising agmatine according to the present invention.
Figure 3 suggests that it is effective in the excessive action of the pharmaceutical composition comprising agmatine according to the present invention.
4 is a result showing the social and cognitive memory improving effect of the pharmaceutical composition containing agmatine according to the present invention, showing the search time for the animal of the same space and the same species and accordingly "social indicator" (animal / bin) Time spent in space).
5 is a result showing the social and cognitive memory improving effect of the pharmaceutical composition containing agmatine according to the present invention, it is a result showing the search time in familiar animals and strangers, according to "social cognition or preference indicators" It is the result of (Searching time of unfamiliar / friendly animal).
6 is a result showing the learning and memory improving effect of the pharmaceutical composition comprising agmatine according to the present invention, it is a result of summarizing the effect on the learning period of memory by displaying the time (Latency) to remember the target point .
Figure 7 is a result showing the learning and memory improvement effect of the pharmaceutical composition comprising agmatine according to the present invention, the index for evaluating the spatial memory capacity of the test animal for 90 seconds after the memory is formed, the target point of the four quadrants This is the result of staying in time.
Figure 8 is a view showing the effect of pre-stimulation of the pharmaceutical composition comprising agmatine according to the present invention.
9 is a view showing an improvement effect on the (social) communication of the 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 preparation examples and experimental examples are only for illustrating the present invention, the scope of the present invention is not limited by the following preparation examples and experimental examples. In addition, the reagents and solvents mentioned below were purchased from Sigma unless otherwise stated.

Experimental Example: Confirmation of Neuropharmacological Effects of Agmatine

The following experiments were carried out using a genetically transgenic animal (Fmr1 KO mouse) deficient in FMRP protein to confirm the therapeutic efficacy of FXS-containing psychoactive neuropathy-containing drugs. The result is shown below.

Preparation Example 1 Preparation of Experiment Animal

A 6-9-week-old FVB-based Fmr1 KO mouse (Jackson Laboratory, USA) of about 26 g to 28 g freely consumes water and feed, and has a temperature of about 23 ± 2 ° C, a humidity of about 55 ± 10%, and a contrast cycle of 12 hours. It was adapted for the rearing (animal laboratory of the College of Pharmacy, Kyung Hee University) and used for the experiment. 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)). Dosing was carried out at the same time, and the weight was measured every week to check the stress and toxicity caused by the drug. Behavioral tests were conducted one week after the administration, and the administration was continued for four weeks. Knock-Out mice lacking FMRP expression were treated with 30 mg / kg of Agmatine (Example 1) or 100 mg / kg (Example 2), respectively. (Control 1) or 100 mg / kg (Control 2) group, Wild type mice received 0.9% physiological saline (saline solution) group (Control 3) and FMRP expression deficient Knock-Out mice 4-10 rats were prepared per group divided into groups (Comparative Example 1) administered 0.9% saline solution (saline solution). The drug administration group was dissolved in 0.9% physiological saline (saline solution) and then intraperitoneally administered at a dose of 30, 100 mg / kg. Meanwhile, 0.9% of saline solution (saline solution) was intraperitoneally administered to the control group.

Experimental Example 1: Marble burying test

For the experiment was prepared by arranging the beads in a cage prepared with a rug. The mice prepared in 3) were placed in a cage containing beads and observed for 30 minutes of action. After the end of the experiment, each ball was photographed and the number was recorded. The higher the number of hidden marbles, the greater the repetitive behavior. The average number of hidden beads of the mice in each group is shown in Table 1 and FIG.

Experimental group Number of Hidden Beads (no) Control group 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 Deficient in FMRP Expression
Agmatine 30 mg / kg) 12.70 ± 1.155 Example 2
Knock-Out Deficient in FMRP Expression
Agmatine 100 mg / kg) 10.83 ± 0.895 Control group 3
(Wild Type; Vehicle) 7.13 ± 1.394 Comparative Example 1
Knock-Out Vehicle Deficient in FMRP Expression 18.30 ± 0.684

As can be seen in Table 1 and Figure 2, in the case of KO group, Example 1 and Example 2 administered with agmat markedly reduced repetitive behavior compared to Comparative Example 1 administered a vehicle. On the other hand, in the WT group of normal animals, the control group 1 and the control group 2, which were treated with the agmantine, were not significantly different from the control group 3, which was administered with the vehicle. Able to know. From this, it was found that agmatine can effectively prevent or treat FXS and its related developmental and mental neurological diseases.

Experimental Example 2: Open field test

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. After that, open field test was performed. The results of the experiment are shown in Table 2 and FIG. 3.

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

As can be seen in Table 2 and Figure 3, in the case of KO group Example 1 and Example 2 administered with agmat it was significantly reduced the distance traveled compared to Comparative Example 1 administered a vehicle. On the other hand, in the WT group of normal animals, the control group 1 and the control group 2, which were treated with the agmantine, were not significantly different from the control group 3, which was administered with the vehicle. Able to know. From this, it was found that administration of agmatine can effectively prevent or treat Fragile X Syndrome (FXS) and related developmental disorders or neuropsychiatric diseases such as hyperactivity.

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

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. Then, social interaction test was performed using three chambers. The results of the experiment are shown in Table 3 below and FIGS. 4-5.

Experimental group Social indicators (%) Social cognitive indicators (%) Control group 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 Deficient in FMRP Expression
Agmatine 30 mg / kg) 64.03 ± 5.959 45.17 ± 1.659 Example 2
Knock-Out Deficient in FMRP Expression
Agmatine 100 mg / kg) 68.59 ± 4.351 58.36 ± 3.481 Control group 3
(Wild Type; Vehicle) 62.60 ± 3.049 58.33 ± 3.485 Comparative Example 1
Knock-Out Vehicle Deficient in FMRP Expression 31.80 ± 1.164 38.02 ± 1.432

As can be seen in Table 3 and Figures 4-5, in the case of KO group, Example 1 and Example 2 to which agmatine was administered significantly increased social and cognitive abilities compared to Comparative Example 1 to which vehicle was administered. . On the other hand, in the WT group of normal animals, the control group 1 and the control group 2 were not significantly different from the control group 3 in which the agmatine group was administered. Can be. From this, it was found that administration of agmatine can effectively prevent or treat fragile X syndrome (FXS) and related developmental disorders or neuropsychiatric diseases such as social deterioration.

Experimental Example  4: Barnes maze test

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. We then used Barnes maze to evaluate learning and memory. The results of the experiment are shown in Table 4 below and FIGS. 6-7.

Experimental group Time to reach the target point (s) Dwell time at the target point (s) 1 day 2 days 3 days 4 days Control group 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 Deficient in 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 Deficient in FMRP Expression
Agmatine 100 mg / kg) 180 123.0 ± 17.35 94.0 ± 9.14 98.1 ± 14.36  43.13 ± 2.967 Control group 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 Deficient in 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 Figures 6-7, Example 1 and Example 2 administered with Agmatine in the case of KO group compared to the target Example 1 administered the vehicle during the four-day training period The time to reach was significantly reduced. In addition, on the test day, the time to stay at the target point increased significantly. On the other hand, in the WT group of normal animals, the control group 1 and the control group 2 were not significantly different from the control group 3 in which the agmatine group was administered. Can be. From this, it was found that administration of agmatine can effectively prevent or treat cognitive diseases such as learning and memory deterioration.

Experimental Example 5: Prepulse inhibition test

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. Subsequent sensorimotor gating was assessed through a prior stimulation suppression test. The results of the experiment was converted by Equation 1 below and the results are shown in Table 5 and FIG. 8.

The preceding stimulatory inhibitory capacity converted by Equation 1 is shown in Table 5 and FIG. 8.

Experimental group Leading Stimulus Inhibition (%) 3 dB 6 dB 12 dB 16 dB Control group 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 Deficient in 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 Deficient in FMRP Expression
Agmatine 100 mg / kg) 3.0 ± 9.90 18.1 ± 11.19 30.7 ± 11.89 51.2 ± 2.57 Control group 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 Deficient in 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 Figure 8, in the case of the KO group, Example 1 and Example 2 administered with agmatin compared to Comparative Example 1 administered a vehicle increased the pre-stimulation inhibition. On the other hand, in the WT group of normal animals, the control group 1 and the control group 2 were not significantly different from the control group 3 in which the agmatine group was administered. Can be. From these results, it was found that the administration of agmatine can effectively prevent or treat mental neurological diseases, which indicate an abnormal stimulation inhibitory disorder represented by sensorimotor gating deficit.

Experimental Example 6: Ultrasonic vocalization test

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. Then, ultrasonic vocalization was evaluated using Sonotrack. The results of the experiment are shown in Table 6 and FIG. 9.

Experimental group Total number of ultrasounds Control group 1
(Wild Type; Agmatine 30 mg / kg) 1495 ± 143.2 Example 1
Knock-Out Deficient in FMRP Expression
Agmatine 30 mg / kg) 631 ± 164.7 Control group 3
(Wild Type; Vehicle) 1104 ± 152.4 Comparative Example 1
(Knock-Out; Vehicle Deficient in FMRP Expression) 190.3 ± 100.9

As can be seen in Table 6 and FIG. 9, in the case of KO group, Example 1 in which agmatine was administered increased as compared with Comparative Example 1 in which a vehicle was administered. In other words, it can be seen that the communication between each other is active. On the other hand, in the case of control animal 3, which is a normal animal, it can be seen that the drug administration was not significantly affected. From these results, it was found that administration of agmatine can effectively prevent or treat developmental disorders and mental neurological disorders that indicate communication or social problems.

Claims (7)

A pharmaceutical composition for preventing or treating Fragile X Syndrome (FXS) or related diseases containing Agmatine or a pharmaceutically acceptable salt thereof as an active ingredient. The method according to claim 1, wherein the agmatine or a pharmaceutically acceptable salt thereof is selected from the group consisting of repeat behavioral symptoms, hyperactivity symptoms, social deficiency symptoms, decreased learning ability or pre-stimulation inhibition in Fragile X Syndrome (FXS). A pharmaceutical composition for the prophylaxis or treatment of Fragile X Syndrome (FXS), characterized by preventing or treating reduction symptoms. The prophylactic or therapeutic pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is formulated in the form of tablets, capsules, pills, granules, powders, injections or liquids. The pharmaceutical composition for preventing or treating Fragile X Syndrome (FXS) according to claim 1, wherein the disease related to Fragile X Syndrome (FXS) is autistic categorical disease. A dietary supplement for the prevention or amelioration of Fragile X Syndrome (FXS) or related diseases containing agmatine or a pharmaceutically acceptable salt thereof as an active ingredient. The method according to claim 5, wherein the agmatine or a pharmaceutically acceptable salt thereof is selected from the group consisting of repeat behavioral symptoms, hyperactivity symptoms, social deficiency symptoms, decreased learning ability or pre-stimulation inhibition in Fragile X Syndrome (FXS). A dietary supplement for the prevention or improvement of Fragile X Syndrome (FXS), characterized by preventing or treating reduction symptoms. The health functional food composition for preventing or ameliorating Fragile X Syndrome (FXS) or a related disease according to claim 5, wherein the disease related to Fragile X Syndrome (FXS) is autistic categorical disease.

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