WO2012020991A2 - Composition pour prévenir et soulager une maladie du cerveau comprenant des acides aminés de la soie et la tyrosine comme ingrédients actifs - Google Patents
Composition pour prévenir et soulager une maladie du cerveau comprenant des acides aminés de la soie et la tyrosine comme ingrédients actifs Download PDFInfo
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- WO2012020991A2 WO2012020991A2 PCT/KR2011/005853 KR2011005853W WO2012020991A2 WO 2012020991 A2 WO2012020991 A2 WO 2012020991A2 KR 2011005853 W KR2011005853 W KR 2011005853W WO 2012020991 A2 WO2012020991 A2 WO 2012020991A2
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- composition
- tyrosine
- preventing
- amino acid
- silk amino
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- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
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- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
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- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
Definitions
- the present invention relates to a composition for preventing and improving brain disease and a method for producing the same using silk amino acids and tyrosine as active ingredients.
- Parkinsonism (Parkinsonism or Parkinson's disease, PD) is a serious brain disease estimated to have more than half a million patients in the United States alone, resulting in the loss of dopamine neurons in the substantia nigra pars compacta (SN) region. It is characterized by the loss of exercise ability due to the reduced dopamine secretion in the striatum, and the current standard treatment for Parkinson's disease is dopamine precursor L-3,4-dihydroxyphenylalanine ( L -DOPA or Levo-DOPA). In addition, the drug significantly alleviates the symptoms, but long-term use is known to have serious side effects.
- L -DOPA dopamine precursor L-3,4-dihydroxyphenylalanine
- Silk is a protein polymer, the composition, structure and composition of which are completely different depending on the type of insect. The most commonly characterized silks are from silkworms (Bombyx mori) and spiders (Nephila clavipes and Araneus diadematus). .
- Silk consists of two polypeptides, sericin and fibroin, and as its chemical composition is found to be pure natural amino acids, various effects according to the physiological activity of the composition amino acids have been suggested.
- the inventors of the present invention while studying a composition for preventing / treating brain diseases that can be administered for a long time without serious side effects, the composition of silk amino acid with tyrosine inhibits exercise ability, dopamine increase, nerve cell protection due to dopamine and dopamine neuronal abnormalities It confirmed that the effect was excellent, and completed this invention.
- An object of the present invention is to provide a composition for preventing and improving brain diseases.
- Another object of the present invention to provide a method for producing a composition for preventing and improving brain diseases.
- Still another object of the present invention is to provide a method for preventing and / or treating a brain disease, which comprises administering the composition.
- the present invention provides a composition for preventing and improving brain diseases, including silk amino acids and tyrosine as an active ingredient.
- the present invention also provides a method for producing a composition for preventing and improving brain diseases comprising silk amino acids and tyrosine as an active ingredient, and a method for preventing and / or treating brain diseases comprising administering the composition.
- composition of the present invention has the effect of preventing, ameliorating, and treating brain diseases by protecting dopaminergic neurons or increasing the concentration of dopamine and / or its metabolites.
- 1 shows TH-positive neurons in the area of black matter (SN) in the brain 15 days after 6-OHDA administration.
- Figure 2 shows TH-positive neurons in the area of black matter (SN) in the brain 30 days after 6-OHDA administration.
- the present invention relates to a composition for preventing, treating and improving brain diseases, including silk amino acid and tyrosine as active ingredients.
- the present invention provides a method for producing a composition for preventing, treating and improving cerebral disease, comprising mixing silk amino acid and tyrosine.
- the present invention provides a method for preventing and / or treating a brain disease comprising administering a composition comprising silk amino acid and tyrosine as an active ingredient.
- the present invention provides a brain disease prevention, treatment and improvement of the composition comprising a silk amino acid (typical amino acid) and tyrosine (tyrosine) as an active ingredient.
- a silk amino acid typically amino acid
- tyrosine tyrosine
- the present invention also provides the use of a composition comprising silk amino acids and tyrosine as an active ingredient for the manufacture of a medicament for the prevention, improvement and treatment of brain diseases.
- Silk amino acid of the present invention can be prepared using silkworm or silkworm pupa.
- the silk amino acid of the present invention can be prepared using the silk protein.
- the silk protein may be fibroin and / or sericin.
- the silk amino acid may be prepared by acid hydrolysis of silkworm, silkworm pupae or silk protein, but is not limited thereto.
- the tyrosine may be synthetic tyrosine or natural tyrosine.
- the tyrosine of the present invention may also be derived from silk, cocoon and the like. However, if it is tyrosine, there will be no problem in implementing this invention, and it will be said that it corresponds to the tyrosine of this invention regardless of its origin.
- the brain disease is not limited to Parkinson's disease, cerebral infarction, stroke, dementia, but will be applicable if the brain disease associated with abnormalities of dopamine and / or dopaminergic neurons.
- the composition for preventing and improving brain diseases of the present invention can prevent, treat, and improve brain diseases by increasing the concentration of dopamine or preventing, delaying, and protecting nerve cells from being destroyed.
- the composition of the present invention can restore and improve the motor function of the body inhibited by brain diseases.
- the composition for preventing and improving brain diseases of the present invention may include 0.01 to 50 parts by weight of tyrosine, preferably 0.02 to 20 parts by weight, and most preferably 0.02 to 12 parts by weight, based on 100 parts by weight of the composition. We can include vice. With respect to 100 parts by weight of the composition, when the tyrosine exceeds 50 parts by weight, the prevention / improvement effect of the brain disease is increased, and when mixing tyrosine and silk amino acids, it is difficult to homogeneously mix and excessively increase the mixing time. The efficiency of the process is lowered. In addition, when tyrosine is less than 0.01 parts by weight based on 100 parts by weight of the composition, it is difficult to expect an increase in the prevention / improvement of brain diseases due to the addition of tyrosine.
- composition for preventing and improving brain diseases of the present invention may be a pharmaceutical composition or a food composition.
- the pharmaceutical composition for preventing and improving brain diseases of the present invention can be administered orally or parenterally and can be used in the form of a general pharmaceutical preparation.
- Preferred pharmaceutical preparations include oral preparations such as tablets, hard or soft capsules, solutions, suspensions and the like, which can be used in the form of excipients in conventional pharmaceutically acceptable carriers such as oral preparations, Binders, disintegrants, lubricants, solubilizers, suspending agents, preservatives or extenders can be used.
- the dosage of the pharmaceutical composition for preventing and improving brain diseases of the present invention may be determined by a specialist depending on various factors such as the patient's condition, age, sex, and complications, but generally 0.1 mg to 10 g per kg of adult, preferably Preferably from a dose of 10 mg to 5 g.
- it is intended to contain a daily dose of the pharmaceutical composition or a dose of 1/2, 1/3 or 1/4 thereof per unit dosage form, and may be administered 1 to 6 times a day.
- the amount may be below the above range, and the active ingredient may be used in an amount above the above range because there is no problem in terms of safety.
- the patient of the present invention is a brain disease patient.
- the patient of the present invention may be a patient having a disease such as Parkinson's disease, cerebral infarction, stroke, dementia, but is not limited thereto.
- Patients with brain diseases associated with abnormalities of dopamine and / or dopaminergic neurons correspond to patients of the invention.
- the present invention also provides a food composition for preventing and improving brain diseases.
- the food is not limited to, but not limited to, health supplements, health functional foods, functional foods, and the like, and natural foods, processed foods, and general food materials, including the addition of the composition for preventing and improving brain diseases of the present invention.
- the food composition for preventing and improving brain diseases of the present invention may be added as it is or used with other food or food compositions, and may be appropriately used according to a conventional method.
- the blending amount of the active ingredient can be suitably determined according to the purpose of its use (prevention, health or therapeutic treatment). Generally, 0.1 to 70 parts by weight, preferably 2 to 50 parts by weight, of the brain disease prevention and improvement composition of the present invention may be added to 100 parts by weight of the raw material of the food or beverage during the preparation of the food or beverage.
- the effective dose of the composition for preventing and improving brain diseases can be used in accordance with the effective dose of the pharmaceutical composition, but may be less than the above range in the case of long-term intake for the purpose of health and hygiene or health control. In addition, since the active ingredient has no problem in terms of safety, it may be used in an amount above the above range.
- the food composition for preventing and improving brain diseases can be used in the form of oral preparations, such as tablets, hard or soft capsules, liquids, suspensions, etc., these preparations are acceptable conventional carriers, such as oral administration
- oral preparations such as tablets, hard or soft capsules, liquids, suspensions, etc.
- these preparations are acceptable conventional carriers, such as oral administration
- excipients, binders, disintegrants, lubricants, solubilizers, suspending agents, preservatives or extenders can be used.
- Examples of foods to which the composition for preventing and improving brain diseases can be added include meat, sausages, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gums, dairy products including ice cream, various soups, Beverages, teas, drinks, alcoholic beverages and vitamin complexes, but are not limited to these kinds of foods.
- Silk amino acid was obtained from World Way, Inc. as a pale yellow powder obtained by acid hydrolysis of silk protein, which was used while stored at 4 ° C. Prior to administration, the required amount by concentration was dissolved in sterile purified water and administered orally, and the solvent control group was administered the same amount of sterile purified water.
- a composition was prepared in which silk amino acids were mixed with tyrosine. Specifically, a composition containing 2 parts by weight of tyrosine (Example 1), a composition containing 4 parts by weight of tyrosine (Example 2), and a composition containing 8 parts by weight of tyrosine (executed) based on 100 parts by weight of the silk amino acid Example 3), the composition which mixed 12 weight part tyrosine (Example 4), the composition which mixed 16 weight part tyrosine (Example 5), and the composition which mixed 20 weight part tyrosine (Example 6).
- SD rats of 14-15 days of gestation bred under the same conditions were killed by cervical dislocation, and the abdomen was excised to separate fetuses under aseptic conditions.
- the ventral midbrain containing black matter was excised from the brains of the isolated fetuses, and neurons were cultured.
- the brain tissues from which the meninges were completely removed were washed with DMEM / F12 1: 1 culture medium to remove blood, and then isolated cells were obtained using a small diameter Paster pipette and transferred to a centrifuge tube, followed by centrifugation at 700 rpm for 8 minutes.
- the precipitated cells were then resuspended in culture and the same procedure repeated twice, followed by DMEM / F12 containing 10% fetal calf serum and 2 mM glutamine, 50 U / ml penicillin, 50 ⁇ g / ml streptomycin. After floating in a 1: 1 culture medium, the number of cells was measured under an optical microscope, and 6 ⁇ 10 6 cells were cultured in a 60 mm cell culture plate, and 6 ⁇ 10 4 cells were cultured in each well in a 96 well plate. Serum-free cultures were used for culturing neural neurons.
- the culture vessel was coated with poly-L-lysine (10 ⁇ g / mL), washed three times with distilled water, and then used after removing water. After treatment for 24 hours in the MPP + culture medium of day four a concentration started to culture investigate toxicity to dopamine neurons silk amino acid, tyrosine, Examples 1 to 6 and L -DOPA (positive control) to a pre-treatment prior to one MPP + for 1 Until the end of the experiment.
- Tyrosine Daily recommended amount 840mg / 60kg
- Example 2 As a result of combining the results of Experimental Example 2, it was confirmed that the composition of Example 2 added 4% tyrosine significantly increased the content of dopamine, DOPAC, HVA, and the most suitable concentration of tyrosine does not aggregate with each other, Hereinafter, the in vivo test was conducted using the composition of Example 2.
- the experimental animals were supplied with 7-week-old male Sprague-Dawley (SD) rats from Daehan Biolink (Neongbuk-neum) and used for about 200-250 g of body weight after approximately 1 week of acclimatization. Animals were housed in rats two by two. The environment of the animal laboratory was adjusted to a temperature of 23 ⁇ 2 ° C, a relative humidity of 55 ⁇ 10%, a ventilation frequency of 12 times / hour, a lighting cycle of 12 hours, and an illuminance of 150-300 Lux. Purina Rat Chow ® biopia (Gunpo, Gyeonggi-do, Korea) was used as a pellet-type solid feed for experimental animals. The experiment was conducted in accordance with the Institute's Standard Operation Procedures (SOP) with the approval of the Institutional Animal Care and Use Committee (IACUC) of the Chungbuk National University.
- SOP Institute's Standard Operation Procedures
- IACUC Institutional Animal Care and Use Committee
- the silk amino acid, silk amino acid, and tyrosine compositions of the present invention were dissolved in sterile purified water (5 mL / kg) at doses (50, 160 or 500 mg / kg) for 30 days from the induction of Parkinson's disease for 31 days.
- sterile purified water 5 mL / kg
- Tyrosine was also administered orally (40 mg / kg) and L- DOPA (positive control) was injected intraperitoneally (25 mg / kg).
- T turn the time until the animal's head is turned upward with the head of the animal facing up on the top of the rod with a rough surface of 10 mm diameter and 55 cm in length
- T LA the time to the bottom
- Example 2 At 30 days after 6-OHDA administration, 86% of brain-induced animals fell during the pole test, indicating that the brain injury was further developed. However, the improvement effect of the composition of Example 2 was further enhanced than day 15, only 15% and 17% dropped at 50 and 160 mg / kg, respectively, and showed a similar effect to L-DOPA (positive control) at 500 mg / kg There was no animal falling. In addition, only 15% of animals fell in the tyrosine-treated group, and no falling animals were observed in the L- DOPA (positive control) -treated group as in the 15th day. In the silk amino acid group, 50 mg / kg to 500 mg / kg was ineffective at 15 days compared to the Parkinson's group.
- the Parkinson's group had a 53% increase in drop rate, whereas the silk amino acid group was 50 mg / kg to 500 mg / kg.
- the drop rate was increased by up to 16%, indicating that the drop rate increase was significantly reduced compared to the Parkinson's group.
- T turn which is the time the animal heads down on the pole
- T LA which is the time to reach the bottom
- T turn and T LA decreased in the silk amino acid treatment group than in the Parkinson's group, but not in the high dose group.
- the T turn and T LA were significantly improved to about 8 and 30 seconds, respectively, showing the best effect.
- T turn and T LA were delayed to 46 and 81 seconds, respectively, indicating more severe physical dysfunction than day 15.
- This severe bodily dysfunction was significantly improved overall with administration of the composition of Example 2, with a significant decrease in T turn in the 160 mg / kg dose group and T LA in the 50 mg / kg and 500 mg / kg dose groups.
- tyrosine which had little effect on day 15, significantly reduced both T turn and T LA to 17 and 43 seconds on day 30.
- the silk amino acid administration group shortened T turn and T LA , but the effect was lower than that of the tyrosine administration group and the composition administration group of Example 2 in which tyrosine and silk amino acid were mixed.
- T turn and T LA were significantly improved to 18 seconds and 40 seconds, respectively (Table 4).
- the ipsilateral forelimb (the left and right brains) is responsible for the other side of the body, and the left forefoot is damaged when the right brain is damaged.
- Loss of function i.e., the ratio of force to the right forefoot.
- Example 2 On day 15, 38% of normal animals used the right forefoot during standing up 10 times because normal animals used the left and right forelimbs at about the same frequency. In contrast, Parkinson's disease-induced animals that injured the right brain with 6-OHDA and reduced the function of the left foot increased the use of intact right paw to 68%.
- the composition of Example 2 was administered to the right foot biased use, the dose-dependent frequency of bias was improved.
- the concentration was restored to 50%.
- tyrosine or L- DOPA (positive control) group also significantly improved the use of the right forefoot.
- 50 mg / kg and 160 mg / kg did not show a significant effect in the silk amino acid group, but improved to a significant level in the 500 mg / kg group (Table 5).
- Example 2 On the other hand, on the 30th day, the effect of the composition of Example 2 was further enhanced, and improved to the normal control level at the high dose as well as the 160 mg / kg administration group.
- the tyrosine-treated group was slightly weaker than the 15th day, and the L- DOPA (positive control) -treated group showed the same effect as the normal control group.
- the levels were similar at both 15 and 30 days (Table 5).
- Apomorphine (0.05 mg / kg) was injected subcutaneously and the number of times the animal was contralateral circling for 1 hour using CCTV was recorded. At this time, the rotation was recorded once when the 360-degree full rotation using CCTV.
- the animals were anesthetized by anesthesia 30 minutes after the administration of the test substance on the following day, i.e., on days 16 and 31.
- Brain tissues were perfused with cold saline, fixed in 10% neutral formalin solution for 24 hours, and stored in 30% sucrose solution for 1 week. 40 ⁇ m frozen sections were prepared so that the fixed brain tissue showed black matter (AP -3.00 ⁇ -3.16).
- TH In order to determine the degree of death of dopamine neurons by 6-OHDA, immunostaining was performed on TH to measure the number of neurons containing TH. In order to remove endogenous peroxidase present in the tissues, the cells were treated with 3% hydrogen peroxide (H 2 O 2 ) and then pretreated with 3% bovine serum albumin (BSA) for 120 minutes at room temperature. Tissue slides were reacted with anti-TH primary antibody (rabbit polyclonal IgG, 1: 100, Millipore, Temecula, USA) overnight at 4 ° C and washed several times with phosphate-buffered saline (PBS).
- H 2 O 2 hydrogen peroxide
- BSA bovine serum albumin
- Example 2 In the administration group of the composition, the low dose (50 mg / kg) did not recover to about 30, but the medium dose (160 mg / kg) recovered to 55, especially the high dose (500 mg / kg). Esau excels at about 145. In comparison, the tyrosine (40 mg / kg) group recovered to about 115 and showed a significant cytoprotective effect. The L- DOPA (positive control) 25 mg / kg group also did not meet the effect of the high dose group of the Example 2 composition. Significant improvement was shown. On the other hand, the silk amino acid administration group had no significant effect at low dose (50 mg / kg), but significantly recovered to 53 at medium dose (160 mg / kg) and improved to about 83 at high dose (500 mg / kg). (Table 7).
- the number of dopamine neurons in Parkinson's disease-causing animals was about 50, which was significantly reduced compared to 250 in normal animals.
- the composition of Example 2 was restored to about 70 at low doses, significantly improved to about 125 at medium doses, and particularly to about 190 at high doses for excellent cytoprotective efficacy. Showed. Tyrosine also showed excellent protection against about 145.
- L- DOPA positive control group
- silk amino acid in the high dose administration group is about 102 cells protection The effect was the lowest.
- Dopamine and its metabolite 3,4-dehydroxyphenylacetic acid (DOPAC) and 3-methoxy-4-hydroxyphenylacetic acid (homovanillic acid (HVA)) were analyzed from the brain tissues of some animals. Perfusion of the cerebral tissue with cold saline, rapid extraction and weighing was performed, followed by adding 0.1 M perchloric acid (500 ⁇ L) and 10-5 M isoproterenol (50 ⁇ L) containing 0.05% disodium ethylenediamine tetraacetic acid (EDTA). Homogenized.
- DOPAC 3,4-dehydroxyphenylacetic acid
- HVA 3-methoxy-4-hydroxyphenylacetic acid
- HPLC high performance liquid chromatograph
- the HPLC system consists of a solvent delivery pump (Waters Model 1525), an electrochemical detector (Waters Model 2465), and a Watchers 120 ODS-BP column (5 ⁇ m, 150 x 4.6 mm), with 0.1 M citric acid monohydrate, 0.1 M for the mobile phase.
- Sodium acetate, 100 ⁇ M EDTA, 0.01% sodium octane sulfonate (SOS) and 7% methanol were used, and the flow rate was 1 mL / min.
- composition for preventing and improving cerebral disease including silk amino acid and tyrosine of the present invention as an active ingredient has an excellent effect in preventing and treating Parkinson's disease, cerebral infarction, stroke or dementia.
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Abstract
La présente invention concerne une composition pour prévenir et soulager une maladie du cerveau comprenant des acides aminés de la soie et la tyrosine comme ingrédients actifs et concerne un procédé de production de celle-ci. La composition de la présente invention est exceptionnellement efficace dans la maladie de Parkinson, l'infarctus cérébral, l'accident vasculaire cérébral ou la démence.
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WO2006014033A1 (fr) * | 2004-07-31 | 2006-02-09 | Brainguard Co., Ltd. | Peptide de soie ameliorant les effets neuroprotecteurs et neurofonctionnels et methode de preparation |
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KR20040073425A (ko) * | 2004-07-30 | 2004-08-19 | 주식회사 바이오그랜드 | 두뇌 또는 인지 기능 증진용 조성물 |
WO2006014033A1 (fr) * | 2004-07-31 | 2006-02-09 | Brainguard Co., Ltd. | Peptide de soie ameliorant les effets neuroprotecteurs et neurofonctionnels et methode de preparation |
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