KR102253667B1 - A composition comprising Ukgansan for preventing or treating dyskinesia - Google Patents

Abstract

The present invention relates to a composition for preventing or treating dyskinesia comprising Ekgansan or any one or more extracts of its constituents as an active ingredient, and specifically, dysbiosis including Ekgansan or any one or more extracts of its constituents A pharmaceutical composition for preventing or treating symptoms, a food composition for preventing or improving dyskinesia containing any one or more extracts of Ekgansan or its constituents, a feed composition, and any one or more extracts of Ekganic acid or its constituents, excluding humans It relates to a method for preventing or treating dyskinesia comprising the step of administering to an individual. Ekgansan according to the present invention did not affect the therapeutic effect of levodopa on Parkinson's disease, but at the same time treated abnormal involuntary exercise induced by dopamine, and reduced the levels of dopamine receptors, ERK, and FosB increased by levodopa close to that of the normal group. So, it can be usefully used as a composition for preventing or treating dyskinesia.

Description

[A composition comprising Ukgansan for preventing or treating dyskinesia}

The present invention relates to a composition for preventing or treating dyskinesia containing Ekgansan, specifically a pharmaceutical composition for preventing or treating dyskinesia comprising an extract of any one or more of Ekgansan or its constituents, Ekgansan or its It relates to a method for preventing or treating dyskinesia comprising administering a food composition for preventing or improving dyskinesia comprising an extract of any one or more of the constituents, a feed composition, and the pharmaceutical composition to individuals other than humans.

Parkinson's disease is a chronic and progressive degenerative brain disease, characterized by a decrease in voluntary movements due to dopamine cell death in the substantia nigra region of the midbrain. Dopamine replacement therapy is a representative Parkinson's disease treatment. Among them, administration of levodopa, a dopamine precursor, is known to be the most effective and most commonly used treatment for Parkinson's disease.

However, dopamine drug therapy can promote dopamine cell death in the black matter region, and many patients complain of side effects such as dyskinesia (involuntary movements) caused by long-term dopamine drug therapy. In particular, dopamine-induced dyskinesia is a symptom that occurs in 90% of Parkinson's disease patients who have been treated with dopamine therapy, and an effective therapy is required to suppress or treat it.

On the other hand, Eunggansan is Poria cocos Wolf, Atractylodes lancea De Candolle, Uncaria sinensis Havil, Angelica acutiloba kitagawa, Cnidium officinale Makino, Bupleurum falctatum Linne, and licorice. ( Glycyrrhiza uralensis Fischer), a prescription that has been used in traditional medicine for symptoms such as helplessness, anxiety, and trembling.In modern times, this prescription is applied to degenerative brain diseases such as Parkinson's disease and Alzheimer's disease, and Parkinson's disease in Korea. It is known as the most commonly applied herbal medicine.

Eokgansan is reported to have an effect on improving movement against Parkinson's disease, but no effect has been reported on dyskinesia, and there is no known whether the extract or active ingredient consisting of Eokgansan is effective against dyskinesia.

Accordingly, as a result of the present inventors' intensive research efforts to treat dyskinesia, Ekgansan treats abnormal involuntary movements caused by levodopa, and decreases dopamine receptors, ERK phosphorylation, and FosB levels increased by levodopa. By confirming that it can be cured for dyskinesia, the present invention was completed.

One object of the present invention is to provide a pharmaceutical composition for preventing or treating dyskinesia comprising an extract of any one or more of Eokgansan or its constituents.

Another object of the present invention is to provide a food composition for preventing or improving dyskinesia comprising an extract of any one or more of Eokgansan or its constituents.

Another object of the present invention is to provide a feed composition for preventing or improving dyskinesia comprising an extract of any one or more of Ekgansan or its constituents.

Another object of the present invention is to provide a method for preventing or treating dyskinesia comprising administering to an individual other than humans an extract of Eokgansan or any one or more of its constituents.

Another object of the present invention is to provide a pharmaceutical composition for preventing or treating dyskinesia, including the pharmaceutical composition and levodopa.

Another object of the present invention is to provide a pharmaceutical composition for treating Parkinson's disease with reduced side effects, including the pharmaceutical composition and levodopa.

One aspect for achieving the above object provides a pharmaceutical composition for preventing or treating dyskinesia comprising an extract of any one or more of Eokgansan or its constituents.

In the present invention, the term "Eokgansan" is one of the prescriptions of traditional medicine, which has been used for symptoms such as weakness, anxiety, and tremors in traditional medicine. In modern times, this prescription is used for degenerative brain diseases such as Parkinson's disease and Alzheimer's disease. It is applied and is known as the most widely applied herbal medicine for Parkinson's disease in Korea.

The Eokgansan has been reported to improve exercise in Parkinson's disease, but no effect on dopamine-induced dyskinesia has been reported, and was first identified by the present inventors.

The Eokgansan is composed of Jogudeung, Baekchul, Baekbokryeong, Angelica, Cheongung, Siho, and Licorice as constituents, and has a therapeutic effect on dyskinesia even if one of the above ingredients is removed or another ingredient is added. , It may be included without limitation in the scope of the present invention.

In the present invention, the term "constituents thereof" refers to the constituents constituting Eokgansan, specifically, it means jogudeung, baekchul, baekbokryeong, angelica, cheonggung or licorice, and jogudeung, baekchul, used in the present invention Baekbokryeong, angelica, cheonggung, or licorice can be harvested or cultivated in nature or purchased commercially, but is not limited thereto.

In the present invention, the term "extract" refers to the form of an extract obtained by extraction with one or more solvents, and as a solvent used for preparing the extract, water, carbon number 1 (C ₁ ) to carbon number 4 (C ₄ ) Alcohol, preferably methanol, ethanol or butanol, or a mixed solvent thereof may be used, but is not limited thereto. As the extraction method, a method such as solvent extraction, hot water extraction, cold needle extraction, reflux cooling extraction, ultrasonic extraction, or steam extraction may be used, but is not limited thereto.

In the present invention, the term "dyskinesia" refers to symptoms in which voluntary movements are reduced and involuntary movements, such as tics or chorea, appear. Specifically, dyskinesia manifested by drugs that increase the stimulation of dopamine receptors. It can mean. In addition, such dyskinesia often appears as a side effect of dopamine agonists of Parkinson's disease, but is not the only cause, and the characteristics of these dyskinesia are movement disorders, such as the appearance of slow and uncooperative involuntary movements, tremors, Includes spasticity and impaired mobility.

The term “dopamine agonist” refers to any agent that increases dopamine receptor stimulation. Specifically, the dopamine agonist may be levodopa, levodopa decarboxylase, monoamine oxidase B, bromocriptine, pergolide, pramipexole, ropinirol, cabergoline, apomorphine, or lisuride.

In the present invention, the dopamine-induced dyskinesia may specifically be a dyskinesia caused by long-term administration of levodopa to Parkinson's disease, but is not limited thereto.

In the present invention, the term "levodopa" is an amino acid precursor of dopamine having anti-Parkinsonian properties. Levodopa can cross the blood circulation barrier and can be converted to dopamine by dopa decarboxylase. The levodopa has the IUPAC name of L-3,4-dihydrocyphenylalanine roxyphenylalanine [L-3,4-dihydroxyphenylalanine]. For this reason, when levodopa is administered to Parkinson's disease patients, it enters blood vessels in the brain and is converted to dopamine, and it has the effect of treating Parkinson's disease by stimulating dopamine receptors to prevent endogenous dopamine depletion seen in Parkinson's disease.

Specifically, Parkinson's patients treated with levodopa often have reduced Parkinson's symptoms, but they experience increasingly difficult to maintain standing or even sitting. Most of the patients develop this dyskinesia after continued use of levodopa. Dyskinesia can appear at any point during a treatment cycle with levodopa.

A specific aspect of the present invention may be used in combination treatment with levodopa (L-DOPA) or a pharmaceutically acceptable salt thereof, but is not limited thereto.

Eokgan acid or any one or more extracts of its constituents is used in combination with levodopa or a pharmaceutically acceptable salt thereof, thereby preventing or treating more effective dopamine-induced dyskinesia, and more specifically, of Parkinson's disease caused by long-term administration of levodopa. Prevention or treatment of dyskinesia can be brought.

In a specific embodiment of the present invention, as a result of administering levodopa to a mouse inducing Parkinson's disease with 6-OHDA, it was confirmed that movement disorders, a symptom of Parkinson's disease, were treated (FIG. 1).

The levodopa-induced dyskinesia is one of the symptoms that occurs in patients who have used levodopa for a long time to treat Parkinson's disease, and 40% of those who have been taking levodopa for 4 to 6 years and 90% of those who have taken levodopa for 9 to 15 years have the above abnormalities. It was found to have experienced dyskinesia. The mechanism by which levodopa-induced dyskinesia occurs is not clearly known, but a recent report on an animal model of Parkinson's disease shows that NMDA (N-methyl-D-aspartate) antagonists alleviate levodopa-induced dyskinesia. In addition, human studies have also reported that the NMDA antagonist, dextromethorphan, and its metabolite index, dextrophan, alleviate levodopa-induced motor complications (Papa SM et al. , 1996; Verhagen ML et al., 1996).

In the present invention, the extract of Eokgan acid or one or more of its constituents may reduce the expression level of dopamine receptors and decrease the level of ERK phosphorylation and the expression level of FosB. In a specific embodiment of the present invention, as a result of measuring the expression level of dopamine receptor by administering levodopa to a mouse in which Parkinson's disease was induced by 6-OHDA and then administering Eokgan acid, the amount of expression of dopamine receptors was measured. It was confirmed that the expression level of the dopamine receptor in the experimental group administered with liver acid decreased close to that of the normal group (FIG. 7).

In addition, in a specific embodiment of the present invention, as a result of measuring the phosphorylation level of ERK by administering levodopa to mice induced with Parkinson's disease by 6-OHDA and then administering Eokgan acid, administration of levodopa compared to the experimental group to which only levodopa was administered. It was confirmed that the phosphorylation level of ERK decreased close to that of the normal group in the experimental group to which Ekgan-san was administered (FIG. 8).

In addition, in a specific embodiment of the present invention, as a result of measuring the expression level of FosB by administering levodopa to mice in which Parkinson's disease was induced by 6-OHDA and then administering Eokgan acid, after administration of levodopa compared to the experimental group to which only levodopa was administered. In the experimental group to which Eokgansan was administered, it was confirmed that the expression level of FosB decreased close to that of the normal group (Fig. 9).

In the present invention, the term "prevention" refers to any action that suppresses or delays the symptoms of levodopa-induced dyskinesia by administration of the composition containing Ekganic acid according to the present invention.

In the present invention, the term "treatment" refers to any action in which the symptoms of levodopa-induced dyskinesia are improved or beneficially changed by administration of the composition containing Ekganic acid according to the present invention.

The term "pharmaceutical composition" used in the present invention means that it is prepared for the purpose of preventing or treating diseases, and may be formulated and used in various forms according to each conventional method. For example, it may be formulated in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups, and the like, and may be formulated in the form of external preparations, suppositories, and sterile injectable solutions. Specifically, it may be formulated and used in a form suitable for eye drop administration, for example, an eye drop, a cream, an ointment, a gel, or a lotion.

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

The pharmaceutical composition of the present invention may contain 0.01 to 80%, specifically 0.01 to 70%, and more specifically 0.01 to 60% by weight, of redundant acid or a pharmaceutically acceptable salt thereof based on the total weight of the composition. As long as it shows the effect of preventing or treating symptoms, it is not limited thereto.

The composition of the present invention may be prepared in the form of a pharmaceutical composition for preventing or treating levodopa-induced dyskinesia further comprising an appropriate carrier, excipient, or diluent commonly used in the manufacture of pharmaceutical compositions, wherein the carrier is It may include a non-naturally occuring carrier.

In the present invention, the carriers, excipients and diluents that may be included in the pharmaceutical composition include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, Calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil.

In the case of formulation, it is prepared using diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, and surfactants that are usually used. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, and these solid preparations include at least one excipient, such as starch, calcium carbonate, in the upper leaf extract and its fractions. , Sucrose (sucrose) or lactose (lactose), gelatin, etc. are mixed and prepared. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid preparations for oral use include water and liquid paraffin, which are simple diluents commonly used for suspensions, liquid solutions, emulsions, syrups, etc., and various excipients such as wetting agents, sweetening agents, fragrances, and preservatives. have. Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized formulations, and suppositories. As the non-aqueous solvent and suspending agent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, and injectable ester such as ethyl oleate may be used. As a base for suppositories, witepsol, macrogol, tween 61, cacao butter, laurin paper, glycerogelatin, and the like may be used.

The pharmaceutical composition of the present invention can be administered orally, parenteral, rectal, topical, transdermal, intravenous, intramuscular, intraperitoneal, subcutaneous, etc. according to a desired method, and the active ingredient of the pharmaceutical composition is the age of the subject to be administered. , Sex, weight, pathology and severity, route of administration, or the judgment of the prescriber. Determination of the application amount based on these factors is within the level of those skilled in the art, and its daily dose is, for example, 0.1 mg/g/day to 100 mg/g/day, more specifically 5 mg/g/day to 50 mg/day. It may be g/day, and the frequency of administration of the composition of the present invention is not particularly limited thereto, but may be administered once a day or several times by dividing the dose. The above dosage does not limit the scope of the present invention in any way.

Another aspect of the present invention provides a food composition for preventing or improving dyskinesia, including extracts of one or more extracts of Ekgansan or its constituents.

In addition, the present invention provides a feed composition for preventing or improving dyskinesia (dyskinesia) comprising an extract of any one or more of Eokgansan or its constituents.

In the present invention, the terms "Ekgansan", "constituents thereof", "extract", and "dyskinesia" are as described above.

The food composition of the present invention may further include a food pharmaceutically acceptable carrier.

The feed composition may further include a feed rationally acceptable carrier.

There is no particular limitation on the types of foods to which the composition containing Ekgan acid of the present invention can be added, and for example, there are various beverages, gums, teas, vitamin complexes, health supplement foods, and the like. Other ingredients that do not interfere with the therapeutic effect of dyskinesia may be added to the food composition, and the kind is not particularly limited. For example, as an ordinary food, various herbal extracts, food additives or natural carbohydrates that are acceptable for food may be contained as an additional component.

The food additives are added to prepare food compositions of each formulation, and may be appropriately selected and used by those skilled in the art. For example, various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic flavors and natural flavoring agents, coloring agents and fillers, pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickeners, pH adjusters , Stabilizers, preservatives, glycerin, alcohol, carbonates used in carbonated beverages, etc. are included, but the types are not limited by the above examples.

At this time, the content of the extract contained in the food is not particularly limited thereto, but may be included in 0.01 to 100% by weight, more preferably 1 to 80% by weight based on the total weight of the food composition.

When the food is a beverage, it may be included in a ratio of 1 to 30 g, preferably 3 to 20 g, based on 100 ml. In addition, the composition may include additional ingredients that are commonly used in food compositions to improve odor, taste, vision, and the like. For example, vitamins A, C, D, E, B1, B2, B6, B12, niacin, biotin, folate, panthotenic acid, and the like may be included. In addition, minerals such as zinc (Zn), iron (Fe), calcium (Ca), chromium (Cr), magnesium (Mg), manganese (Mn), and copper (Cu) may be included. In addition, amino acids such as lysine, tryptophan, cysteine, and valine may be included. In addition, preservatives (potassium sorbate, sodium benzoate, salicylic acid, sodium dehydroacetate, etc.), disinfectants (bleached and highly bleached, sodium hypochlorite, etc.), antioxidants (butylhydroxyanisole (BHA), butylhydroxytoleuene ( BHT), etc.), colorants (tar colors, etc.), coloring agents (sodium nitrite, sodium nitrite, etc.), bleach (sodium sulfite), seasoning (MSG sodium glutamate, etc.), sweeteners (dulsin, cyclamate, saccharin, sodium, etc.) , Flavorings (vanillin, lactones, etc.), expanding agents (alum, D-potassium hydrogen stannate, etc.), reinforcing agents, emulsifying agents, thickening agents (thickening agents), coating agents, gum base agents, foam inhibitors, solvents, and food additives such as improving agents. ) Can be added. The additive is selected according to the type of food and used in an appropriate amount.

The food composition of the present invention can be prepared by a method commonly used in the art, and at the time of the production, it may be prepared by adding raw materials and ingredients commonly added in the art. In addition, unlike general drugs, it has the advantage of not having side effects that may occur when taking drugs for a long time by using food as a raw material, and it may be excellent in portability.

Another aspect of the present invention provides a method for preventing or treating dyskinesia, comprising administering to an individual other than humans an extract of Ekgansan or any one or more of its constituents.

In the present invention, the terms "Ekgansan", "constituents thereof", "extract" and "dyskinesia" are as described above.

The term "individual" as used in the present invention may mean all animals including humans who have or are likely to develop dyskinesia. The animals may be mammals such as cattle, horses, sheep, pigs, goats, camels, antelopes, dogs, cats, etc. in need of treatment for symptoms similar to humans, but are not limited thereto.

The prevention or treatment method of the present invention may specifically include administering the composition in a pharmaceutically effective amount to an individual who has or is at risk of developing dyskinesia.

As used herein, the term "administration" means introducing the pharmaceutical composition of the present invention to a patient by any suitable method, and the route of administration of the composition of the present invention is oral or parenteral as long as it can reach the target tissue. It can be administered through a variety of routes.

Another aspect of the present invention provides a pharmaceutical composition for preventing or treating dyskinesia, including the pharmaceutical composition and levodopa.

In addition, another aspect of the present invention provides a pharmaceutical composition for treating Parkinson's disease with reduced side effects, including the pharmaceutical composition and levodopa.

In the present invention, the term "pharmaceutical composition" is as described above, and specifically, it may be a composition comprising an extract of any one or more of Ekgansan or its constituents. In addition, "levodopa" and "dyskinesia" are as described above.

In a specific embodiment of the present invention, when co-administration of levodopa and euganic acid in mice induced Parkinson's disease with 6-OHDA, the effect of treating dyskinesia caused by Parkinson's disease is not reduced compared to the experimental group to which only levodopa was administered. It was confirmed (Fig. 1).

In addition, in another embodiment of the present invention, when levodopa is administered in mice induced Parkinson's disease with 6-OHDA and then Ekgan acid is administered, the level of abnormal involuntary exercise is reduced compared to the experimental group to which only levodopa was administered. It was confirmed (Figs. 3 to 6).

Therefore, since the composition containing Ekgansan or an extract of any one or more of its constituents according to the present invention can reduce dopamine-induced dyskinesia while not inhibiting the therapeutic effect of levodopa, it is used in combination with levodopa. It can be used for the prevention or treatment of symptoms, and further suggests that it can be used as a composition for treating Parkinson's disease with reduced side effects.

Eokgansan according to the present invention did not affect the therapeutic effect of levodopa on Parkinson's disease, but at the same time treated abnormal involuntary exercise, and reduced the levels of dopamine receptors, ERK, and FosB increased by levodopa close to that of the normal group. It can be usefully used as a composition for preventing or treating movement syndrome.

FIG. 1 is a graph showing the results of measuring passive exercise capacity through the rotarod test of the normal group, 6-OHDA induction group, levodopa administration group after 6-OHDA induction, levodopa administration after 6-OHDA induction, and Eungan acid administration group.
Figure 2 is a graph showing the measurement results of the number of times of use of the forefoot of the normal group, 6-OHDA induction group, levodopa administration group after 6-OHDA induction, levodopa administration after 6-OHDA induction, and Ekgan acid administration group.
3 is a graph showing the total AIM score of the 6-OHDA induction group, the levodopa administration group after 6-OHDA induction, the levodopa administration after 6-OHDA induction, and the Eungan acid administration group.
FIG. 4 is a graph showing the Axial AIM scores of the 6-OHDA induction group, the levodopa administration group after 6-OHDA induction, the levodopa administration after 6-OHDA induction, and the Eungan acid administration group.
5 is a graph showing the Limb AIM score of the 6-OHDA induction group, the levodopa administration group after 6-OHDA induction, the levodopa administration after 6-OHDA induction, and the Eungan acid administration group.
6 is a graph showing the Orolingual AIM score of the 6-OHDA induction group, the levodopa administration group after 6-OHDA induction, the levodopa administration after 6-OHDA induction, and the Eungan acid administration group.
FIG. 7 is a graph showing the results of measuring the expression level of dopamine receptors in the striatum of the normal group, 6-OHDA induction group, levodopa administration group after 6-OHDA induction, levodopa administration after 6-OHDA induction, and enggansan acid administration group.
FIG. 8 is a graph showing the results of measuring ERK phosphorylation levels in striatal regions of the normal group, 6-OHDA induction group, levodopa administration group after 6-OHDA induction, levodopa administration after 6-OHDA induction, and Eungan acid administration group.
9 is a graph showing the results of measuring the amount of FosB expression in the striatal region of the normal group, 6-OHDA induction group, levodopa administration group after 6-OHDA induction, levodopa administration after 6-OHDA induction, and Ekgansan acid administration group.

Hereinafter, the present invention will be described in more detail through examples. However, these examples are for illustrative purposes only, and the scope of the present invention is not limited to these examples.

Example 1. Preparation of Eokgansan

Ekgansan of the present invention was purchased and used from Tsumura.

Example 2. Measurement of the effect of levodopa in the treatment of motor disorders upon administration of Eokgan-san

In order to determine whether the effect of levodopa on Parkinson's disease was affected by the combination administration of Ekgansan, the effect of the combination administration was analyzed.

In order to determine whether the therapeutic efficacy of levodopa was affected by co-administration of Ekgansan for movement disorders arising in 6-OHDA-induced Parkinson's disease mice, passive motor ability was measured for mice through a rotarod test. In the normal group, the 6-OHDA induction group, the levodopa administration group after 6-OHDA induction, the levodopa administration after 6-OHDA induction, and the Eungansan acid administration group, exercise time in the rotarod apparatus was measured. Specifically, after training for 3 minutes in a rotarod device, the time to exercise at the measured RPM (maximum 3 minutes) was measured.

As a result, as shown in FIG. 1, it was confirmed that exercise time was significantly reduced in the 6-OHDA induction group compared to the normal group, and by confirming that it was increased by administration of levodopa, the efficacy of levodopa in treating Parkinson's movement disorder was confirmed, Even if 500 mg/kg of Eokgansan was administered with levodopa, it was confirmed that levodopa maintained the therapeutic effect of Parkinson's disease on movement disorders.

In addition, the number of use of the forefoot was measured using a cylinder in the normal group, 6-OHDA induction group, levodopa administration group after 6-OHDA induction, levodopa administration after 6-OHDA induction, and Eungan acid administration group with respect to mice. Specifically, the number of times the cylinder wall touched the cylinder wall with the left forefoot and left forefoot was measured for 3 minutes, and then the percentage of the number of times the right leg was touched was calculated from the total number of forefoot use.

As a result, as shown in FIG. 2, it was confirmed that the number of pinching of the left leg was significantly reduced in the 6-OHDA-induced group compared to the normal group, and by confirming that it was increased by administration of levodopa, the efficacy of levodopa in treating Parkinson's movement disorders was confirmed. It was confirmed that even if 500 mg/kg of Eokgansan was administered with levodopa, it was confirmed that levodopa maintained the therapeutic effect of Parkinson's disease on movement disorders.

Example 3. Analysis of the effect of Eokgansan on the treatment of levodopa-induced dyskinesia

3-1. Measurement of abnormal involuntary motor changes following administration of levodopa followed by administration of Ekgan-san

In order to determine whether levodopa-induced dyskinesia was treated with Ekganic acid in 6-OHDA-induced Parkinson's disease mice, 6-OHDA induction group, levodopa administration group after 6-OHDA induction, levodopa administration and suppression after 6-OHDA induction. Abnormal involuntary movements (AIM) were measured for 20 days in the liver acid administration group. Specifically, involuntary exercise was measured at 3-day intervals during 21 days of administration of Ekgansan from the time when levodopa-induced dyskinesia was expressed. Involuntary exercise was evaluated for 1 minute (monitoring period) at 20 minute intervals for 180 minutes after administration of levodopa, and the evaluation criteria were classified into three subtypes: axial (lateral dystonia of the neck and upper body), limbs ( limb: tremor of the femoral extremities on the side of the lesion) and atypical (oroligual: vacuum jaw movement and tongue protrusion). Each subtype was scored on a severity scale from 0 to 4 (0: none, 1: occasional, 2; frequent, 3: continuous, 4: continuous and not disturbed by external stimuli). The total AIM score corresponds to the sum of the scores for each subtype.

As a result, as shown in Figs. 3 to 6, it was confirmed that the AIM score was increased by the administration of levodopa for each subtype as well as the total AIM score. It was confirmed that the score significantly decreased.

Accordingly, it was confirmed that the composition according to the present invention can treat abnormal involuntary movement caused by levodopa.

3-2. Measurement of changes in the expression level of dopamine receptors after administration of levodopa followed by administration of Ekgan-san

In order to determine whether levodopa-induced dyskinesia was treated with Ekgan acid in 6-OHDA-induced Parkinson's disease mice, normal group, 6-OHDA induction group, levodopa administration group after 6-OHDA induction, levodopa after 6-OHDA induction. The expression level of the dopamine receptor 1 (D1 receptor) in the striatum of the administration and administration groups of Eokgansan was measured. Specifically, the expression level of the D1 receptor at the site where 6-OHDA was injected and the site opposite to the injection site was measured using a Western blot method.

As a result, as shown in FIG. 7, it was confirmed that the expression of D1 receptor was increased by administration of levodopa, and it was confirmed that the expression of D1 receptor decreased to the level of the normal group when 500 mg/kg of Euganic acid was co-administered with levodopa.

Accordingly, it is suggested that the composition according to the present invention can treat levodopa-induced dyskinesia by reducing the expression level of dopamine receptors.

3-3. Measurement of changes in ERK phosphorylation level after administration of levodopa and administration of Ekgan-san

In order to determine whether levodopa-induced dyskinesia was treated with Ekganic acid in 6-OHDA-induced Parkinson's disease mice, 6-OHDA induction group, levodopa administration group after 6-OHDA induction, levodopa administration and suppression after 6-OHDA induction. The degree of phosphorylation of extracellular signal-regulated kinase (ERK) in the striatum of the liver acid administration group was measured. Specifically, the degree of ERK phosphorylation at the site where 6-OHDA was injected and the site opposite to the injection site was measured using a Western blot method.

As a result, as shown in FIG. 8, it was confirmed that ERK phosphorylation was increased by administration of levodopa, and it was confirmed that the degree of ERK phosphorylation decreased to the level of the normal group when 500 mg/kg of euganic acid was administered in combination with levodopa.

Therefore, it is suggested that the composition according to the present invention can treat levodopa-induced dyskinesia by reducing the level of ERK phosphorylation.

3-4. Measurement of changes in the expression level of FosB after administration of levodopa and administration of Ekgan-san

In order to determine whether levodopa-induced dyskinesia was treated with Ekgan acid in 6-OHDA-induced Parkinson's disease mice, normal group, 6-OHDA induction group, levodopa administration group after 6-OHDA induction, levodopa after 6-OHDA induction. The amount of expression of FosB in the striatal region of the administration and Eokgansan administration groups was measured. Specifically, the expression level of FosB at the site where 6-OHDA was injected and the site opposite to the injection site was measured using a Western blot method.

As a result, as shown in FIG. 9, it was confirmed that the expression level of FosB was increased by administration of levodopa, and it was confirmed that the expression of FosB decreased to the level of the normal group when 500 mg/kg of Euganic acid was co-administered with levodopa.

Therefore, it is suggested that the composition according to the present invention can treat levodopa-induced dyskinesia by reducing the expression level of FosB.

Taken together, it was confirmed that Eokgansan according to the present invention can treat abnormal involuntary exercise caused by levodopa, and improves the level change of dopamine receptor, ERK, or FosB affected by levodopa close to that of the normal group. , It was confirmed that Eokgansan has the therapeutic effect of levodopa-induced dyskinesia.

In the present specification, details that can be sufficiently recognized and inferred by those of ordinary skill in the technical field of the present invention have been omitted, and the technical spirit or essential configuration of the present invention other than the specific examples described in the present specification has been changed. More various modifications are possible within the range that does not. Accordingly, the present invention may be implemented in a manner different from that specifically described and illustrated in the present specification, which is a matter that can be understood by those of ordinary skill in the technical field of the present invention.

Claims (11)

A pharmaceutical composition for the prevention or treatment of dyskinesia induced by dopamine containing Ekgan acid as an active ingredient.
The method of claim 1,
The Eokgansan is one or more selected from the group consisting of Jogudeung, Baekchul, Baekbokryeong, Angelica, Cheongung, Siho and Licorice.
delete The method of claim 1,
The composition is to reduce the expression level of the dopamine receptor, pharmaceutical composition.
The method of claim 1,
The composition is to reduce the level of ERK phosphorylation, the pharmaceutical composition.
The method of claim 1,
The composition is to reduce the expression of FosB, pharmaceutical composition.
A food composition for preventing or improving dyskinesia induced by dopamine containing Ekgansan as an active ingredient.
A method for preventing or treating dopamine-induced dyskinesia, comprising administering Ekgan-san to an individual other than humans.
A feed composition for preventing or improving dyskinesia induced by dopamine containing Ekgansan as an active ingredient.
A pharmaceutical composition for the prevention or treatment of dopamine-induced dyskinesia, comprising the composition of any one of claims 1, 2, and 4 to 6 and levodopa.
A pharmaceutical composition for treating Parkinson's disease with reduced side effects, including the composition of any one of claims 1, 2, and 4 to 6 and levodopa.

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