KR20170034662A - Composition comprising silibinin for preventing or treating epilepsy - Google Patents
Composition comprising silibinin for preventing or treating epilepsy Download PDFInfo
- Publication number
- KR20170034662A KR20170034662A KR1020150133257A KR20150133257A KR20170034662A KR 20170034662 A KR20170034662 A KR 20170034662A KR 1020150133257 A KR1020150133257 A KR 1020150133257A KR 20150133257 A KR20150133257 A KR 20150133257A KR 20170034662 A KR20170034662 A KR 20170034662A
- Authority
- KR
- South Korea
- Prior art keywords
- silibinin
- treatment
- present
- kainic acid
- composition
- Prior art date
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Abstract
Description
The present invention relates to a composition for preventing or treating brain metastasis comprising silibinin as an active ingredient.
Cerebral infarction is a disease that causes intermittent nervous system disturbance due to seizure discharge of brain cells due to organic or functional disorders and symptoms such as neurological symptoms, loss of consciousness, convulsions, and sensory disturbances. It is the third most common neurological disorder following Alzheimer's and Stroke, with about 0.5% to 2% of the world's population suffering from epilepsy. In addition, there are about 45 new cases per 100,000 people worldwide, and about 30 ~ 400,000 cases of epilepsy in our country. According to the age distribution of patients with epilepsy, it is known that 70% of all epilepsy starts at the age of pediatric adolescence, especially in early childhood. In addition, the incidence and prevalence are the highest within 1 year after birth, fall sharply, show a suddenly increasing U-shape in elderly people over 60 years of age, and the prevalence of life-long seizures is 10 to 15%.
Epilepticus is a chronic disease in which epileptic seizures occur repeatedly. Its cause is very diverse, and the exact cause of it is unknown. However, recent developments in neuroimaging techniques have enabled us to observe microscopic pathological changes in the brain that could not be observed in the past, and the causes of brain metastasis are increasingly being identified. In some epidemiologic studies, more than one-third of patients have been reported to have pathological changes in the brain or a history of brain damage. Major causes include stroke, congenital anomalies, head trauma, encephalitis, brain tumors, degenerative encephalopathy, Genetics, preterm infants, and damage before and after delivery.
On the other hand, treatment of brain metastasis can be divided into drug treatment and extrapulmonary treatment, that is, surgery, ketone diet, vagus nerve stimulation. However, drug treatment has been used only for patients who are resistant to drugs, and medication has been used as a major method for treatment of brain tumors. Conventional drugs include Phenytoin (Dilantin), Valproate (Orfil, Depakine, Depakote), Carbamazepine (Tegretol), Phenobarbital (Luminal), Ethosuximide Recently, Topiramate (topamax), Lamotrigine (Lamictal), Vigabatrin (Sabril) and Oxcarbazepine (Trileptal) have been developed and commercialized.
Despite these drug treatments, over 30% of patients with epilepsy do not have seizure control even with various drugs of action, and some drugs have skin rashes due to immune hypersensitivity reactions, gastrointestinal irritation due to drugs, and dizziness And it has been difficult to treat effective epilepsy. Therefore, studies on a new therapeutic agent for cerebral apoplexy have been actively conducted (Korean Patent Publication No. 10-2013-0065646).
Disclosure of the Invention The present invention has been made in order to solve the above problems, and the present inventors have confirmed the effect of delaying the seizure onset and the frequency of occurrence of the epileptic seizure according to the treatment with Silibinin, and completed the present invention based on this.
Accordingly, an object of the present invention is to provide a pharmaceutical composition for preventing or treating brain metastasis comprising silibinin as an active ingredient.
Another object of the present invention is to provide a health functional food composition for prevention or amelioration of cerebral embryogenesis which contains silibinin as an active ingredient.
However, the technical problem to be solved by the present invention is not limited to the above-mentioned problems, and other matters not mentioned can be clearly understood by those skilled in the art from the following description.
In order to achieve the object of the present invention, the present invention provides a pharmaceutical and / or health functional food composition for preventing, ameliorating or treating the episodes of cerebrospinal fluid comprising silibinin as an active ingredient.
In another embodiment of the present invention, the composition can inhibit the dispersion of granule cells.
In another embodiment of the present invention, the composition may inhibit the activity of mTORC1 (mammalian target of rapamycin complex 1).
The present invention provides a method for treating epilepsy comprising the step of administering the above pharmaceutical composition to a subject.
The present invention provides the use of a composition comprising Silibinin for the treatment of brain tumors.
The composition according to the present invention contains silibinin as an active ingredient and confirmed the effect of delaying the occurrence of epileptic seizures and reducing the incidence of the epileptic seizures. In addition, it has been confirmed that silibinin can inhibit the granulocyte dispersion and the activity of mTORC1 (mammalian target of rapamycin complex 1), and it is useful as a pharmaceutical composition for preventing or treating epilepsy which solves the side effects of the conventional therapeutic agent It is expected that it can be used.
Figure 1 shows the effect of delayed seizure latency following treatment with various concentrations of silibinin (50, 100, 200 mg / kg) in an animal model in which brain growth was induced by kainic acid (KA; KA + S (100), kainic acid and
FIG. 2 shows the effect of reducing the seizure frequency according to treatment with silibinin (200 mg / kg) in an animal model in which brain growth was induced by kainic acid (KA; kainic acid treatment group (control group), KA + S 200); kainic acid and Silibinin 200 mg / kg treated group).
FIG. 3 shows the degree of granulation of granulosa cells treated with various concentrations of silibinin (50, 100, 200 mg / kg) in 0.5% cresyl violet (Sigma) staining in an animal model in which brain growth was induced by kainic acid KA + S (100); kainic acid and
Figure 4 shows the results of quantitative analysis of the degree of granulation of granulocytes following treatment with various concentrations of silibinin (50, 100, 200 mg / kg) in an animal model in which brain growth was induced by kainic acid (CON; KA + S (100), kainic acid and
FIG. 5 shows the change in the activity of mTORC1 (mammalian target of rapamycin complex 1) according to treatment with silibinin (200 mg / kg) in an animal model in which brain growth was induced by kainic acid, using p-4E-BP1 (CON; non-treated with kainic acid, KA; treated with kainic acid, KA + S (200); treated with kainic acid and
FIG. 6 shows the results of quantitative comparison of the activity of mTORC1 (mammalian target of rapamycin complex 1) according to treatment with silibinin (200 mg / kg) in an animal model in which brain growth was induced by kainic acid (CON; KA + S (200) treated with kainic acid and
The present inventors confirmed the delayed and inciduous effect of epileptic seizure induced by silibinin treatment using an animal model in which brain growth was induced by kainic acid and showed that granulocyte dispersion and mTORC1 (mammalian target of rapamycin complex 1 ) Can be inhibited, and the present invention has been completed on the basis thereof.
Hereinafter, the present invention will be described in detail.
The present invention provides a pharmaceutical composition for preventing or treating brain metastasis comprising silibinin as an active ingredient.
In the composition of the present invention, the active ingredient silibinin ((2R, 3R) -3,5,7-trihydroxy-2 - [(2R, 3R) -3- (4-hydroxy-3-methoxyphenyl) - (hydroxymethyl) -2,3-dihydrobenzo [b] [1,4] dioxin-6-yl] chroman-4-one is one of the compounds isolated from Milk thistle, And poisoning, and recent studies have found that silicinin can be used to prevent the metastasis of lung cancer. Despite these studies, however, there has been no report on the association between silicinem and epilepsy.
The "epilepticism", which is a preventive or therapeutic disease to be prevented or treated by the composition of the present invention, is a phenomenon in which some of the nerve cells generate seizure in a short time due to synchronization with abnormal abnormal excitement of the brain, Which is a serious neurological disorder accompanied by neurobiological, psychological, cognitive and social changes. In addition, unlike general brain neurological diseases, in which neurons regress or die, cognitive disorders, behavioral disorders, and the like, brain neurosis is characterized by a neurological disorder caused by abnormally excessive activation of nerve cells. In addition, hippocampal sclerosis, gonadal hyperplasia (Hippocampal sclerosis, etc.) in the hippocampus of cerebral regions, where pathological damage due to brain injury is evident due to excitotoxicity caused by hyperexcitability of abnormal neurons, gliosis, abnormal neurogenesis, cytoarchitectural abnormality of dentate granule cells, and aberrant syn- passic circuit. As the pathological phenomenon of the hippocampus progresses, a chronic epileptic seizure develops and refractory refractory epilepsy which does not respond to medication treatment as well as cognitive and memory disorders occurs.
As used herein, the term "prophylactic " means any action that inhibits or delays the development of the brain metastasis by administration of the pharmaceutical composition according to the present invention.
As used herein, the term "treatment" means any action that improves or alters the symptoms of epilepsy by administration of the pharmaceutical composition according to the present invention.
In one embodiment of the present invention, it has been found that continuous treatment of silibinin in an animal model in which brain growth is induced by kainic acid can not only delay seizure latency but also reduce seizure occurrence frequency See Example 2). Also, as a result of the above, it is possible to effectively inhibit the activity of mTORC1 (mammalian target of rapamycin complex 1), which is a pharmaceutical composition for prevention or treatment of brain metastasis, (See Examples 3 and 4).
The pharmaceutical composition according to the present invention may contain a pharmaceutically acceptable carrier in addition to the active ingredient. The pharmacologically acceptable carriers are those conventionally used at the time of formulation and include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose But are not limited to, polyvinylpyrrolidone, cellulose, water, syrup, methylcellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. Further, in addition to the above components, a lubricant, a wetting agent, a sweetener, a flavoring agent, an emulsifying agent, a suspending agent, a preservative, and the like may be further included.
The pharmaceutical composition of the present invention may be administered orally or parenterally (for example, intravenously, subcutaneously, intraperitoneally or topically) depending on the intended method, and the dose may vary depending on the condition and the weight of the patient, The mode of administration, the route of administration, and the time, but may be appropriately selected by those skilled in the art.
The pharmaceutical composition of the present invention is administered in a pharmaceutically effective amount. In the present invention, the term "pharmaceutically effective amount" means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment, and the effective dose level will depend on the type of disease, severity, The sensitivity to the drug, the time of administration, the route of administration and the rate of release, the duration of the treatment, factors including co-administered drugs, and other factors well known in the medical arts. The pharmaceutical composition according to the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, sequentially or concurrently with conventional therapeutic agents, and may be administered singly or in multiple doses. It is important to take into account all of the above factors and to administer the amount in which the maximum effect can be obtained in a minimal amount without side effects, which can be easily determined by those skilled in the art.
Specifically, the effective amount of the pharmaceutical composition of the present invention may vary depending on the age, sex, condition, body weight, the degree of absorption of the active ingredient in the body, the rate of inactivation and excretion, the type of disease, 100 to 500 mg / kg of body weight may be administered daily or every other day, or one to three times a day. However, the dosage may be varied depending on the route of administration, the severity of obesity, sex, weight, age, etc. Therefore, the dosage is not limited to the scope of the present invention by any means.
The present invention also provides a health functional food composition for preventing or ameliorating epilepsy comprising silibinin as an active ingredient.
As used herein, the term "improvement" means all actions that at least reduce the degree of symptom associated with the condition being treated. At this time, the health functional food composition may be used either simultaneously with or separately from the medicament for treatment before or after the onset of the disease for the prevention or improvement of epilepsy.
The term "food composition" as used in the present invention means a food composition comprising at least one of carrier, diluent, excipient and additives and being formulated into one selected from the group consisting of tablets, pills, powders, granules, powders, capsules, . Examples of foods that can be added to the composition of the present invention include various foods, powders, granules, tablets, capsules, syrups, drinks, gums, tea, vitamin complexes, and health functional foods. Examples of the additive that can be further included in the present invention include natural carbohydrates, flavors, nutrients, vitamins, minerals (electrolytes), flavors (synthetic flavors, natural flavors and the like), colorants, fillers, At least one component selected from alginic acid and its salts, organic acids, protective colloid thickening agents, pH adjusting agents, stabilizers, preservatives, antioxidants, glycerin, alcohols, carbonating agents and fats can be used. Examples of the above-mentioned natural carbohydrates include monosaccharides such as glucose, fructose and the like; Disaccharides such as maltose, sucrose and the like; And polysaccharides, for example, conventional sugars such as dextrin, cyclodextrin and the like, and sugar alcohols such as xylitol, sorbitol and erythritol. As the above-mentioned flavors, natural flavors (tautatin, stevia extract (for example, rebaudioside A and glycyrrhizin) and synthetic flavors (saccharin, aspartame, etc.) can be advantageously used. The composition according to the present invention can be used in various forms such as flavorings such as various nutrients, vitamins, minerals (electrolytes), synthetic flavors and natural flavors, colorants and heavies, factic acid and its salts, alginic acid and its salts, , a pH adjusting agent, a stabilizer, a preservative, a carbonating agent used in glycerin, an alcohol, a carbonated drink, etc. In addition, the composition according to the present invention may contain flesh for the production of natural fruit juice and vegetable drinks Specific examples of the carrier, excipient, diluent, and additive include, but are not limited to, lactose, dextrose, But are not limited to, sucrose, sorbitol, mannitol, erythritol, starch, acacia, calcium phosphate, alginate, gelatin, calcium phosphate, calcium silicate, microcrystalline cellulose, polyvinylquilolidone, cellulose, polyvinylpyrrolidone, methylcellulose, It is preferable to use at least one selected from the group consisting of sugar syrup, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.
In another aspect of the present invention, the present invention provides a method for treating brain metastasis comprising administering the pharmaceutical composition to a subject. The term " individual "as used herein refers to a subject in need of treatment of a disease, and more specifically refers to a mammal such as a human or non-human primate, mouse, dog, cat, horse, do.
Hereinafter, preferred embodiments of the present invention will be described in order to facilitate understanding of the present invention. However, the following examples are provided only for the purpose of easier understanding of the present invention, and the present invention is not limited by the following examples.
[Example]
Example 1. Experimental preparation and method
1-1. Induction of brain metastasis by treatment with kainic acid
Anesthesia was induced by intraperitoneal injection of chloral hydrate (360 mg / kg, Sigma, St. Louis, Mo. USA) to adult male C57BL / 6 mice (8 weeks of age, BioLink, , Tujunga, CA, USA), respectively. Specifically, a hamilton syringe needle (30S) and a syringe pump (KD Scientific, NewHope, USA) were attached to the hippocampus of a rat (AP: -2.0mm, ML: -1.2mm, DV: -1.5mm; Franklin and Paxinos, (KA) (0.2 μg in phosphate-buffered saline (PBS), Sigma) was directly administered to the mice to induce brain metastasis. In accordance with the protocol and guidelines of the present invention.
1-2. Administration of silibinin
Silibinin (Sigma) was dissolved in physiological saline (0.9% saline) containing 0.25% carboxymethyl cellulose (Sigma). (50, 100, 200 mg / kg) was injected intraperitoneally before the administration of kainic acid and before the administration of kainic acid, and to the effect of kainic acid treatment on epileptic After seizure induction, silibinin was administered for 6 days once a day from the following day.
In order to investigate the effects of spontaneous recurrent seizure (SRS) induced by kainic acid treatment on seizure frequency, kainic acid was added to the
1-3. Statistical analysis
All values were expressed as mean ± standard error of the mean (SEM) using the Sigma plot 12.0 program. Multiple comparisons were performed using one-way analysis of variance (ANOVA) using the Tukey post-test.
Example 2. Silibinin Treatment delay and seizure frequency reduction effect
In this example, the effect of silibinin treatment on delayed seizure latency and seizure incidence using an animal model in which brain growth was induced by kainic acid was examined.
2-1. Check for delayed seizure effects
Behavioral seizure stages are identified in five stages, one for each stage; Facial movement,
As a result, as shown in Fig. 1, the generation of epileptic seizures was significantly delayed in the group treated with the continuous treatment with silicin (50, 100, 200 mg / kg) as compared with the control group without the treatment with the siibinin And this tendency could be observed more clearly as the concentration of silibinin treatment increased.
2-2. Identify the effect of reducing the incidence of seizures
Whether or not spontaneous recurrent seizure (SRS) was spontaneous recurrent seizure was assessed by video recording from week 3 to week 2 (9 hours a day, 6 days a week, 108 hours a total of 2 weeks) after treatment with kainic acid Respectively. The incidence of spontaneous recurrent epilepsy was recorded as the occurrence of seizure activity in stages 3 to 5 during the shooting period.
As a result, as shown in Fig. 2, it was confirmed that the incidence of spontaneous epileptic seizures was remarkably reduced in the group (200 mg / kg) in which the silibinin was continuously treated as compared with the control group not treated with the silibinin .
Example 3 Inhibitory Effect of Silibinin Treatment on Granule Cell Dispersion
In this example, an attempt was made to determine the degree of granulation cell granulation by silibinin treatment using an animal model in which brain growth was induced by kainic acid. Specifically, on day 7 after treatment with kainic acid, euthanasia was induced by intraperitoneal injection of chloral hydrate (360 mg / kg; Sigma) into an animal model in which brain tumors were induced. % paraformaldehyde was perfused through the heart. The corneal brain sections of 30 μm thickness were prepared using cryotat (Microm International GmbH, Walldorf, Germany), and the sections attached to the slides were stained with 0.5% cresyl violet (Sigma) Respectively. The degree of granulocyte dispersion (GCD) was measured by comparing the average width of the granule cell layer at the inner 1/4 point and the midpoint of the granule cell layer (GCL) in the dentate gyrus (DG) The average width of the horny tooth and granule cell layer treated with kainic acid was compared with the mean width of the granule cell layer of the teeth and analyzed as a percentage.
As a result, as shown in Fig. 3 and Fig. 4, in the group (50, 100, 200 mg / kg) in which the silibinin was continuously treated (50, 100 and 200 mg / kg) as compared with the control group not treated with the silibinin, And the tendency was clearly observed as the concentration increased as in Example 2-1.
Example 4 Inhibitory Effect on Granulocyte Dispensation-Related Factors by Silibinin Treatment
In this example, the activity of mTORC1 (mammalian target of rapamycin complex 1) related to granulosa cell disintegration by silibinin treatment was examined using an animal model in which brain growth was induced by kainic acid. Specifically, after kainic acid treatment, euthanasia was performed on day 7, and hippocampal tissues of an animal model that had not been treated with or treated with silibinin were extracted. The extracted hippocampal tissues were homogenized and centrifuged to separate the supernatant (4 ° C, 15 min, 14000 g). Protein concentration was determined using a bicinchoninic acid assay kit (BCA kit; Bio-Rad Laboratories, Hercules, Calif., USA) and proteins were separated by SDS-PAGE (Sodium Dodecyl Sulfate-Polyacrylamide Gel Electrophoresis). The separated proteins were transferred to the membrane using an electrophoretic transfer system (Bio-Rad Laboratories) and the primary antibodies [anti-p-4E-BP1 (1: 1000, Cell Signaling), anti- : 4000, Cell Signaling)] at 4 ° C for one day. The cells were then reacted with secondary antibodies (Amersham Biosciences, Piscataway, NJ, USA) and developed with ECL Western blot detection reagents (Amersham Biosciences). For quantitative analysis, the density of each protein was measured using a computer program Image gauge 4.0 (FUJIFILM Science Lab).
As a result, as shown in Fig. 5 and Fig. 6, in the group (200 mg / kg) in which the silibinin was continuously treated (200 mg / kg) as compared with the control group not treated with silibinin, the activity of mTORC1 Respectively.
It will be understood by those skilled in the art that the foregoing description of the present invention is for illustrative purposes only and that those of ordinary skill in the art can readily understand that various changes and modifications may be made without departing from the spirit or essential characteristics of the present invention. will be. It is therefore to be understood that the above-described embodiments are illustrative in all aspects and not restrictive.
Claims (4)
Wherein the composition inhibits the granulation of the granule cells.
Wherein said composition inhibits the activity of mTORC1 (mammalian target of rapamycin complex 1).
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