KR20210099220A - Composition for preventing or treating ischemic brain disease comprising SAHA as an active ingredient - Google Patents

Abstract

The present invention relates to a composition for preventing or treating ischemic brain diseases which contains SAHA as an active component. Since SAHA increases brain activity in an animal model of hypoxic ischemic encephalopathy, so that SAHA is expected to be used as a treatment for ischemic brain diseases, especially HIE, which occurs frequently in newborns.

Description

Composition for preventing or treating ischemic brain disease comprising SAHA as an active ingredient

The present invention relates to a composition for preventing or treating ischemic encephalopathy comprising SAHA (suberoylanilide hydroxamic acid) as an active ingredient.

According to the 2001 statistical survey on the cause of death in Korea, the death rate from cerebrovascular disease (the number of deaths per 100,000 people) reached 73.8, the second highest after cancer, and the social and economic cost was estimated to be KRW 2.31 trillion. Since the demand for treatments for cerebrovascular diseases is very high, it is important to research and develop treatments to reduce social and economic losses through treatment of cerebrovascular diseases. Cerebrovascular disease is particularly prevalent in the elderly, and once it occurs, the mortality rate is very high. Looking at the ratio of the elderly population in Korea announced in October 2003 by the National Statistical Office, Korea has entered an aging society, with the proportion of the population aged 65 and older accounting for 7.2% of the total population in 2000. In 2019, this ratio will rise to 14 It is expected to exceed this percentage and enter an aged society.

Cerebrovascular diseases can be broadly classified into two types. One is hemorrhagic brain disease, which can be seen in cerebral hemorrhage, and the other is ischemic brain disease, which is caused by occlusion of blood vessels in the brain. Hemorrhagic brain disease is mainly caused by traffic accidents, and ischemic brain disease is a disease that occurs frequently in elderly people. Ischemic brain disease can be subdivided into thrombosis, embolism, transient ischemic attack, and small infarction. It is a pathological abnormality in the supplying blood vessels.

Neonatal hypoxic ischemic encephalopathy (HIE), one of the ischemic brain diseases, is caused by housework in the newborn, leading to abnormal neurobehavioral findings such as dyspnea, decreased muscle tone, change of consciousness, loss of primitive reflexes, convulsions, and lactation disorders. is in a visible state. It accounts for 23% of all neonatal deaths, and in the case of severe injuries, about 50-100% die, and it is reported that 65-75% of surviving children have severe motor/cognitive impairments and convulsions that last a lifetime. The only existing treatment for HIE is hypothermia, but the effect is weak, and about 44% of them suffer from death and long-term neurological sequelae, especially in the severe type, there is no effect of improvement. Therefore, it is very important and urgent to develop an effective and distinct treatment for HIE in newborns due to its intractability.

Moreover, the low fertility rate problem in Korea has not improved despite various government support policies, so lowering the morbidity rate of newborns would be the most efficient and sure way to increase the effective economic population in the future. Therefore, the development of a next-generation high-efficiency therapeutic agent that can treat neonatal hypoxic ischemic encephalopathy, which accounts for a significant portion of the total neonatal mortality and causes serious complications during survival, is urgent and urgent in countries with low fertility.

SAHA is an inhibitor of histone deacetylase and is known to inhibit cell growth of cancer cells and induce cancer cell death at concentrations that are not toxic to normal cells. In clinical studies, SAHA's anticancer effect showed significant anticancer effect not only on liver cancer cells but also on normal solid cells, and has been approved by the US FDA for clinical use in T-cell lymphoma.

However, there is no known treatment for ischemic encephalopathy including SAHA, particularly hypoxic ischemic encephalopathy in newborns.

Republic of Korea Patent Publication No. 10-2018-0084610

Accordingly, the present inventors confirmed for the first time that SAHA (suberoylanilide hydroxamic acid) can be used as a treatment for hypoxic ischemic encephalopathy (HIE) by increasing brain plasticity and cortical functional activity.

Accordingly, an object of the present invention is to provide a pharmaceutical composition for preventing or treating ischemic encephalopathy comprising SAHA or a pharmaceutically acceptable salt thereof as an active ingredient.

Another object of the present invention is to provide a food composition for preventing or improving ischemic brain disease comprising SAHA or a pharmaceutically acceptable salt thereof as an active ingredient.

Another object of the present invention is to provide a composition for enhancing neuroplasticity comprising SAHA or a pharmaceutically acceptable salt thereof as an active ingredient.

However, the technical problem to be achieved by the present invention is not limited to the above-mentioned problems, and other problems not mentioned will be clearly understood by those skilled in the art from the following description.

In order to achieve the object of the present invention as described above, the present invention provides a pharmaceutical composition for preventing or treating ischemic brain disease comprising SAHA or a pharmaceutically acceptable salt thereof as an active ingredient.

In addition, the present invention provides a food composition for preventing or improving ischemic brain disease comprising SAHA (suberoylanilide hydroxamic acid) or a pharmaceutically acceptable salt thereof as an active ingredient.

In addition, the present invention provides a composition for enhancing neuroplasticity comprising SAHA (suberoylanilide hydroxamic acid) or a pharmaceutically acceptable salt thereof as an active ingredient.

In one embodiment of the present invention, the ischemic brain disease is stroke, cerebral infarction, cerebral ischemia, thrombosis, embolism, transient ischemic attack, small infarction (lacune), head trauma , cerebral circulation metabolic disorder, brain dysfunction, traumatic brain injury and hypoxic ischemic encephalopathy (HIE) may be at least one selected from the group consisting of, but is not limited thereto.

In another embodiment of the present invention, the SAHA may be represented by the following Chemical Formula 1:

[Formula 1]

In another embodiment of the present invention, the ischemic brain disease may be one or more ischemic brain diseases selected from the group consisting of newborns, infants, infants and children, but is not limited thereto.

In another embodiment of the present invention, the newborns, infants, infants and children may be between the age of birth and less than 12 years of age, but the present invention is not limited thereto.

In another embodiment of the present invention, the SAHA may restore neuroplasticity, but is not limited thereto.

In addition, the present invention provides a method for preventing or treating ischemic brain disease by administering a composition comprising SAHA as an active ingredient to a subject.

The present invention also provides the use of SAHA for the manufacture of a medicament for the prevention or treatment of ischemic brain disease.

In addition, the present invention provides a use of a composition comprising SAHA as an active ingredient for treating ischemic encephalopathy.

In addition, the present invention provides a method for enhancing neuroplasticity by administering a composition comprising SAHA as an active ingredient to a subject.

In addition, the present invention provides a neuroplasticity enhancing use of a composition comprising SAHA as an active ingredient.

The composition according to the present invention contains SAHA as an active ingredient, and when administered to an animal model of hypoxic ischemic encephalopathy, brain activity was increased. It is also expected to be used as a treatment for diseases.

1 shows the BOLD activity region for electrical stimulation in each forepaw of rats in the normal-HDI administration group (Normal+HDI), disease-control group (HI+DMSO), and disease-HDI administration group (HI+HDI).
Figure 2 is each normal-HDI administration group (Normal+HDI), disease-control group (HI+DMSO), disease-HDI administration group (HI+HDI) for the rats of the adhesive tape removal (Adhesive tape removal) behavioral test evaluation result graph where A is the tape contact time result for the forepaw on the lesion side of the brain (normal side, ipsilesional forepaw), B is the tape removal time result for the lesion side forepaw (normal side, ipsilesional forepaw) of the brain, and C is the result of the tape removal time for the brain lesion side forepaw (normal side, ipsilesional forepaw). The tape contact time results for the forepaw (injured side, contralesional forepaw), and D shows the tape removal time results for the forepaw on the contralateral side of the brain (injured side, contralesional forepaw).

The present inventors first confirmed that SAHA exhibits a mechanism for increasing brain activity through increased neuroplasticity. Accordingly, the present invention relates to ischemic brain comprising SAHA (suberoylanilide hydroxamic acid) or a pharmaceutically acceptable salt thereof as an active ingredient. It provides a composition for preventing, treating or ameliorating a disease.

Hereinafter, the present invention will be described in detail.

In the present invention, SAHA (suberoylanilide hydroxamic acid) is a substance also called vorinostat, which has an activity to inhibit histone deacetylases (HDAC), known as histone deacetylase inhibitors (HDI), It has the structure of Formula 1.

Vorinostat is sold under the trade name Zolinza and is a compound approved by the US FDA as a treatment for cutaneous T cell lymphoma (CTCL).

[Formula 1]

In one embodiment of the present invention, it was confirmed that when SAHA was administered to an animal model of hypoxic ischemic encephalopathy, the functional activity response of the brain increased in both the normal group and the disease group administered with SAHA, thereby enhancing brain plasticity (Example) see 2).

In addition, in another embodiment of the present invention, as a result of administering SAHA to an animal model of hypoxic ischemic encephalopathy and performing an adhesive tape removal behavioral experiment, both the normal group and the disease group administered with SAHA had brain function compared to the non-administered group. was found to be excellent (see Example 3)

Accordingly, it is expected that SAHA can be applied to the prevention, improvement or treatment of ischemic brain disease.

In the present invention, "ischemic brain disease" refers to a brain disease caused by ischemia or reperfusion after ischemia. The ischemic brain disease is, for example, stroke, cerebral infarction, cerebral ischemia, thrombosis, embolism, transient ischemic attack, small infarction (lacune), head trauma, cerebral circulation metabolism It may be at least one selected from the group consisting of disorders, brain dysfunction, traumatic brain injury, and hypoxic ischemic encephalopathy (HIE), but is not limited thereto.

In the present invention, 'hypoxic ischemic encephalopathy' refers to a state in which the function or structure of the brain is changed due to a severe lack of oxygen in the brain, and may be temporarily recoverable, but sometimes irreversible permanent damage occurs.

In the present invention, the ischemic brain disease may be one or more ischemic brain diseases selected from the group consisting of newborns, infants, infants and children, but is not limited thereto.

In the present invention, the newborn, infant, infant and child may be less than 12 years of age from the date of birth, but is not limited thereto.

The age classification of the newborn to the child may be specifically as described in Table 1 below, but is not limited thereto.

Classification of Children's Age by The International Conference on Harmonization (ICH) Classification designation age newborn baby Date of birth to less than 28 days infant More than 28 days and less than 24 months child
[Infant + Child] More than 24 months and less than 12 years old
[Infant: 24 months to 6 years old]
[Children: 6 to 12 years old]

In the present invention, the SAHA may be to restore neuroplasticity, but is not limited thereto.

In the present invention, "prevention" means any action that inhibits or delays the onset of a desired disease, and "treatment" refers to any action in which the symptoms of the desired disease are improved or beneficially changed by administration of the pharmaceutical composition according to the present invention. It means an action, and "improvement" means any action of reducing a parameter related to a desired disease, for example, the degree of a symptom by administration of the composition according to the present invention.

The compound of the present invention may be used in the form of a pharmaceutically acceptable salt, and as the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful.

As used herein, the term "salt" is useful as an acid addition salt formed by a pharmaceutically acceptable free acid. Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid, and aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanes. It is obtained from non-toxic organic acids such as dioates, aromatic acids, aliphatic and aromatic sulfonic acids. Such pharmaceutically non-toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, ioda. Id, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate , sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, Toxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, beta-hydroxybutyrate, glycol late, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate or mandelate.

The acid addition salt according to the invention is prepared by a conventional method, for example, by dissolving the compound in an aqueous solution of an excess of acid, and precipitating the salt using a water-miscible organic solvent, for example methanol, ethanol, acetone or acetonitrile. It can be manufactured by It can also be prepared by evaporating the solvent or excess acid from the mixture and drying the mixture, or by suction filtration of the precipitated salt.

In addition, a pharmaceutically acceptable metal salt may be prepared using a base. The alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and evaporating and drying the filtrate. In this case, it is pharmaceutically suitable to prepare a sodium, potassium or calcium salt as the metal salt. The corresponding silver salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (eg silver nitrate).

In addition, the compound of the present invention includes all salts, isomers, hydrates and solvates that can be prepared by conventional methods as well as pharmaceutically acceptable salts.

The SAHA of the present invention may be included in the composition in an amount of 1 pg to 30 g w/v%, but is not limited thereto.

In the present invention, the term "individual" is not limited as long as it is a vertebrate, but specifically includes humans, mice, rats, guinea pigs, rabbits, monkeys, pigs, horses, cattle, sheep, antelopes, dogs, cats, fish and reptiles. It can be applied, and preferably a human.

In the present invention, "administration" means introducing the pharmaceutical composition of the present invention to a patient by any suitable method, and the administration route 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

In the present invention, the pharmaceutical composition may further include suitable carriers, excipients, and diluents commonly used in the preparation of pharmaceutical compositions.

In the present invention, "carrier" is also called a vehicle, and refers to a compound that facilitates the addition of proteins or peptides into cells or tissues. For example, dimethyl sulfoxide (DMSO) is a cell of an organism. or a commonly used carrier that facilitates the introduction of many organic substances into tissues.

In the present invention, "diluent" is defined as a compound that is diluted in water which not only stabilizes the biologically active form of the compound of interest, but also dissolves the compound. Salts dissolved in buffer solutions are used as diluents in the art. A commonly used buffer solution is phosphate buffered saline because it mimics the salt state of human body fluids. Because buffer salts can control the pH of a solution at low concentrations, buffer diluents rarely modify the biological activity of a compound. As used herein, the compounds containing azelaic acid may be administered to a human patient as such or as a pharmaceutical composition admixed with other ingredients as in combination therapy or with suitable carriers or excipients.

In addition, the pharmaceutical composition according to the present invention may be formulated and used in the form of external preparations such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, etc. and sterile injection solutions, respectively, according to conventional methods. Carriers, excipients and diluents that may be included in the composition include lactose, dextrose, sucrose, oligosaccharides, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, 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 commonly used diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, and surfactants. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid preparations include at least one excipient in the compound, for example, starch, calcium carbonate, sucrose ) or lactose, gelatin, etc. In addition to simple excipients, lubricants such as magnesium stearate talc are also used. Liquid preparations for oral use include suspensions, solutions, emulsions, syrups, etc. In addition to water and liquid paraffin, which are commonly used simple diluents, various excipients, for example, wetting agents, sweeteners, fragrances, preservatives, etc. may be included. . Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. Non-aqueous solvents and suspending agents include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin, glycerogelatin, and the like can be used.

The pharmaceutical composition of the present invention may be administered orally or parenterally, preferably parenterally, and in the case of parenteral administration, intramuscular injection, intravenous injection, subcutaneous injection, intraperitoneal injection, topical administration, transdermal administration, etc. can

A suitable dosage of the pharmaceutical composition of the present invention is variously prescribed depending on factors such as formulation method, administration method, age, weight, sex, pathological condition, food, administration time, administration route, excretion rate and reaction sensitivity of the patient. can be

The pharmaceutical composition of the present invention is prepared in unit dosage form by formulating using a pharmaceutically acceptable carrier and/or excipient according to a method that can be easily carried out by a person of ordinary skill in the art to which the present invention pertains. Or it can be prepared by putting it in a large-capacity container. In this case, the formulation may be in the form of a solution, suspension, or emulsion in oil or an aqueous medium, or may be in the form of an extract, powder, granule, tablet or capsule, and may additionally include a dispersant or stabilizer.

In addition, the present invention relates to a composition for enhancing neuroplasticity comprising SAHA (suberoylanilide hydroxamic acid) or a pharmaceutically acceptable salt thereof as an active ingredient.

As used herein, neuroplasticity refers to the ability of the human brain to be changed by experience. Brain neuroplasticity refers to a phenomenon in which the neural pathways of the brain are structurally and functionally changed and reorganized by external stimulation, experience, and learning.

In addition, the present invention relates to a food composition for preventing or improving ischemic brain disease comprising SAHA (suberoylanilide hydroxamic acid) or a pharmaceutically acceptable salt thereof as an active ingredient.

In addition, the composition comprising SAHA may be added to food for the purpose of preventing or improving ischemic brain disease.

In the present invention, food includes functional food and health functional food.

When the SAHA of the present invention is used as a food additive, it can be added as it is or used together with other foods or food ingredients, and can be appropriately used according to a conventional method. The mixed amount of the active ingredient may be appropriately determined according to the purpose of use (prevention, health or therapeutic treatment). In general, in the production of food or beverage, the SAHA of the present invention is added in an amount of 15% by weight or less, preferably 10% by weight or less, based on the raw material. However, in the case of long-term ingestion for health and hygiene purposes or for health control, the amount may be less than the above range, and since there is no problem in terms of safety, the active ingredient may be used in an amount above the above range.

There is no particular limitation on the type of the food. Examples of foods to which the above substances can be added include meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gums, dairy products including ice cream, various soups, beverages, tea, drinks, There are alcoholic beverages and vitamin complexes, and includes all health functional foods in the ordinary sense.

The health beverage composition according to the present invention may contain various flavoring agents or natural carbohydrates as additional ingredients, like a conventional beverage. The above-mentioned natural carbohydrates are monosaccharides such as glucose and fructose, disaccharides such as maltose and sucrose, polysaccharides such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol and erythritol. As the sweetener, natural sweeteners such as taumatine and stevia extract, synthetic sweeteners such as saccharin and aspartame, and the like can be used. The proportion of the natural carbohydrate is generally about 0.01-0.20 g, preferably about 0.04-0.10 g per 100 mL of the composition of the present invention.

In addition to the above, the composition of the present invention includes various nutrients, vitamins, electrolytes, flavoring agents, coloring agents, pectic acid and its salts, alginic acid and its salts, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohol, Carbonating agents used in carbonated beverages, etc. may be contained. In addition, the composition of the present invention may contain fruit for the production of natural fruit juice, fruit juice beverage, and vegetable beverage. These components may be used independently or in combination. The proportion of these additives is not critical, but is generally selected in the range of 0.01-0.20 parts by weight per 100 parts by weight of the composition of the present invention.

In addition, the present invention relates to a method for preventing or treating ischemic brain disease by administering a composition comprising SAHA as an active ingredient to a subject.

The present invention also relates to the use of SAHA for the manufacture of a medicament for the prevention or treatment of ischemic brain disease.

In addition, the present invention relates to the use of a composition comprising SAHA as an active ingredient for treating ischemic encephalopathy.

In addition, the present invention relates to a method for enhancing neuroplasticity by administering a composition comprising SAHA as an active ingredient to a subject.

In addition, the present invention relates to the use of a composition comprising SAHA as an active ingredient to enhance neuroplasticity.

Hereinafter, preferred examples are presented to help the understanding of the present invention. However, the following examples are only provided for easier understanding of the present invention, and the contents of the present invention are not limited by the following examples.

[ Example ]

Example One. hypoxic Preparation of ischemic encephalopathy disease animal model

As an animal model of hypoxic ischemic encephalopathy (HIE), surgery was performed in 7-day-old neonatal rats. Specifically, the skin just above the right common carotid artery (CCA) of newborn rats (7 days old) was incised, the right CCA was exposed, and then tied using silk (5/0). After ligation of the common carotid artery, the operated neonatal rat was placed in a hypoxic maintenance chamber, and hypoxic brain injury was induced (8% O ₂ , 37°C for 150 min).

Example 2. In animal models SAHA's to confirm the effect of treatment fMRI performance result

24 hours after the operation of the animal model prepared in Example 1, a T2-weighted MR image was obtained and the degree of damage was confirmed, and then the experiment was performed. The normal group used a model in which the skin was incised just above the right CCA and then sutured.

Experimental group is normal-HIE administration group, HDI (HDAC inhibitor) drug administration group (n=6) to normal rats, disease-control group is DMSO administration group to brain disease (HI) model rats (n=6), disease-HDI group The administration group was divided into one group in which HDI drugs were administered to brain disease (HI) model rats (n=6).

SAHA (vorinostat) was used as HDI, and the drug was administered from 33 to 42 days (once/day) for a total of 10 days, and the administration method was intraperitoneal (IP) intraperitoneal injection. did. SAHA was administered at a dose of 25 mg/kg.

T2-weighted MR images were acquired on the 8th day of life (24 hours after animal modeling), and fMRI imaging was performed at 42 days (6 weeks of age) after drug administration to a model in which certain damage was confirmed.

Specifically, the MR image acquisition method is as follows. First, a 16-gauge catheter was intubated into the airway to artificially control respiration for maintaining the physiological state of the rat. Connect the secured catheter tube to the _{ventilator to maintain breathing so that PCO 2} =35-45 mmHg, PO ₂ =80-100 mmHG, and at the same time, maintain 1.2% using isoflurane as an inhalation anesthetic through this tube. did. In order to give electrical stimulation for BOLD-fMRI signal acquisition, two needle-electrodes are inserted into each forelimb (between the 2nd and 4th toes) and a device that generates a constant current is used to generate a constant current, frequency 12 Hz, pulse width = 1.0 Electrical stimulation was applied in ms, current = 1.4 mA. Before and after application, MR image signals were obtained using EPI (echo planar imaging) imaging techniques, and images showing brain regions responding to stimuli were obtained through post-processing of the images. The stimulation paradigm consisted of a 20-second pre-stimulus period, a 20-second stimulus, and a 40-second post-stimulus period. At least 10 images were obtained for each forelimb to obtain an average image. At this time, in order to minimize the signal caused by the habituated stimulus, the time interval between repeatedly obtained images was 3 minutes or more. For fMRI images, single-shot gradient echo planar imaging (SS-EPI) sequence technique was used, and the following MR image acquisition parameters were used: echo time (TE) = 15 ms, repetition time (TR) = 1000 ms, flip angle = 45, in-plane resolution = 469 × 469 μm, slice thickness = 1.5 mm, number of coronal slices = 5, total scan time = 1 min 20 s.

As a result, as shown in FIG. 1, with respect to the lesion-side forepaw stimulated (ipsilesional forepaw stimulated), the disease-HDI administration group (HI+HDI) was compared to the normal-HDI administration group (Normal+HDI), disease-control group (HI+DMSO) It was confirmed that it expanded to a wider contralesional sensory-motor area, including functionally active areas, such as the sensory motor cortex and primary cingulate cortex (Ai in FIG. 1 , Aii, Aiii).

In addition, with respect to the contralesional forepaw stimulated on the opposite side of the lesion where the hypoxic ischemic brain disease occurred, the functionally active region was not seen in the disease-control group (HI+DMSO) (Bii in FIG. 1 ), whereas the disease-HDI administration group (HI) +HDI), it was confirmed that plasticity was improved, and an activation reaction was also observed in other regions (backside, opposite side) than the functional original active region (Biii in FIG. 1).

In addition, in the normal rat group, the sensorimotor area contralateral to the lesion also showed a functionally active response to the electrical stimulation of the forelimb (Ai,Bi in FIG. 1), whereas in the rat with hypoxic ischemic encephalopathy, cerebral infarction due to ischemia occurred in the right brain. As a result, it was confirmed that no active response could be shown in the sensorimotor area opposite to the lesion.

In addition, it was confirmed that in the disease-HDI-administered group, the plasticity improved by HDI administration showed an activity response extending backward in the sensorimotor area on the opposite side of the lesion. (Biii in FIG. 1)

That is, in the brain disease model group to which HDI was administered, it was confirmed that the functional activity response increased in both the lesion side and the contralateral side, thereby improving plasticity. Through this, it was found that SAHA can be used as a therapeutic agent for HIE through cortical function activity.

Example 3. Behavioral evaluation results for confirming the therapeutic effect of SAHA in an animal model

Using the hypoxic ischemic encephalopathy animal model prepared in Example 1, adhesive tape removal according to SAHA administration was evaluated.

Specifically, after attaching the tape to the forelimb of the rat to be measured, putting the rat back into the cage, using a timer to measure the time to detect with the mouth to remove the tape, and then completely remove it from the forelimb Time to remove was measured.

As a result, as shown in FIG. 2 , the disease-HDI administration group (HI+HDI) had higher functionality of the normal side (ipsilesional forepaw) than the normal-HDI administration group (Normal+HDI), disease-control group (HI+DMSO). Confirmed.

In addition, as a result of confirming the functionality of the contralesional forepaw in the disease-HDI administration group (HI+HDI), it was reduced to a level similar to that of the normal-HDI administration group (Normal+HDI), disease-control group (HI+DMSO) It was confirmed that the functionality was excellent.

The above description of the present invention is for illustration, and those of ordinary skill in the art to which the present invention pertains can understand that it can be easily modified into other specific forms without changing the technical spirit or essential features of the present invention. will be. Therefore, it should be understood that the embodiments described above are illustrative in all respects and not restrictive.

Claims (13)

A pharmaceutical composition for preventing or treating ischemic brain disease comprising SAHA (suberoylanilide hydroxamic acid) or a pharmaceutically acceptable salt thereof as an active ingredient.
According to claim 1,
The ischemic brain disease includes stroke, cerebral infarction, cerebral ischemia, thrombosis, embolism, transient ischemic attack, lacune, head trauma, cerebral circulation metabolic disorder, brain function. A pharmaceutical composition, characterized in that at least one selected from the group consisting of coma, traumatic brain injury and hypoxic ischemic encephalopathy (HIE).
According to claim 1,
The SAHA is a pharmaceutical composition, characterized in that represented by the following formula (1).
[Formula 1]

According to claim 1,
The ischemic brain disease is one or more ischemic brain disease selected from the group consisting of newborns, infants, infants and children, the pharmaceutical composition.
5. The method of claim 4,
The newborns, infants, infants and children are characterized in that the age of birth to less than 12 years of age, the pharmaceutical composition.
According to claim 1,
The SAHA is characterized in that it restores neuroplasticity, a pharmaceutical composition.
A composition for enhancing neuroplasticity comprising SAHA (suberoylanilide hydroxamic acid) or a pharmaceutically acceptable salt thereof as an active ingredient.
A food composition for preventing or improving ischemic brain disease comprising SAHA (suberoylanilide hydroxamic acid) or a pharmaceutically acceptable salt thereof as an active ingredient.
9. The method of claim 8,
The ischemic brain disease includes stroke, cerebral infarction, cerebral ischemia, thrombosis, embolism, transient ischemic attack, lacune, head trauma, cerebral circulation metabolic disorder, brain function. A food composition, characterized in that at least one selected from the group consisting of coma, traumatic brain injury and hypoxic ischemic encephalopathy (HIE).
9. The method of claim 8,
The SAHA is a food composition, characterized in that represented by the following formula (1).
[Formula 1]

9. The method of claim 8,
The ischemic brain disease is one or more ischemic brain disease selected from the group consisting of newborns, infants, infants and children, the food composition.
12. The method of claim 11,
The newborns, infants, infants and children are from the date of birth to less than 12 years of age, characterized in that, the food composition.
9. The method of claim 8,
The SAHA is characterized in that it restores neuroplasticity, a food composition.

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