JP6162536B2 - Composition for prevention / improvement of cerebrovascular dementia - Google Patents

Description

  The present invention relates to a composition for preventing / ameliorating dementia, including chologi. Among the dementia, it particularly relates to prevention / improvement of cerebrovascular dementia.

  As we face an aging society, the issue of how to control increasing dementia is a global issue. Dementia is a serious social problem not only for patients themselves but also for the mental, physical and economic burdens on their families.

  Dementia is roughly classified into Alzheimer type dementia and cerebrovascular dementia. Alzheimer-type dementia causes senile plaques, neurofibrillary tangles, neuronal loss and brain atrophy, but the cause is still unknown. Cerebrovascular dementia is caused by cerebral vascular disorders, cerebral infarction and cerebral hemorrhage, which prevents oxygen and nutrients from reaching brain neurons.

  There are Aricept, Memary, Reminil, and Ixeron as Alzheimer's disease treatment drugs used in Japan. On the other hand, there is no drug for treating cerebrovascular dementia itself, and a cerebral blood flow improving drug, a cerebral vasodilator, a cerebral metabolic activator and the like are used for the treatment of cerebral vascular disorders, cerebral infarction and the like.

  In recent years, extracts have been prepared from plants, and their brain function improving effects have been reported. For example, it has been reported that the extract of perennial plants belonging to the family Ranunculaceae, which is a dicotyledonous plant, has a neurotoxicity-protecting action and the like by β-amyloid (Patent Document 1). Alternatively, it has been reported that a Kumictin extract, which is a perennial plant of Lamiaceae, has a cognitive management effect (Patent Document 2).

  However, the current situation is that prevention / treatment for dementia is not sufficient with existing drugs, and it is an urgent need to provide a useful substance for prevention / improvement of new cerebrovascular dementia.

JP 2012-246511 A JP 2013-514972 A

  An object of the present invention is to provide a useful composition for preventing / ameliorating cerebrovascular dementia derived from chorogi.

  The present inventor has intensively studied in view of the above object. As a result, it has been found that learning memory impairment is improved when chorogi extract with water exceeding 40 ° C. is administered to a cerebrovascular dementia model animal. Furthermore, even when not only chorogi but also a ginkgo biloba extract was administered to the model animal, it was found that learning memory impairment was improved and the present invention was completed.

That is, the present invention is as follows:
[1] A composition for preventing / ameliorating cerebrovascular dementia, comprising chorogi or a solvent extract thereof.
[2] The composition according to [1], wherein the solvent is water exceeding 40 ° C.
[3] The composition according to [1] or [2], wherein the extract is in a dry form.
[4] The composition according to any one of [1] to [3], wherein the extract is concentrated.
[5] The composition according to any one of [2] to [4], wherein the temperature of extraction with water is 80 ° C to 100 ° C.
[6] The composition according to any one of [1] to [5], further comprising a ginkgo biloba extract.
[7] A food preparation for preventing / ameliorating cerebrovascular dementia, comprising the composition according to any one of [1] to [6].
[8] A food containing the food additive according to [7].
[9] The composition according to any one of [1] to [6], which is a medicine.

  The chorogi extract of the present invention can prevent and / or improve cerebrovascular dementia. Furthermore, not only chorogi but also ginkgo biloba extract can be used together to prevent and / or improve cerebrovascular dementia.

1 shows a step-through passive avoidance learning device used in the present invention. It shows that learning memory impairment in a cerebrovascular dementia model animal was improved by administration of 10 g / kg and 20 g / kg chologi extract. This shows that learning memory impairment in cerebrovascular dementia model animals was improved by administration of 400 mg / kg Ginkgo biloba extract. It shows that the cell death of the hippocampus was suppressed by administration of 10 g / kg, 20 g / kg chorogi extract, and 400 mg / kg ginkgo biloba extract. In model mice in which scopolamine-induced cognitive dysfunction was induced, learning memory impairment was not improved by administration of 10 g / kg, 20 g / kg chologi extract, and 400 mg / kg ginkgo biloba extract.

Details of the present invention will be described below.
The present invention provides a composition for preventing and / or improving cerebrovascular dementia comprising chorogi or a solvent extract thereof.

  In one embodiment, the raw material used in the present invention is chorogi (scientific name Stachys affinis or Stachys sieboldii). Chorogi tuber can be used as the part. It may be used by chopping or crushing raw chorogi. As another embodiment, dried chorogi may be used after being pulverized (hereinafter referred to simply as “chorogi” inclusive of the above-mentioned pulverized product and dried product). Chorogi can be produced in any country such as Japan or China.

  The chorogi extract of the present invention can be extracted with a solvent. Examples of the solvent include water, alcohols such as methanol and ethanol, and mixtures thereof, but water is preferable.

  Examples of water used for extraction include, but are not limited to, ion-exchanged water, distilled water, pure water, ultrapure water, natural water, natural mineral water, and regular water (according to Japanese Pharmacopoeia). Not.

  Although there is no restriction | limiting in particular in the temperature of a solvent, When a solvent is water, it is preferable to exceed 40 degreeC, More preferably, it is 80 to 100 degreeC, More preferably, it is 90 to 100 degreeC, More preferably, it is 93 to 97 ° C, especially 95 ° C. Hereinafter, in the present specification, the term “hot water” is used to include all water exceeding 40 ° C. unless otherwise specified.

  The amount of the solvent to be used can be appropriately determined according to the amount of the raw material chorogi. For example, in the case of water, it is 5 to 15 parts by weight of the raw material, preferably 8 to 10 parts by weight.

  The time for one extraction reaction with a solvent can be appropriately selected according to the type of solvent, the form of the cricket used as a raw material, and the like, for example, 30 minutes to 2 hours, preferably 50 minutes to 1 hour.

  In the extraction method of the present invention, the extraction reaction can be performed for the above-mentioned time while adding a solvent such as the above-mentioned hot water to the cricket and maintaining the temperature of the solvent. Any method can be used as long as the temperature of the solvent can be maintained. For example, reflux with a mantle heater can be performed. Moreover, as one aspect, the extraction operation with hot water may be performed twice or more.

  The extract treated by the above-described method can be further separated into a residue and an extract by means of filtration or centrifugation. The size of the filtration filter may be appropriately selected. For example, a 150 mesh filter can be used, but is not limited thereto. The extract can be made into a concentrate by concentration under reduced pressure or the like.

  The concentrate can be further processed to obtain a chorogi extract. Examples of the processing include, but are not limited to, sterilization (such as heat sterilization), drying (such as spray drying), and sieving (such as 60 mesh).

  Moreover, the said extract or concentrated liquid can be processed by general methods, such as drying under reduced pressure and freeze-drying, and it can also be used as a dried product of a chorogi extract (powder) or a dried product of a chorogi concentrate (powder).

  In one embodiment, the chorogi extract or chorogi concentrate may be further purified. Examples of the purification method include, but are not limited to, methods known per se, such as a countercurrent distribution method and column chromatography. For example, the active ingredient can be purified by administering each fraction fractionated by any of the methods described above to a cerebrovascular dementia model animal and obtaining a fraction in which symptom improvement was observed. . In addition, since the present inventors have confirmed that the active ingredient activates the Nrf2-ARE pathway, the fraction having the activity is obtained using the Nrf2-ARE pathway as an indicator, Purification may be performed by a purification method. Each purified fraction obtained by the purification treatment can be used after being dried by ordinary means such as drying under reduced pressure or freeze drying.

  As another embodiment, a method known per se can be applied in order to identify the active substance present in the extract of chorogi. Examples of the method include, but are not limited to, separation by chromatography (silica gel column chromatography, HPLC, reverse phase HPLC, etc.), molecular weight determination by mass spectrum, etc., and structure determination by NMR.

  The composition of the present invention can contain ginkgo biloba extract in addition to chorogi or chorogi extract or chorogi extract obtained by the above-described method.

  The ginkgo biloba extract used in the present invention can be extracted from ginkgo leaves by a method known per se. Ginkgo as a raw material can be produced in any place such as Japan or China. A commercially available ginkgo biloba extract (manufactured by Maruzen Pharmaceutical Co., Ltd.) can also be used.

The composition of the present invention can be used for preventing and / or improving cerebrovascular dementia. Furthermore, the composition may be used for foods (health foods, dietary supplements (supplements, nutritional drinks), foods for specified health use, etc.), pharmaceuticals (medical drugs, general drugs or quasi drugs), etc. it can.
If the composition of the present invention is a food product, examples of the food product include food, bread, buckwheat, udon, somen, soy noodles, ramen, spaghetti, bread, harsame, Chinese bun, cooked rice Moisture, curry powder, stewed rice, bean sprout rice, soup rice, rice noodles, kamaboko, chikuwa, croquette, agar, tofu, deep-fried, sausage, konjac, ham, corned beef, shumai, gyoza, sprinkle, manju , Sheepkan, hail, rice cracker, rice cake, cake, jelly, cookies, castella, pudding, chocolate, snacks, bavaroa, mousse, cream puff, miso, soy sauce, sauce, mayonnaise, ketchup, mirin, cooking oil, jam, juice, coffee, Yogurt, tea, wine, beer, liquor, Inn, milk, cocoa and the like.
In addition, the composition of the present invention can be in the form of a food formulation for preventing and / or improving cerebrovascular dementia and can be blended into foods when used.
Examples of commodities to be blended include juice, rice, miso soup, curry, stew, gratin, tea, coffee, yogurt, milk, boiled food, fried food, and seasoned food.

  Examples of pharmaceutical forms include, but are not limited to, tablets, pills, powders, granules, capsules and the like. Examples of liquid pharmaceuticals and quasi drugs include, but are not limited to, suspensions, emulsions, syrups and the like.

  The composition of the present invention may contain additives. Additives include, but are not limited to, excipients, binders, colorants, flavoring agents, lubricants, solubilizers, stabilizers, solubilizers, preservatives, thickeners, and the like. . These additives are used in amounts conventionally used in the field of pharmaceutical technology. Moreover, you may use these additives, mixing 2 or more types in a suitable ratio.

  Furthermore, preservatives, color formers, fragrances, stabilizers, acidulants and the like that are generally used in foods can also be added. Examples thereof include ethyl vanillin, vanillin, glycerin fatty acid ester, medium chain fatty acid triglyceride and the like. These additives are used in amounts conventionally used in the technical field of pharmaceutical preparations. These additives may be used by mixing two or more kinds at an appropriate ratio.

  Examples of the excipient include, but are not limited to, maltitol, maltol, erythritol, D-mannitol, D-sorbitol, xylitol, purified sucrose, sucrose, fructose, glucose, powdered reduced maltose water candy, lactose and the like.

  Examples of the binder include, but are not limited to, hydroxypropyl cellulose, polyvinyl alcohol, polyvinyl pyrrolidone, pullulan, macrogol, gum arabic, gum arabic powder, and gelatin.

  As a corrigent, what is necessary is just to be used as a sweetener, a refreshing agent, a fragrance | flavor, etc. For example, yogurt flavor, vanilla flavor, aspartame, amateur powder, saccharin, caramel, cinnamon powder, dipotassium glycyrrhizinate, stevia, mint oil, orange oil, lemon oil, pine oil, 1-menthol, fruit flavor, chocolate flavor, etc. For example, but not limited to.

  Examples of the lubricant include, but are not limited to, magnesium stearate, calcium stearate, talc, sodium lauryl sulfate, light anhydrous silicic acid, hydrous silicon dioxide, and sucrose fatty acid ester.

  Examples of solubilizers include, but are not limited to, L-aspartic acid, ethanol, polyoxyethylene hydrogenated castor oil, refined soybean lecithin, soybean oil, polyvinylpyrrolidone (povidone), polysorbate, macrogol, maleic acid, and the like. .

  As stabilizers, adipic acid, ascorbic acid, L-ascorbic acid stearate, sodium L-ascorbate, L-aspartic acid, sodium L-aspartate, aminoethylsulfonic acid, DL-alanine, L-arginine, Sodium alginate, propylene glycol alginate, albumin, benzoic acid, sodium benzoate, ethanol, disodium calcium edetate, sodium edetate, calcium chloride, sodium chloride, magnesium chloride, cysteine hydrochloride, carmellose calcium, carmellose sodium, xanthan gum, Citric acid, calcium citrate, sodium citrate, glycine, glycerin, glycerin fatty acid ester, tartaric acid, purified gelatin, sorbitan sesquioleate, dex Orchid, lactic acid, lactose, concentrated glycerin, ethyl paraoxybenzoate, butyl paraoxybenzoate, methyl paraoxybenzoate, calcium pantothenate, propylene glycol, bentonite, boric acid, propyl gallate, povidone, polyacrylic acid partial neutralized product, Examples include, but are not limited to, polyoxyethylene hydrogenated castor oil, polysorbate, polyvinyl pyrrolidone, polyvinyl alcohol, and macrogol.

  Examples of solubilizers include, but are not limited to, adipic acid, sodium benzoate, capric acid, citric acid, tartaric acid, castor oil, povidone, and the like.

  As preservatives, benzoic acid, sodium benzoate, aminoethylsulfonic acid, sodium edetate, agar, dl-camphor, citric acid, sodium citrate, salicylic acid, sodium salicylate, phenyl salicylate, sorbic acid, potassium sorbate, 2 -Naphthol, isobutyl paraoxybenzoate, isopropyl paraoxybenzoate, ethyl paraoxybenzoate, butyl paraoxybenzoate, propyl paraoxybenzoate, methyl paraoxybenzoate, and the like, but are not limited thereto.

  Examples of the thickener include, but are not limited to, nonionic surfactants such as polyoxyethylene hydrogenated castor oil and sucrose fatty acid ester, and lecithin.

  Moreover, you may add the component used for normal liquid agents, such as caffeine, various amino acids, a sweetener, a fragrance | flavor, and a pH adjuster. Furthermore, extracts other than chorogi and ginkgo, herbal medicines and the like can be appropriately blended.

  The composition of the present invention comprises about 0.1 g / kg body weight to about 50 g / kg body weight, preferably about 10 g / kg body weight to about 20 g / kg body weight once a day to several times as the dry weight of the chorogi extract. Can be administered in divided doses. When the composition of the present invention further contains a ginkgo biloba extract, the dry weight of the ginkgo biloba extract is about 100 mg / kg body weight to about 1 g / kg body weight, preferably about 300 mg / kg body weight to about 500 mg / kg body weight. It can be administered once to several times a day.

  The subject to be administered includes humans, but can also be applied to mammals other than humans (eg, mice, rats, hamsters, rabbits, cats, dogs, cows, sheep, monkeys, etc.).

  The effectiveness of the composition of the present invention in preventing / ameliorating cerebrovascular dementia can be confirmed using a cerebrovascular dementia model animal. An example of the animal includes, but is not limited to, a cerebral ischemic animal caused by bilateral common carotid artery ligation described in Examples described later.

  In the present invention, the pharmacological activity of a chorogi extract or chorogi extract can be confirmed by a method known per se. As an example, a method for measuring Nrf2-ARE pathway activation by an in vitro assay system (for example, linking a reporter gene such as luciferase downstream of a promoter containing an ARE sequence in a target gene of Nrf2 such as quinone oxidoreductase (NQO1) And a method of examining an increase in the expression of a reporter gene by introducing it into an animal cell that expresses Nrf2 and bringing the chorogi extract or chorogi extract into contact with the cell, but is not limited thereto. It can also be administered to animals such as mice and rats and confirmed in vivo effects.

  EXAMPLES Hereinafter, although an Example is shown and this invention is demonstrated more concretely, this invention is not limited at all by the Example shown below.

Evaluation of learning and memory impairment in global cerebral ischemia model mice 3 days after global cerebral ischemia treatment by bilateral common carotid artery ligation, it is established that learning and memory impairment is significantly expressed compared to the sham operation group (Bilateral common carotid artery ligation method; BCAO) was applied to ddY male mice (SLC) (J. Pharm. Pharmacol., 2013) to produce whole brain ischemia model mice.
Experiments were performed in two groups, a vehicle group and a cricket group, and a vehicle group and a ginkgo leaf group. Dose is Chorogi extract (hot water extract, the same applies below) 1, 5, 10, 20 g / kg / day (n = 6, 11, 11, 11), Ginkgo biloba extract (Maruzen Pharmaceutical, the same applies below) 100, 200 , 400 mg / kg / day (n = 6-8) was orally administered once a day for 5 days before preparation of the cerebral ischemia model (BCAO). Vehicle was administered to the sham operation group. The administration time was between 9:00 and 12:00.

  For evaluation of learning and memory impairment, a one-trial step-through passive avoidance learning device (Ohara, Tokyo, Japan) was used. The apparatus is shown in FIG. The device is composed of a light room and a dark room, and when an animal is put into a light room and moved to a dark room (using the habit of preferring dark places in animals), an electric shock is applied. Then, if a mouse that has experienced an electric shock does not attempt to move to a dark room after being placed in a bright room, it is determined that the mouse has learned and stored. Hematoxylin eosin staining was performed for evaluation of cell damage (infarct formation). An open field test was used to evaluate the amount of spontaneous exercise.

  The results are shown in FIGS. BCAO 3 days later, learning and memory deficits were suppressed in a dose-dependent manner in mice administered chorogi extract and ginkgo biloba extract at doses of chologi extract 10 g / kg and 20 g / kg, ginkgo biloba extract 400 mg / kg. It was significant. A similar effect was also shown on the expression of nuclear enriched cell death after 3 days of BCAO. In addition, it was also confirmed that both the chorogi extract and the ginkgo biloba extract do not affect the body weight and the amount of spontaneous exercise, that is, there is no problem in the state of the mouse used.

  Furthermore, neuronal cell death in the hippocampus was confirmed when chologi extract 10 g / kg and 20 g / kg and ginkgo biloba leaf extract 400 mg / kg were administered to BCAO. The results are shown in FIG. Neuronal cell death was suppressed by administration of chologi extract 10 g / kg and 20 g / kg and ginkgo biloba extract 400 mg / kg.

Evaluation for scopolamine-induced learning and memory impairment Scopolamine is a muscarinic acetylcholine receptor antagonist and is known to cause memory impairment in animals and humans. Therefore, a model was produced in which scopolamine was administered to ddY male mice (SLC) to induce cognitive impairment. Scopolamine was administered as a single intraperitoneal dose of 0.5 or 1 mg / kg (0.1 ml / 10 g) 30 minutes before step-through training.
Experiments were performed in three groups: a vehicle group, a cricket group, and a ginkgo leaf group. The dose was orally administered once a day for 5 days before scopolamine administration so that the dosage was Chorogi extract 5, 10, 20 g / kg / day, and Ginkgo biloba extract 400 mg / kg / day. Vehicle was administered to the sham operation group.
For evaluation of learning and memory impairment, a one-trial step-through passive avoidance learning device (Ohara, Tokyo, Japan) was used.

  Learning and memory impairment due to scopolamine administration was significantly higher than in the vehicle group. However, neither the chorogi extract nor the ginkgo biloba extract showed any improvement against the disorder. The results in the case of scopolamine 1 mg / kg administration are shown in FIG.

  Although the present invention has been described with emphasis on preferred embodiments, it is obvious to those skilled in the art that the preferred embodiments can be modified.

  The contents of all publications, including the patents and patent application specifications mentioned herein, are hereby incorporated by reference herein to the same extent as if all were expressly cited. .

  According to the present invention, a composition containing an extract from a solvent such as water of chorogi and further a ginkgo biloba extract can be used for prevention / amelioration of cerebrovascular dementia. The composition of the present invention is useful as a food or a medicine.

Claims (9)

  A composition for prevention / amelioration of cerebrovascular dementia, comprising chorogi or an extract thereof.   The composition of claim 1, wherein the solvent is water above 40 ° C.   The composition according to claim 1 or 2, wherein the extract is in dry form.   The composition according to any one of claims 1 to 3, wherein the extract is concentrated.   The composition according to any one of claims 2 to 4, wherein the temperature of extraction with water is 80 ° C to 100 ° C.   The composition according to any one of claims 1 to 5, further comprising a ginkgo biloba extract.   A food preparation for preventing / ameliorating cerebrovascular dementia, comprising the composition according to any one of claims 1 to 6. A food for preventing / ameliorating cerebrovascular dementia, comprising the food preparation according to claim 7. The composition according to any one of claims 1 to 6, which is a medicine.