JP2018177748A - Astrocyte glucose metabolism activator - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a material useful for improving intracerebral neural activity, or preventing or improving brain dysfunction.SOLUTION: The present invention provides an agent for activating glucose metabolism of astrocyte, containing hot water extract of Eucommia ulmoides as an active ingredient, an agent for activating intracerebral neurons, an agent for inhibiting deterioration of brain functions, an agent for improving brain functions, or an agent for preventing or improving brain dysfunction.SELECTED DRAWING: None

Description

  The present invention relates to a material that activates astrocyte glucose metabolism.

  The brain uses glucose as an important energy substrate and maintains its activity using ATP produced by its metabolism. The energy metabolism of brain neurons is important in the maintenance of brain function, and brain energy metabolism research has been actively conducted until now. A 1988 study by Fox et al. Using Positron Emission Tomography (PET) measured brain glucose consumption, cerebral blood flow and cerebral oxygen consumption in human visual cortex, and brain function activation by visual stimulation. It has been shown that glucose consumption is increased and that this metabolism is anaerobic (Non-patent Document 1). Thus, it is believed that brain glucose metabolism correlates with brain functional activity. On the other hand, brain glucose metabolism has been reported to decrease with age or from the early stage of Alzheimer's disease (Non-patent Documents 2 and 3). Improvement of brain glucose metabolism is considered to be useful for prevention and alleviation of brain dysfunction associated with aging and dementia including Alzheimer's disease (Patent Document 1).

  Until now, there have been many questions about the brain glucose metabolism mechanism. In 2000, the concept of neurovascular unit was proposed that intercellular networks are important in considering brain function. Similarly, in the case of brain glucose metabolism, a network between neurons, brain microcirculation (microvessels), and astrocytes is considered to be important. At present, although there are various rebuttals, the astrocyte-neuron lactate shuttle hypothesis (ANLSH) is generally supported as a brain glucose metabolism mechanism. According to this hypothesis, during functional activity of the brain, glucose is mainly taken up into cells via astrocyte glucose transporter 1 (GLUT1) and metabolized by glycolysis to lactate It is converted. Thereafter, lactic acid is transported extracellularly by the function of lactate transport carrier 1 (monocarboxylate transpoter 1; MCT 1) and lactate transport carrier 4 (monocarboxylate transpoter 4; MCT 4) on astrocytes, and taken up into neurons. Neurons produce ATP using the taken-in lactic acid as an energy substrate, and act using this as an energy source (Non-patent Document 4). Although neurons themselves can also take up glucose, they selectively take up lactic acid over glucose and use it as an energy substrate (Non-patent Document 5). Therefore, lactic acid supply by astrocyte glucose metabolism is considered to be very important for maintenance of neuronal activity and function.

  Therefore, in recent years, research on brain lactate has been actively conducted. In Non-Patent Document 6, memory formation is reduced in mice lacking MCT1 or MCT4, which is a lactate transport carrier present in astrocytes, and administration of lactate into the brain of this mouse improves the reduction in memory formation And that glucose administration has no effect on the reduction and improvement of memory formation, and it is reported from these findings that lactic acid supply from astrocytes to neurons is considered to be very important in forming memory .

  On the other hand, Patent Document 1 describes a method for improving the mental activity of a patient by administering a substance that improves insulin sensitivity and enhances glucose utilization in the brain. However, according to Non-Patent Document 6, enhancement of glucose utilization by neurons in the brain is insufficient for improving brain function, and increase in lactate production by astrocytes and supply of lactate from astrocytes to neurons are important. It is believed that there is.

  Jin Zhi is a plant conventionally used as a raw material for traditional Chinese medicine, and its leaves are used as tea for drinking. It is described in Patent Document 2 that an anchovy extract may be further added to an anti-aging composition containing wasabi extract, rush extract, and Kusuno crab extract. Patent Document 3 describes that a medicinal material selected from Tochu, etc. or an extract thereof may be further added to a composition comprising a extract of Kikyo for preventing or treating degenerative brain disease in a mammal. It is done. In Patent Document 4, the bark or leaf of Tonooki tree is extracted with hot water, the obtained residue is extracted with an aqueous alkaline solution, the filtrate is neutralized, and the extract obtained by separating the extract is It has been described to prevent the adsorption and proliferation of AIDS virus to cells and to improve brain symptoms. Patent Document 5 describes an anti-dementia agent containing a herbal medicine containing a tochu as an active ingredient.

Japanese Patent Application Publication No. 2002-532416 JP, 2006-063038, A Japanese Patent Application Publication No. 2005-501018 Patent No. 2875397 JP 06-056684 A

Science, 241: 462-464, 1988 J Neurol Sci, 181 (1-2): 19-28, 2000 Neuroimage, 17: 302-316, 2002 Cell Metabo, 14 (6): 724-738, 2011 Cerebral circulatory metabolism, 21: 18-27, 2010 Cell, 144: 810-823, 2011

  The present invention relates to providing a material that is effective for improving intracerebral nerve activity or for preventing or improving brain dysfunction caused by aging, dementia such as Alzheimer's disease and the like.

  As a result of searching for an effective component for activation of intracerebral glucose metabolism, the present inventors have found that the hot water extract of Tononaka has an action to activate astrocyte glucose metabolism, and the neural activity in the brain. It has been found that it is effective in activation of, improvement or suppression of brain function, or prevention or improvement of brain dysfunction.

Therefore, the present invention provides an astrocyte glucose metabolism activator, which comprises a hot water extract of Tonochi as an active ingredient.
The present invention also provides a brain nerve cell activator, which comprises a hot water extract of Tononaka as an active ingredient.
The present invention also provides a brain function decrease inhibitor comprising a hot water extract of Tononaka as an active ingredient.
The present invention also provides a brain function improving agent which comprises a hot water extract of Tononaka as an active ingredient.
The present invention also provides a preventive or ameliorating agent for cerebral dysfunction, which comprises a hot water extract of Tononaka as an active ingredient.

  The present invention has an excellent astrocyte glucose metabolism activating action, and can provide a material effective for improving the energy supply to neurons in the brain and for enhancing the intracerebral neural activity. According to the present invention, it is possible to improve brain function, to suppress depression of brain function, or to prevent or improve brain dysfunction caused by dementia such as aging, Alzheimer's disease and the like.

Glucose metabolism activation activity of astrocytes by persimmon leaf extract. A: Hot water extract, error bar = ± standard error (n = 5-6). B: 50% (v / v) ethanol extract and 99.5% (v / v) ethanol extract, error bars = ± standard error (n = 3-6). * p <0.05, *** p <0.001 (Dunnett's test, vs control).

  As used herein, “activation of astrocyte glucose metabolism” preferably refers to the metabolic activity of converting astrocyte glucose into lactic acid or the improvement of lactic acid production activity by astrocytes. Changes in astrocyte glucose metabolism levels can be assessed by measuring changes in glucose uptake or lactate production by astrocytes. Changes in glucose uptake or lactate production by astrocytes can be measured by culturing astrocytes in a glucose-containing medium and comparing the amount of glucose or lactate in the medium before and after the culture. Alternatively, changes in astrocyte glucose metabolism levels can be assessed by culturing astrocytes in a glucose-containing medium and measuring oxygen consumption or measuring pH change of the medium due to lactic acid produced . The change in pH of the medium can be measured by measuring the change in hydrogen ion concentration in the medium. The measurement of cellular oxygen consumption and pH change of the culture medium can be performed, for example, by an extracellular flux analyzer (Seahorse Bioscience).

  Alternatively, changes in astrocyte glucose metabolism levels can be assessed by measuring glucose uptake in astrocytes, expression levels of genes or proteins involved in glucose to lactate conversion or lactate transport. As a gene or protein involved in astrocyte glucose uptake, glucose-to-lactate conversion or lactate transport, glucose transporter 1 (GLUT1), lactate transporter 1 (monocarboxylate transpoter 1; MCT1), lactate transport Carrier 4 (monocarboxylate transpoter 4; MCT4), and genes encoding them, and homologs, paralogs and orthologs of the genes can be mentioned. Methods commonly used in the art can be used to measure the expression level of the gene or protein. For example, the expression level of a gene can be measured by quantitative RT-PCR, RNAse protection assay, Northern blot analysis, RNA-Seq analysis using a next-generation sequencer, DNA microarray analysis, etc. The expression level can be measured by a conventional immunoassay, such as RIA, ELISA, bioassay, proteome, Western blot and the like.

  In the present specification, "brain function" includes memory, learning, thinking, attention or perception, language, spatio-temporal recognition, orientation, other abstract event recognition or comprehensive judgment ability, execution ability, etc. May include memory or learning ability, general judgment ability, and execution ability. Therefore, in the present specification, “brain function depression suppression” and “brain function improvement” preferably refer to memory, learning, thinking, attention or perception, language, spatio-temporal recognition, orientation, other abstract event recognition or The overall judgment ability and the execution ability are to suppress the deterioration of the ability and to improve the ability. Furthermore, “brain dysfunction” in the present specification preferably refers to memory disorders, learning disorders, thinking abilities, cognitive or cognitive problems caused by aging, trauma, or dementia such as Alzheimer's disease or vascular dementia. Refers to a disorder or a symptom or sign of dementia such as Alzheimer's disease or cerebrovascular dementia.

  In the present specification, "non-therapeutic" refers to a concept that does not include medical practice, that is, a concept that does not include a method for surgery, treatment or diagnosis of a human being, more specifically, a doctor or a person who receives instructions It is a concept that does not include methods for performing surgery, treatment or diagnosis on humans.

  As used herein, "prevention" refers to preventing, suppressing or delaying the onset of a disease, condition or condition in an individual, or reducing the risk of developing a disease, condition or condition of an individual. In the present specification, "improvement" means improvement of disease, condition or condition, prevention, suppression or delay of deterioration of disease, condition or condition, or reversal, prevention, suppression or delay of progression of disease, condition or condition Say

  As used in the present invention, Tochu-chuu refers to Eucommia ulmoides. In the present invention, whole trees, leaves (including leaf blades and stems), bark, wood parts, branches, fruits (including skins and seeds), flowers (including petals and ovaries), roots, etc. A combination of can be used. Preferably, Toka Nakanoha is used.

  In the present invention, Tonari may be used as it is or after cutting, crushing, crushing or squeezing, or a dried product thereof may be used. Preferably a dry matter is used. The dried material may be cut, crushed, crushed or powdered.

  The Toshinaka extract used in the present invention may be an extract of Toshina as it is, or may be an extract extracted from dried, cut, crushed, crushed or squeezed, but preferably the Toshinari dried product Or the extract from the dried, cut, crushed, crushed or pulverized.

  Examples of extraction means for obtaining the extract include solid-liquid extraction, squeezing extraction, liquid-liquid extraction, immersion, decocting, leaching, reflux extraction, Soxhlet extraction, ultrasonic extraction, microwave extraction, stirring, etc. The means of can be used. These extraction means may be combined. For example, immersion, solid-liquid extraction and liquid-liquid extraction may be combined, or when the extraction time is shortened, solid-liquid extraction with stirring may be performed.

  The Toshinaka extract used in the present invention is preferably a Toshinari hot water extract. The hot water extract of Tononaka used in the present invention refers to a water extract of Tononaka having a temperature of 50 ° C. or higher. Preferably, the temperature of water used for the extraction is 80 ° C. or more, more preferably 85 ° C. or more, still more preferably 90 ° C. or more, still more preferably 95 ° C. or more. The upper limit of the temperature of water used for the extraction is not particularly limited, but is preferably equal to or lower than the boiling point, and more preferably 100 ° C. or lower, from the viewpoint of easiness of temperature control. The temperature range of water used for the extraction is preferably 85 to 100 ° C., more preferably 90 to 100 ° C., still more preferably 95 to 100 ° C. However, the Toshinaka extract used in the present invention is not an extract obtained by extracting the residue after hot water extraction by Toshinaka with an aqueous alkali solution.

  As a usage-amount of the solvent (water) in the said extraction, 1-100 mL is preferable with respect to 1 g of plants (dry mass conversion). The extraction conditions are not particularly limited as long as sufficient extraction can be performed. Generally, the lower the solvent temperature, the longer the time, and the higher the solvent, the shorter an extraction. For example, the extraction time is preferably 1 minute or more, more preferably 60 minutes or more, and preferably 24 hours or less, more preferably 12 hours or less. Examples of preferred extraction times include 60 minutes to 12 hours and the like, but are not limited thereto and can be appropriately selected by those skilled in the art.

  The extract obtained by the above-mentioned procedure is, if necessary, a purification treatment generally used for the production of plant extract, for example, organic solvent precipitation, centrifugation, ultrafiltration membrane, high performance liquid chromatograph, Column chromatography, liquid-liquid distribution, gel filtration, treatment using activated carbon or the like can also be performed.

  The hot water extract obtained by the above-described procedure may be used as it is, by using the extract or a fraction thereof alone or as a mixture, or as a diluted solution diluted with an appropriate solvent, or concentrated Alternatively, it may be prepared as a concentrated extract or a dry powder or paste by lyophilization or the like. Alternatively, the concentrated extract or dry powder or paste is diluted at the time of use with a solvent such as water, ethanol, propylene glycol, butylene glycol, water-ethanol mixed solution, water-propylene glycol mixed solution, water-butylene glycol mixed solution, etc. Can also be used. Alternatively, the concentrated extract, dry powder or paste may be used by being encapsulated in vesicles such as liposomes or microcapsules.

  The hot water extract of Tononaka has an effect of activating astrocyte glucose metabolism (Example 1 described later). Activation of astrocyte glucose metabolism increases the activity of neurons in the brain by supplying more lactic acid as an energy substrate to neurons in the brain (see, for example, non-patent documents 1 and 4), and brain function (For example, memory, learning, cognitive function such as integrated judgment ability, and ability to execute) to improve or suppress its decline (see, for example, non-patent documents 2 and 6). Therefore, the hot water extract of Tochu is for activating the astrocyte glucose metabolism, for improving the energy supply to neurons in the brain, for activating neurons in the brain, for improving brain function or decreasing brain function. It is effective for suppression and also for prevention or improvement of brain dysfunction.

Therefore, in one aspect, the present invention provides an astrocyte glucose metabolism activator, which comprises a hot water extract of Tonka as an active ingredient. The present invention also relates to an agent for improving the energy supply to neurons in the brain, an agent for activating nerve cells in the brain, an agent for improving brain function, an inhibitor for reducing brain function, or brain dysfunction comprising a hot water extract of Tononaka as an active ingredient. Provide a preventive or remedy for
In another aspect, the present invention provides a glucose metabolism activator for astrocytes, an agent for improving energy supply to neurons in the brain, an activator for intracerebral nerve cells, an agent for improving brain function, an inhibitor for reducing brain function, or brain function Provided is the use of a hot water extract of Tonoca for the manufacture of a preventive or remedy for disorders.
In one embodiment, the agent may consist essentially of the hot water extract of Tono. In another embodiment, the agent may be a composition containing at least a hot water extract of Tonoca. Examples of the composition include pharmaceuticals, quasi-drugs, foods, etc. described later.

In yet another embodiment, the present invention provides glucose metabolism activation of astrocytes, enhancement of energy supply to neurons in the brain, activation of neurons in the brain, enhancement of brain function, suppression of brain function decline, or prevention of brain function disorder or Provide the use of Yuzhong hot water extract for improvement.
In yet another embodiment, the present invention provides glucose metabolism activation of astrocytes, enhancement of energy supply to neurons in the brain, activation of neurons in the brain, enhancement of brain function, inhibition of brain function decline, or prevention of brain function disorder or To provide a hot water extract of Tongchuan for use in improvement.

  The use according to the invention may be a therapeutic or non-therapeutic use. Examples of therapeutic uses include use for those who have been diagnosed with dementia or who have severe cognitive impairment and who have a disability in daily life. As an example of non-therapeutic use, those who do not disturb their daily lives by lowering brain function but need improvement in brain function, depression of brain function depression or prevention of brain function disorder, for example, mild cognitive impairment (MCI ), Those who feel deterioration in brain function such as memory, learning, cognitive function, etc., those who desire further improvement of memory and learning ability, etc. Also, for example, non-therapeutic use means that the brain function improvement, brain function reduction suppression or brain function disorder preventing effect, etc., in order to cause others to administer or consume the hot water extract of Tokai instead of medical action. It is about offering them.

  In the present invention, Tonkai's hot water extract can be used for both human and non-human animals. Non-human animals include non-human mammals, birds and the like, and non-human mammals include, for example, apes, other primates, mice, rats, hamsters, dogs, cats, companion animals and the like.

  In the present invention, the hot water extract of Toshinaka is used to activate glucose metabolism of astrocytes and improve energy supply to neurons in the brain with respect to pharmaceuticals, quasi drugs, foods (including foods for non-human animals), etc. It can be used as an active ingredient for imparting a function of nerve cell activation in the brain, improvement in brain function, suppression of decline in brain function, or prevention or improvement of brain dysfunction.

  The medicines (including quasi drugs) include glucose metabolism activation of astrocytes, improvement of energy supply to neurons in the brain, activation of neurons in the brain, improvement of brain functions, suppression of brain function decline, or brain dysfunction It is a medicine for prevention or improvement, and contains hot water extract of Tononaka as an active ingredient for the function. Furthermore, the pharmaceutical preparation may contain a pharmaceutically acceptable carrier, or other active ingredients, pharmacological ingredients, etc., as needed, as long as the function of the active ingredient is not lost.

  The mode of administration of the medicine (including quasi-drugs) may be either oral administration or parenteral administration. The dosage form of the pharmaceutical is not particularly limited as long as it can be orally or parenterally administrable, and for example, injections, suppositories, inhalants, transdermal absorption agents, various external preparations, tablets, capsules, Granules, powders, solutions, syrups and the like may be used, and the preparation of such various dosage forms may be carried out by using a hot water extract of Tochu pharmaceutically acceptable carrier (eg, an excipient, a binder, etc.) , Extenders, disintegrants, surfactants, lubricants, dispersants, buffers, preservatives, preservatives, flavoring agents, perfumes, coatings, diluents, etc., and other medicinal ingredients etc. It can be prepared according to

  The content (in dry matter) of the hot water extract of Tonochi in the medicine (including quasi-drugs) is not particularly limited, but is preferably 0.01% by mass or more, more preferably 0.1% of the total mass. The content is preferably not less than 1.0% by mass, more preferably not less than 10% by mass, and preferably not more than 95% by mass, more preferably not more than 80% by mass, still more preferably not more than 60% by mass. Furthermore, as an example of the said content, 0.01-95 mass%, 0.01-80 mass%, 0.01-60 mass%, 0.1-95 mass%, 0.1-80 mass%, 0 .1 to 60 mass%, 1.0 to 95 mass%, 1.0 to 80 mass%, 1.0 to 60 mass%, 10 mass% to 95 mass%, 10 mass% to 80 mass%, and 10 mass% %-60 mass% are mentioned.

  The food provides a function to activate astrocyte glucose metabolism, improve energy supply to neurons in the brain, stimulate neurons in the brain, improve brain function, suppress brain function decline, or prevent or improve brain function disorder. And a hot water extract of Tononaka as an active ingredient for the function. The concept of this food is to activate glucose metabolism in astrocytes, improve energy supply to neurons in the brain, stimulate neurons in the brain, improve brain function, suppress brain function decline, or prevent or improve brain function disorder. Foods for the sick who indicated as such, and food with functional nutrition, food for specified health use, food for functional health use such as food with functional indication are included as necessary. These foods, for example, "increase memory," "prevent forgetfulness and verbal words," "increase language, judgment, understanding or thinking ability", "prevent or improve deterioration of brain function due to aging," " It may be provided with a functional indication such as “relieving or preventing delusions, depression or hallucinations due to cognitive decline.”

  The food provided by the present invention comprises a beverage. Therefore, the said food can be paraphrased as food and drink. The form of the food may be solid, semi-solid or liquid (eg, beverage). Examples of the food include confectionery such as breads, noodles, rice, cookies, jelly, dairy products, soups, frozen foods, instant foods, processed starch products, processed fish meat products, other processed foods, seasonings Dietary supplements and beverages such as tea and coffee beverages, fruit beverages, carbonated beverages, jelly-like beverages and the like, as well as their ingredients. Alternatively, the food may be a supplement having the form of an oral preparation such as tablets, capsules, granules, powders, solutions, syrups and the like.

  The food may be a hot water extract of Tochu, any food material or food acceptable additive (eg, solvent, softener, oil, emulsifier, preservative, aromatherapy, sweetener, stabilizer, coloring agent, The composition can be prepared according to a conventional method by appropriately combining with a UV absorber, an antioxidant, a moisturizer, a thickener, a fixing agent, a dispersant, a wetting agent and the like.

  The content (in dry matter) of the hot water extract of Toboshi in the food is not particularly limited, but is preferably 0.0001% by mass or more, more preferably 0.001% by mass or more, and more preferably the total mass. Is 0.01% by mass or more, more preferably 0.1% by mass or more, still more preferably 1% by mass or more, and preferably 50% by mass or less, more preferably 20% by mass or less, still more preferably 10% by mass % Or less. Furthermore, as an example of the said content, 0.0001-50 mass%, 0.0001-20 mass%, 0.0001-10 mass%, 0.001-50 mass%, 0.001-20 mass%, 0 0.010 to 10% by mass, 0.01 to 50% by mass, 0.01 to 20% by mass, 0.01 to 10% by mass, 0.1 to 50% by mass, 0.1 to 20% by mass, and 0.1. 1-10 mass%, 1-50 mass%, 1-20 mass%, and 1-10 mass% are mentioned.

  In still another aspect, the present invention provides a method for glucose metabolism activation of astrocytes in a subject. The present invention also provides a method for improving energy supply to neurons in a subject's brain. The present invention also provides a method of stimulating intracerebral neurons in a subject. The present invention also provides a method for improving brain function or suppressing brain function decline in a subject. The present invention also provides a method for the prevention or amelioration of brain dysfunction in a subject. The method comprises administering to the subject an effective amount of the Tononaka hot water extract. The method may be therapeutic or non-therapeutic.

  Targets in this method include glucose metabolism activation of astrocytes, improvement of energy supply to neurons in the brain, activation of neurons in the brain, improvement of brain function, suppression of brain function decline, or prevention or improvement of brain function disorder. Animals that are or need them. The animal is not particularly limited as long as it is an animal having a brain, and includes the above-described human and non-human animals, and more preferably a human.

  The method for activating glucose metabolism of astrocytes according to the present invention, the method for improving energy supply to neurons in the brain, and the method for stimulating neurons in the brain may be in vitro methods. Subjects for in vitro methods can include brain tissue and cultured astrocytes from human or non-human animals as described above.

  The effective amount of administration in the above method may be an amount capable of achieving glucose metabolism activation of astrocytes in a subject. Preferably, the effective amount is an amount capable of statistically significantly increasing the glucose metabolism of astrocytes in the administration group as compared to the non-administration group. Also preferably, the effective amount is an amount capable of increasing glucose metabolism of the administration group to 105% or more, preferably 110% or more, more preferably 120% or more of the non-administration group in the cultured astrocytes. . Alternatively, the effective amount is an amount capable of statistically significantly increasing brain activity in the administration group as compared to the non-administration group. The measurement of brain activity can be measured by functional MRI, PET, single photon emission tomography (SPECT), near infrared spectroscopy (NIRS), magnetoencephalograph (MEG) or the like.

  In the present invention, the dosage and administration schedule of the Toinoma hot water extract may be appropriately determined by those skilled in the art according to the species, body weight, sex, age, condition or other factors of the subject. The dose of the hot water extract (in dry matter equivalent) according to the present invention is preferably 1 mg or more, more preferably 5 mg or more, and still more preferably 15 mg or more per adult, per day, although not limited thereto. And preferably it is 10 g or less, more preferably 5 g or less, still more preferably 1 g or less. It is preferable to divide the above dose into, for example, once, twice or three or more times a day, and continuously administer for several weeks to several months.

  The present invention also includes the following substances, production methods, uses, methods and the like as exemplary embodiments. However, the present invention is not limited to these embodiments.

[1] An astrocyte glucose metabolism activator comprising as an active ingredient a hot water extract of Tomonaka.
[2] A brain nerve cell activator, which comprises a hot water extract of Tomonaka as an active ingredient.
[3] A brain function decrease inhibitor comprising a hot water extract of Tononaka as an active ingredient.
[4] A brain function improving agent comprising a hot water extract of Tononaka as an active ingredient.
[5] An agent for preventing or improving brain dysfunction, which comprises a hot water extract of Tononaka as an active ingredient.
[6] An agent for improving the energy supply to neurons in the brain, which comprises a hot water extract of Tomonaka as an active ingredient.
[7] Use of a hot water extract of Tonka for producing astrocyte glucose metabolism activating agent.
[8] Use of a Tochino hot water extract for the preparation of an intracerebral nerve cell activator.
[9] Use of a hot water extract of Tonchu for producing a brain function hypotensive inhibitor.
[10] Use of a Tonari hot water extract for the production of a brain function improving agent.
[11] Use of a hot water extract of Tononaka for the manufacture of a preventive or ameliorating agent for cerebral dysfunction.
[12] Use of a hot water extract of Tononaka for the production of an agent for improving the energy supply to neurons in the brain.
[13] A hot water extract of Tomonaka for use in glucose metabolism activation of astrocytes.
[14] A hot water medium extract of Tononaka for use in stimulating neurons in the brain.
[15] A hot water extract of Tomonaka for use in suppression of brain function decline.
[16] A hot water extract of Tomonaka for use in improving brain function.
[17] A hot water extract of Tonchu for use in the prevention or amelioration of brain dysfunction.
[18] A hot water extract of Tomonaka for use in improving the energy supply to neurons in the brain.
[19] Use of a hot water extract of Tonchu for glucose metabolism activation of astrocytes.
[20] Use of a Tochino hot water extract for stimulating neurons in the brain.
[21] Use of Tononaka's hot water extract for suppression of brain function decline.
[22] Use of Tonochu's hot water extract for improving brain function.
[23] Use of a Tochino hot water extract for the prevention or amelioration of brain dysfunction.
[24] Use of a Tonozu hot water extract for improving energy supply to neurons in the brain.
[25] A method for glucose metabolism activation of astrocytes in a subject, the method comprising administering an effective amount of a hot water extract of Tononaka to a subject in need thereof.
[26] A method for stimulating a neuronal cell in a subject, comprising administering an effective amount of a hot water extract of Tononaka to a subject in need thereof.
[27] A method for suppressing a decrease in brain function of a subject, comprising administering an effective amount of a hot water extract of Tononaka to a subject in need thereof.
[28] A method for improving brain function of a subject, comprising administering to a subject in need thereof a hot water extract of Tononaka in an effective amount.
[29] A method for the prevention or amelioration of brain dysfunction in a subject, comprising administering to a subject in need thereof an effective amount of the hot water extract of Tochu Nakano.
[30] A method for improving energy supply to neurons in a subject's brain, comprising administering to the subject in need thereof an effective amount of a hot water extract of Tononaka.
[31] In the above [5], [11], [17], [23] and [29], preferably, the brain dysfunction is a memory disorder, learning disorder, thought caused by aging, trauma or dementia. It is a disability or a disorder of cognitive or general judgment ability or a symptom or sign of dementia.
[32] In the above [1] to [12], preferably, the agent is an oral preparation.
[33] In the above [13] to [18], preferably, the use is activation of astrocyte glucose metabolism, activation of intracerebral nerve cells, suppression of brain function reduction, improvement of brain function, prevention of brain function disorder or It is used as a medicine for improving or improving the energy supply to neurons in the brain.
[34] In the above [33], preferably, the drug is an oral drug.
[35] In the above [19] to [24], preferably the use is non-therapeutic use.
[36] In the above [35], preferably, the hot water extract of Tonari is used in the form of a supplement.
[37] In the above [25] to [30], preferably, the administration is oral administration.
[38] In the above [1] to [37], preferably the Toshio is a Toshinori leaf.
[39] In the above [1] to [38], the hot water is 50 ° C. or more, preferably 80 ° C. or more, more preferably 85 ° C. or more, still more preferably 90 ° C. or more, still more preferably 95 ° C. or more Or preferably 50 to 100 ° C., more preferably 85 to 100 ° C., still more preferably 90 to 100 ° C., still more preferably 95 to 100 ° C.
[40] In the above [1] to [39], the hot water extract is not an extract obtained by extracting a residue after hot water extraction of Tonochi with an aqueous alkali solution.

  Hereinafter, the present invention will be described in more detail based on examples, but the present invention is not limited thereto.

Production Example 1 Preparation of Extract (Yunaka Extract)
Add 100 mL of 99.5 (v / v)% ethanol or 50 (v / v)% ethanol to 10 g of dried leaves of Eucommia ulmoides leaves (purchased from Tea Wholesale Main Office), and allow to stand at room temperature. Soak for 7 to 30 days. Thereafter, the extraction residue was removed by filtration, and the obtained extract was concentrated under reduced pressure and lyophilized to obtain an extract.
About hot spring water extract of Tonchu, 120 mL of ion-exchanged water is added to 10 g of dried apricot leaf and stirred for 60 minutes while heating to 95-100 ° C, and then the extract is filtered and lyophilized to obtain an extract Obtained.
The yield of each extract is as follows: 99.5 (v / v)% ethanol extract = 424.1 mg, 50 (v / v)% ethanol extract = 1885.2 mg, hot water extract = 2791.4 mg .

Example 1 Activation of Glucose Metabolism in Astrocytes The cell metabolizes glucose in the form of glycolysis to lactate to release extracellularly, and lactate released extracellularly lowers the pH of the pericellular environment. In this example, by measuring the pH change of the astrocyte culture, the influence of the test substance on the glucose metabolic ability of astrocytes was evaluated. An extracellular flux analyzer (XF96; Seahorse Bioscience) was used to measure the pH change. This instrument measures changes in hydrogen ion concentration in cell cultures by luminescence and calculates the extracellular acidification rate (ECAR). An increase in ECAR reflects an improvement in cellular glucose metabolism. When ECAR is increased by the addition of a test substance, the test substance is a substance that activates the glucose metabolism ability of astrocytes.

  As the test substance, the Toshinaka extract prepared in Production Example 1 was used. These extracts were each dissolved in a solvent to a concentration of 1% (w / v) and used as a sample. As a solvent, 99.5 (v / v)% ethanol extract for 99.5 (v / v)% ethanol extract, 50 (v / v)% ethanol for 50 (v / v)% ethanol extract Water (10% v / v) ethanol water was used as the hot water extract. As a positive control, 1 mM of metformin (a glucose metabolism activator (AMPK activator); Sigma) was used.

Primary cultured astrocytes (SD rat fetal cerebrum origin; Cosmo Bio) were cultured in an incubator maintained at 5% CO ₂ , 95% air, 37 ° C. using an astrocyte exclusive medium (Cosmo Bio). The cells were passaged using trypsin-EDTA (Gibco), and cells of 3 passages were used. Three passages of astrocytes were seeded at 5,000 / well in a 96-well plate and cultured in astrocyte-specific medium for 8 days, and then replaced with DMEM / F12 serum-free medium (Gibco). Each sample (final concentration 0.002% as a test substance) was added to the culture the day before the test. As a control, a test substance-free medium was used.

After adding the sample and culturing overnight, the medium was replaced with a glucose-free DMEM for measurement of XF96 (Seahorse), and ECAR was measured. The measurement is performed with 1 loop as 9 min (mix; 3 min, time delay; 2 min, measure; 4 min), and after 6 loop measurement, glucose (final concentration 5 mM; Wako Pure Chemical Industries) or DMEM medium for XF 96 measurement is added to the medium, We also measured up to 12 loops. The ECAR value before glucose addition (the value of the sixth loop) was 100%, the rate of change of ECAR after glucose addition was calculated, and the area under the curve (AUC) between 6 and 12 loops was determined. The difference in AUC between the glucose addition group and the glucose non-addition group (XF 96 measurement medium addition group) was taken as the glucose metabolism ability of each test substance addition group as in the following formula.
(Glucose metabolism ability) = (glucose addition group AUC)-(glucose no addition group AUC)

  The glucose metabolic capacity of the test substance-free group (control) was 1, and the relative value of the glucose metabolic capacity of each test substance-added group was determined. The results are shown in FIG. In the astrocytes of the culture medium to which the hot water extract of Tonochi had been added, an increase in ECAR elevation by glucose was observed, and it was shown that these hot water extracts have an activating effect on astrocyte glucose metabolism (Fig. 1A). On the other hand, for 50 (v / v)% and 99.5 (v / v)% ethanol extracts, no rising effect of ECAR was observed in any of them, and no activation effect of astrocyte glucose metabolism was observed (FIG. 1B).

Claims (8)

  An astrocyte glucose metabolism activator, which uses the hot water extract of Tononaka as an active ingredient.   A nerve cell activator for intracerebral cells comprising a hot water extract from Tononaka as an active ingredient.   A brain function decrease inhibitor containing a hot water extract of Tononaka as an active ingredient.   Brain function improver containing hot water extract of Tononaka as an active ingredient.   An agent for preventing or improving brain dysfunction, which comprises a hot water extract of Tononaka as an active ingredient.   A food composition for suppressing brain function decline, which comprises a hot water extract of Tononaka as an active ingredient.   A food composition for improving brain function, comprising a hot water extract of Tononaka as an active ingredient.   A food composition for preventing or improving brain dysfunction, which comprises a hot water extract of Tononaka as an active ingredient.

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