WO2011132831A1 - Utilisation de la glutamine pour la prévention, le traitement ou le diagnostic d'une dépression - Google Patents

Utilisation de la glutamine pour la prévention, le traitement ou le diagnostic d'une dépression Download PDF

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WO2011132831A1
WO2011132831A1 PCT/KR2010/007285 KR2010007285W WO2011132831A1 WO 2011132831 A1 WO2011132831 A1 WO 2011132831A1 KR 2010007285 W KR2010007285 W KR 2010007285W WO 2011132831 A1 WO2011132831 A1 WO 2011132831A1
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depression
glutamine
composition
present
preventing
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PCT/KR2010/007285
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English (en)
Korean (ko)
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김현준
이영혁
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경상대학교산학협력단
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants

Definitions

  • the present invention relates to the use of glutamine for preventing, treating or diagnosing depression, and specifically, providing information on the degree of depression by investigating the increase and decrease of glutamate (Glu) and glutamine (Gln) contents in the cerebral cortex.
  • the present invention relates to a method for preventing or treating depression, comprising administering a composition for preventing or treating depression containing glutamine (Gln) as an active ingredient and a composition containing glutamine.
  • Depression or severe depressive disorder is a serious mental disorder accompanied by physical and cognitive dysfunction with subjective emotions such as sadness and lethargy.
  • the most important symptom of depression is the loss of interest and pleasure in universal stimuli.
  • depression is a disease close to us enough to be called a cold of the heart, but when depression is a disease that causes a lot of social and economic loss that makes daily life difficult.
  • 60-70% of suicides one of the leading causes of death, are deaths because of depression.
  • the number of domestic patients is increasing by 20% every year, and as of 2005, the market for antidepressant drugs is 20 trillion won. Therefore, along with the need for continuous development of antidepressants, there is a need for animal models for the study and diagnosis of depression.
  • the present inventors have made diligent efforts to identify the cause of depression and to find a cure for the cause.
  • the inventors observed that the content of glutamate and glutamine in the brain tissue of depressed animals decreased, and depression was administered by administration of glutamine. It was confirmed that the treatment can be completed the present invention.
  • An object of the present invention is to provide a quasi-drug composition for preventing or improving depression comprising the composition.
  • An object of the present invention is to provide a method for preparing a depressed animal model by administering methionine sulfoximine (MSO) or alpha-methyl-amino-isobutyric acid (MeAIB) and a method thereof It is to provide a depression animal model produced by.
  • MSO methionine sulfoximine
  • MeAIB alpha-methyl-amino-isobutyric acid
  • the present invention relates to a method for analyzing the therapeutic efficacy of depression of a test substance, comprising the step of treating a test substance in a depressed animal model disclosed in the present invention, and measuring the depression phase of the depressed animal model. .
  • An object of the present invention relates to a method for providing information on the degree of depression by investigating the increase and decrease of glutamine and glutamate content in the animal model of the cerebral cortex.
  • the depression animal model according to the present invention can be used to demonstrate the effects of antidepressants in vivo, not within cells, and thus the present invention can be applied and applied to the development and study of treatments for general depression patients. .
  • the composition for preventing or treating depression of the present invention provides a new antidepressant having a quick effect and low side effects.
  • L-AAA is L-alpha aminoadipic acid
  • LC represents liquid chromatography
  • FST represents forced swim test
  • Gln represents glutamine
  • Glu represents glutamate
  • MSO represents methionine phosphoxide
  • MeAIB represents alpha-methyl-amino-isobutyric acid.
  • Figure 2 shows the results of immunohistochemical staining for GFAP, a marker protein of astrocytoblasts, by injecting L-AAA into the prelimbic cortex area and sacrifice mice at day 10.
  • Figure 3 was administered to the L-AAA and at the 3rd and 5th day to sacrifice the rats to investigate the glutamate content of the frontal lobe region. There was no difference on the 3rd day of L-AAA and PBS administration, but by the 5th day, the content of glutamate was significantly decreased in the L-AAA group. Animals used here are animals before FST.
  • Figure 4 was administered the L-AAA and the glutamine content of the prefrontal region was examined at the sacrifice of the mice on the 3rd and 5th day. On the 3rd day of L-AAA and PBS administration, there is no difference, but on the 5th day, the content of glutamate in the L-AAA group is significantly reduced. Animals used here are animals before FST.
  • FIG. 5 is a diagram illustrating the results of FST of rats of the sham control group and the L-AAA-administered group to confirm the depression behavior of the animals on the 5th day of L-AAA administration.
  • Figure 6 is a diagram showing the glutamate content of the prefrontal lobe at the sacrifice of rats on day 7 and day 10 after administration of L-AAA.
  • the content of glutamate is maintained lower than that of the control group until 7 days after L-AAA administration, and this phenomenon disappears at 10 days and the content of glutamate of the control group and the experimental group is similar. Animals used here were those that confirmed depression behavior after 5 days of FST.
  • Figure 7 is a diagram showing the glutamine content of the prefrontal region by sacrifice of mice on day 7 and day 10 after administration of L-AAA.
  • the content of glutamine is maintained lower than that of the control group until 7 days after L-AAA administration, and this phenomenon disappears on the 10th day and the glutamine content of the control group and the experimental group are similar. Animals used here were those that confirmed depression behavior after 5 days of FST.
  • FIG. 8 is a diagram showing the results of FST of rats of the sham control group and the L-AAA-administered group to confirm the depression behavior of animals on the 10th day of L-AAA administration. There was no difference in immobility time between the experimental and control rats that received L-AAA. In other words, the depressive symptoms that appeared in the L-AAA-treated group seemed to have disappeared due to the amount of recovered glutamate and glutamine.
  • FIG. 9 is a diagram showing the change of depression phase by FST after administration of glutamine and glutamate of 0.02 and 0.20 ⁇ mol, respectively, to animals that induced depression by administering L-AAA.
  • the FST was administered in the glutamine-administered group 3 hours after drug administration, and the glutamate-administered group 6 hours later.
  • statistically significant relief of depression was observed only in the experimental group administered 0.20 umol glutamine.
  • This result suggests that as the number of astrocytes decreases, the amount of glutamate available to neurons decreases, so that normal activity is possible by supplying glutamine, a precursor for neurons to synthesize glutamate. At the same time, it shows the antidepressant effect of glutamine.
  • the direct supply of glutamate does not affect the improvement of depression.
  • the dose 10 is a result of confirming the antidepressant effect through the FST with the amount of half and twice the amount based on the dosage of the antidepressant effect confirmed in order to learn more about the antidepressant effect on the dose of glutamine.
  • the dose was calculated by converting the dose of 0.20 umol into an amount proportional to the weight using the average body weight of the experimental animals (1.17 mg / kg).
  • the depression pattern of each animal was confirmed in advance through FST, and the depression pattern of each group was examined through FST analysis after drug administration.
  • the control group without the guide cannula was also included.
  • the experimental animals with the guide cannula alone were also tested.
  • 11 is a result of observing behavioral changes by directly injecting MSO, a specific inhibitor of glutamine synthetase, into the brain, resulting in depression behavioral changes, the effect of which depends on the concentration of the injected drug.
  • FIG. 12 is a diagram showing the results of investigating the content of glutamate in the PLC region of mice subjected to FST by injecting MSO. Low amounts of glutamate were detected in predicting depression behavioral changes.
  • FIG. 13 is a diagram showing that the content of glutamine in the PLC region of mice subjected to FST with MSO injection was also detected at a low content expected in the change of depression behavioral pattern.
  • FIG. 14 is a diagram showing the change in the behavior of depression by treatment with a specific inhibitor (MeAIB) to the substance present in the neuronal membrane and to move the extracellular glutamine into the cell.
  • MeAIB a specific inhibitor
  • depression of neurons induces less glutamine, leading to depression, which was observed as a concentration-dependent change.
  • Figure 15 is a diagram showing the results of confirming the change in glutamate content of mice exhibiting depressive behavior due to the administration of MeAIB. Glutamate content in the brains of depressive mice was found to be low.
  • Figure 16 is a diagram showing the results of confirming the change in glutamine content of mice showing depression behavior due to the administration of MeAIB. Glutamine levels in the brains of mice with depressive behavior were found to be lowered.
  • 17 is a diagram showing the results of treatment with MSO and glutamine and MST and glutamine at the same time. As a result, it was confirmed that the symptoms of depression behavior disappeared when treated with MSO alone.
  • FIG. 18 is a diagram showing the results of experiments confirming that the depression behavior caused by MeAIB is changed by administration of glutamine. Glutamine was administered 3 hours after MeAIB treatment and depression behavior was examined after 3 hours. No depression behavior was found in the group treated with glutamine.
  • the present invention provides a composition for preventing or treating depression containing glutamine as an active ingredient.
  • Glutamine in the present invention is an amino acid used by neurons and glia in normal physiological processes.
  • glutamine is not only a structural component for proteins, but also used as a precursor for neurotransmitters such as glutamate and GABA.
  • Glutamine in neurons is provided through two pathways: production via Glu regeneration mediated by GS in the blood and astroglia. In the CNS, the supply of glutamine derived from blood is low compared to the demand.
  • composition of the present invention may be applied without limitation as long as it is accompanied by symptoms of depression that may be caused by various causes known in the art, and preferably may be depression caused by abnormalities of Gln-Glu circulatory control function.
  • Gln-Glu circulation is divided into six stages in neurons and astrocytes: (1) release of Glu from glutamic acid neurons in front of the synapse, and (2) by astrocytes via EAAT1-2. Reuptake of Glu, (3) GS-mediated conversion of Glu to Gln, (4) transport of Glu from astrocytes to extracellular space, (5) transport of Gln from extracellular matrix to neurons, (6) at Gln This occurs as a step of reconversion to Glu. If any of these six steps are not blocked or regulated, the circulation of Glu-Gln is overregulated.
  • prevention refers to any action that inhibits or delays the onset of depression by administration of a composition comprising glutamine according to the present invention.
  • treatment does not only mean healing for depression or the state of depression, but also improved status and various clinically detectable improvements of various depression indices, including improvement of the subjective psychological state of the patient. It shows the state which was completed.
  • composition containing the glutamine of the present invention as an active ingredient has antidepressant activity as described above, so it can be used as a pharmaceutical composition for preventing or treating depression.
  • the present invention provides a pharmaceutical composition for preventing or treating depression, including glutamine as an active ingredient.
  • the glutamine included in the composition for preventing or treating depression of the present invention may be administered to mammals such as mice, mice, livestock, humans, etc., but is preferably administered by cerebral direct injection. Since glutamine is difficult to cross the blood brain barrier, direct injection into brain neurons is preferable to oral administration rather than oral administration, but is not limited thereto, and is active on brain neurons through the blood brain barrier. Any foreseeable way to reach the components is possible.
  • compositions for preventing or treating depression of the present invention can be prepared in pharmaceutical formulations using methods well known in the art to provide rapid, sustained or delayed release of the active ingredient after administration to a mammal.
  • the active ingredient is mixed or diluted with the carrier or enclosed in a carrier in the form of a container.
  • Specific embodiments of the present invention used a parenteral liquid in the form of dissolving glutamine in PBS, but is not limited thereto, and may include various pharmaceutical carriers including all the predictable pharmaceutical diluents described by way of example below. Can be.
  • the composition for preventing or treating depression of the present invention is in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, oral formulations, external preparations, suppositories, and sterile injectable solutions according to conventional methods. It may be formulated and used, and may further comprise suitable carriers, diluents or excipients conventionally used in the preparation of the composition.
  • the present invention provides a pharmaceutical composition further comprising a carrier, diluent or excipient in a composition for preventing or treating depression.
  • carriers, excipients and diluents that may be included in the compositions of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate , Calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.
  • diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents, and surfactants are usually used.
  • composition containing glutamine according to the present invention can be formulated and used according to a conventional method, respectively.
  • it can be made into any one of the formulations selected from the group consisting of suppositories.
  • it may be prepared using diluents or excipients such as commonly used fillers, extenders, binders, wetting agents, disintegrating agents, surfactants, and the like.
  • Solid preparations for oral administration include tablets, pills, powders, granules, capsules and the like, and such solid preparations include at least one excipient such as starch, calcium carbonate, sucrose and lactose. (lactose), gelatin can be prepared by mixing. In addition to simple excipients, lubricants such as magnesium stearate, talc can also be used.
  • Liquid preparations for oral use include suspensions, solvents, emulsions, and syrups, and include various excipients such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin. Can be.
  • Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations and suppositories.
  • non-aqueous solvent and suspending agent propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used.
  • base of the suppository witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerogelatin and the like can be used.
  • Solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, and such solid preparations include at least one excipient such as starch, calcium carbonate, sucrose in the compound. Or lactose, gelatin and the like. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Oral liquid preparations include suspensions, solutions, emulsions, and syrups, and may include various excipients, such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin. have.
  • Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized formulations, suppositories.
  • non-aqueous solvent and suspending agent propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injectable esters such as ethyl oleate and the like can be used.
  • base of the suppository witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerogelatin and the like can be used. Provided that these additional ingredients should not inhibit the activity of the composition according to the invention.
  • the invention in another aspect, relates to a method for preventing or treating depression comprising administering a composition to a subject.
  • prevention and “treatment” are as described above.
  • the term “individual” is any including horses, dogs, cats, pigs, goats, rabbits, hamsters, monkeys, guinea pigs, rats, mice, lizards, snakes, sheep, cattle, fish, and birds. Means an animal (eg, a human).
  • the composition for preventing and treating depression may be administered to various mammals such as mice, mice, livestock, humans, and the like. All modes of administration can be expected and can be administered, for example, by oral, rectal or intravenous, intramuscular, subcutaneous or intracerebroventricular injection.
  • the present invention relates to the use of a composition of the present invention for the manufacture of a medicament for the prevention or treatment of depression.
  • the present inventors confirmed that the therapeutic effect of depression depends on the amount of glutamine administered (FIG. 10), and the depression treatment effect is dependent on the concentration of glutamine (FIG. 9). Therefore, the content of glutamine in the pharmaceutical composition for preventing or treating depression used in the present invention is preferably a high dose, but most preferably contained in an effective amount of 0.58 mg / kg to 2.34 mg / kg. In addition, it is preferable that the concentration of glutamine is high, but it is preferable that it is 0.1 M or more. However, the dosage and the concentration may be increased or decreased according to the condition and the degree of the disease, the drug form, the administration route, the duration, the route of administration, the extent of the disease, sex, weight, age and the like.
  • Administration may be once a day or may be divided several times.
  • An effective amount is the amount of compound required to give the desired effect. Effective amounts may vary depending on the route of administration, the use of excipients, and the possibility of use with other agents, as will be appreciated by those skilled in the art.
  • the pharmaceutical composition for preventing or treating depression of the present invention can be used alone or in combination with methods using surgery, hormone therapy, drug treatment and biological response modifiers for the prevention and treatment of depression.
  • the present invention provides a food composition for preventing or improving depression including glutamine as an active ingredient.
  • the composition containing glutamine of the present invention can be used in various foods for the prevention of depression.
  • the food to which the composition of the present invention can be added include various foods, for example, meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, gum, ice cream, soup, drink, tea, and function. Water, drink, alcoholic beverages and vitamin complex, etc.
  • the food composition of the present invention includes a form of pills, powders, granules, acupuncture, tablets, capsules or liquids, and can be added to the composition of the present invention
  • there are various foods for example, beverages, gum, tea, vitamin complex, health supplements and the like.
  • the food supplement additive may further include food supplement additives, including food supplement additives conventional in the art, such as flavoring agents, flavoring agents, coloring agents, fillers, stabilizers, and the like. .
  • natural carbohydrates examples include monosaccharides such as glucose, fructose, and the like; Disaccharides such as maltose, sucrose and the like; And conventional sugars such as polysaccharides such as dextrin, cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol.
  • natural flavoring agents tauumatin, stevia extract (e.g., rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used. .
  • the food composition of the present invention includes various nutrients, vitamins, minerals (electrolytes), flavors such as synthetic flavors and natural flavors, coloring and neutralizing agents (such as cheese, chocolate), pectic acid and salts thereof, alginic acid and Salts, organic acids, protective colloid thickeners, pH regulators, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated beverages, and the like.
  • Others may contain pulp for the production of natural fruit juices and fruit juice drinks and vegetable drinks. These components can be used independently or in combination.
  • the present invention relates to a quasi-drug composition for preventing or improving depression containing glutamine as an active ingredient. That is, the composition of the present invention can be added to the quasi-drug composition for the purpose of preventing or ameliorating depression.
  • the glutamine of the present invention When the glutamine of the present invention is used as an quasi-drug additive, the glutamine may be added as it is, or may be used together with other quasi-drugs or quasi-drug components, and may be appropriately used according to a conventional method.
  • the mixed amount of the active ingredient may be suitably determined depending on the purpose of use (prevention, health or therapeutic treatment).
  • the quasi-drug composition may be used for the preparation of antiseptic cleaners, shower foams, gagrins, wet tissues, detergent soaps, hand washes, humidifier fillers, masks, ointments, coating agents or filter fillers.
  • the present invention provides a method for providing information on the degree of depression by examining the increase and decrease of glutamine and glutamate content in the cerebral cortex of animal models for depression research.
  • depression degree refers to a mild stage of depression within a range encompassing both a state where depression is induced to improve or treat the depression.
  • Conventional diagnoses of the degree of depression have been made mainly by quantifying changes in the patient's mood.
  • Many criteria have been developed to measure and quantify the extent of mood changes in patients with depression, such as insomnia, difficulty in focusing, lack of energy, feeling worthless and guilty.
  • the present invention discloses a novel method of providing information on the degree of depression by quantifying the degree of depression by correlating the degree of depression with the change in the content of glutamine and glutamate measured according to the present invention.
  • the method for measuring the content of glutamine and glutamate includes various amino acid measurement methods that are well known in the art, and according to a specific embodiment of the present invention, liquid chromatography analysis was used.
  • the inventors Using the depressed mouse model according to the present invention, the inventors have found that the content of glutamate and glutamine is lowered in depressed animals and that the lethargy observed during FST is due to the lack of such amino acids. Therefore, glutamine was administered directly into astrocyte-deleted regions to test whether the administration of glutamine reversed depressive behavior. As a result, in the case of high concentration of glutamine administration, antidepressant effect appeared 3 hours after administration, and this effect was concentration-dependent (FIG. 9).
  • the present invention provides a depressed animal model induced by administration of methionine sulfoximine (MSO) or alpha-methyl-amino-isobutyric acid (MeAIB). .
  • MSO methionine sulfoximine
  • MeAIB alpha-methyl-amino-isobutyric acid
  • the present invention also provides a method for preparing a depressed animal model by administration of methionine sulfoximine (MSO) or alpha-methyl-amino-isobutyric acid (MeAIB). .
  • MSO methionine sulfoximine
  • MeAIB alpha-methyl-amino-isobutyric acid
  • glutamine transporter inhibitor a glutamine transporter inhibitor
  • the present invention also relates to a method for analyzing the therapeutic efficacy of depression of a test substance, comprising the step of treating a test substance in the above-described depression animal model, and measuring the depression phase of the depression animal model.
  • the test substance When the symptoms of depression improve by administering a test substance to the animal model of the present invention, the test substance may be determined to have a therapeutic effect of depression, and the dose, frequency of administration, range and dose of the test substance may be It can be easily selected by those skilled in the art within the appropriate range known in the art.
  • mice 9-week-old C57BL / 6 male mice (SPF grade, Hana, Co., Ltd., Korea), and the animals were controlled for 12 hours of day and night, and kept at a constant temperature (22 ° C) and humidity. It was able to eat water and food freely in the environment, and adapted to the breeding environment for one week before the experiment.
  • mice were perfused with 4% diluted paraformaldehyde solution and mice were sacrificed under CO 2 anesthesia for amino acid analysis. All experiments were conducted following the guidelines for treatment and use of laboratory animals at Gyeongsang National University.
  • a depression model administered with L-AAA was introduced as a recently reported model (Banasr M, Duman RS. Glial loss in the frontal lobe is sufficient to induce depressive-like behaviors. Biol Psychiatry 2008 Nov 15; 64 (10): 863 -870).
  • the guide cannula was inserted into the PLC (position Bregma 1.7 mm, left and right 0.25 mm, depth 2.5 mm) of the mature mouse, fixed using stereosteric (sterotaxic, Stoelting, USA), and xylazine (xylazine). / Zoletile, 0.5 / 1 ⁇ l / g, intra-peritoneal).
  • L-AAA 100 ⁇ g / ⁇ l, Sigma, St. Louis, Missouri
  • cannula and micro drive pumps totaling 0.6 ⁇ l in 0.1 ⁇ l / min on both sides.
  • Equal amounts of PBS were added to the sham control PLCs site.
  • a forced swim test which is a representative depression animal behavior test, was performed to confirm the change of animal behavior related to depression caused by astrocytic destruction and L-AAA administered to the PLC region.
  • FST forced swim test
  • the guide cannula was implanted 7 days prior to administration of L-AAA, and L-AAA was injected twice daily, twice daily.
  • the Glu (glutamate) / Gln (glutamine) content was then analyzed on days 3, 5, 7, and 10, and FST was performed on days 5 and 10.
  • Experiment B was to determine whether exogenous Glu and Gln could inhibit the symptoms of depression by L-AAA administration. Cannulation and infusion of toxins were performed in the same manner as in Experiment A. Depressive behavior was confirmed using FST 5 days after L-AAA administration.
  • mice received methionine sulfoximine (MSO) and alpha-methyl-amino-isobutyric acid (MeAIB) 7 days after cannulation and were identified by FST. The day after the FST, the contents of Glu and Gln were analyzed by liquid chromatography (LC).
  • MSO methionine sulfoximine
  • MeAIB alpha-methyl-amino-isobutyric acid
  • mice were acclimated by drowning for 5 minutes the day before the experiment. On the day of the experiment, mice were forced to swim for 6 minutes. First mouse Adapted to water for 1 minute, and then observed for 5 minutes. Mobility was defined as the change of 7% of the threshold value of the recorded pixel using video tracking software. The water in the chamber was replaced when the mouse changed. Behavior analysis was performed using a video tracking system (EthoVision, Ver. 3.0; Noldus Information Technology, Wageningen, The Netherlands). Experimental values were analyzed using the same software. Mice were placed at the site of FST 1 hour before behavioral analysis.
  • Sections were mounted on gelatin coated slides, dried, dehydrated in graded alcohol in turn, washed with xylene and demineralized to cover slips (Sigma). Sections were observed with a BX51 optical microscope (Olympus, Tokyo, Japan) and digital images were screened and documented. The number of GFAP-positive cells was counted using image processing software (NIH, Image J), and nine sections from each mouse were used to count GFAP-positive cells. Density of GFAP-positive cells was counted by the number of cells per mm 2 area.
  • mice were sacrificed under CO 2 anesthesia.
  • the prefrontal cortex (including the entire marginal zone) was sectioned on ice and flash frozen under liquid nitrogen.
  • the sample was weighed, and 700 ⁇ l of sodium citrate was added as a buffer for glutamate analysis and lithium citrate as a buffer for glutamine analysis. After the mixture was added and centrifuged at 13,000 rpm for 60 minutes, the supernatant was analyzed. The supernatant was filtered with a 5 ⁇ m pore size filter (Ireland, Millipore, Milex syringe filter) before analysis.
  • a 5 ⁇ m pore size filter Ireland, Millipore, Milex syringe filter
  • Glutamate and glutamine were analyzed on a mobile phase (moving rate 25.0 ml / h) with a Biochrome 20 Plus amino acid analyzer (Biochrome Ltd., Cambridge, England). Amino acid concentrations were quantified according to the relative heights of the peaks and expressed as the weight of detected amino acid ( ⁇ g / mg) per tissue weight used for detection.
  • Gln, Glu, MSO and MeAIB were purchased from Sigma and dissolved in PBS. The concentrations of Gln and Glu were used at 0.1 and 1 M. The administered MSO solution was 5 mM and 10 mM. The concentration of MeAIB was 5 mM and 7 mM. All chemical solutions were administered to both sides of the PLC region using guide cannula and microdrive dosing pumps. Doses of each chemical were administered at 0.2 ⁇ l at a rate of 0.1 ⁇ l / min. FST was performed 3 hours after Gln and MSO administration and 6 hours after Glu and MeAIB administration. In order to prevent retention and reflux of the administered solution, it was maintained for 5 minutes after complete administration before withdrawing the injection cannula. The control group received the same amount of PBS.
  • L-AAA administered mice showed low motility during the FST period and showed depression (FIG. 5).
  • the content of Glu and Gln in the L-AAA administration group was significantly lower than in the Siamese control group, but after 10 days of administration, there was no significant difference (FIGS. 6 and 7).
  • the symptoms of depression were switched on day 10 (FIG. 8).
  • immobility persistence during FST a typical depressive behavior that can be converted by antidepressants, is due to a decrease in Glu and Gln in the prefrontal cortex due to astrocytic deletion.
  • Glu regeneration is a major function of astrocytes. This regeneration involves absorbing excess Glu from synaptic gaps and synthesizing Gln from the absorbed Glu. Gln migrates from astrocytes to neurons via specific transporters. Therefore, the present inventors tested and identified two substances, L-Glu and L-Gln, as a therapeutic drug for the depression model of astrocytic deletion. Astrocyte-deleted mice were administered L-Glu, L-Gln or saline (control), and FST was performed. As shown in the results of FIG.
  • Glu-Gln circulation occurs in six stages in neurons and astrocytic cells: (1) release of Glu from glutamic acid neurons in front of synapses, (2) reuptake of Glu by glial cells via EAAT1-2, (3 GS-mediated conversion of Glu to Gln, (4) transport of Glu from astrocytes to extracellular space, (5) transport of Gln from extracellular matrix to neurons, (6) Gln to Glu reversion happenss. If any of these six steps are not blocked or regulated, the circulation of Glu-Gln is overregulated.
  • Gln is synthesized by Gln synthetase (GS) in astrocytes and migrates to neurons via a System A transporter (SAT 2).
  • Gln synthesis is inhibited by methionine sulfoximine (MSO), and Gln transport can be blocked using alpha-methyl-amino-isobutyric acid (MeAIB).
  • MSO methionine sulfoximine
  • MeAIB alpha-methyl-amino-isobutyric acid

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Abstract

La présente invention concerne l'utilisation de la glutamine pour la prévention, le traitement ou le diagnostic d'une dépression. Plus particulièrement, la présente invention concerne un procédé de fourniture d'informations sur le caractère sérieux d'une dépression par recherche de modifications de teneurs en glutamate (Glu) et en glutamine (Gln) dans le cortex cérébral ; et un procédé de prévention ou de traitement d'une dépression, qui comprend l'administration d'une composition pour la prévention ou le traitement d'une dépression, contenant de la glutamine (Gln) comme principe actif ; et une composition contenant de la glutamine. Selon la présente invention, l'effet de l'agent antidépresseur de la présente invention peut être vérifié in vivo, et non pas de manière intracellulaire à l'aide de modèles animaux de la dépression, et ainsi la présente invention est applicable au développement et à l'étude d'une méthode de traitement de patients souffrant de troubles dépressifs généraux ou sérieux. De plus, la composition de la présente invention pour le traitement d'une dépression apporte un nouvel agent antidépresseur ayant des effets rapides mais des effets secondaires minimes.
PCT/KR2010/007285 2010-04-21 2010-10-22 Utilisation de la glutamine pour la prévention, le traitement ou le diagnostic d'une dépression WO2011132831A1 (fr)

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KR10-2010-0036817 2010-04-21
KR20100036817 2010-04-21
KR1020100096535A KR20110117591A (ko) 2010-04-21 2010-10-04 글루타민을 포함하는 우울증 예방 또는 치료용 조성물
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021005310A1 (fr) * 2019-07-10 2021-01-14 Mousset Pierre Yves Composition pour le traitement des troubles des émotions
US11293720B2 (en) 2018-09-04 2022-04-05 Hvrt Corp. Reticles, methods of use and manufacture

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2002529706A (ja) * 1998-11-03 2002-09-10 マクギル ユニバーシティー 神経精神障害におけるポリグルタミン含有タンパク質

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2002529706A (ja) * 1998-11-03 2002-09-10 マクギル ユニバーシティー 神経精神障害におけるポリグルタミン含有タンパク質

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
GREGOR HASLER, ARCH. GEN. PSYCHIATRY, vol. 64, 2007, pages 193 - 200 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11293720B2 (en) 2018-09-04 2022-04-05 Hvrt Corp. Reticles, methods of use and manufacture
WO2021005310A1 (fr) * 2019-07-10 2021-01-14 Mousset Pierre Yves Composition pour le traitement des troubles des émotions
FR3098396A1 (fr) * 2019-07-10 2021-01-15 Indigo Therapeutics Composition pour le traitement des troubles des émotions

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