WO2015056675A1 - 抗うつ用併用剤 - Google Patents
抗うつ用併用剤 Download PDFInfo
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- WO2015056675A1 WO2015056675A1 PCT/JP2014/077351 JP2014077351W WO2015056675A1 WO 2015056675 A1 WO2015056675 A1 WO 2015056675A1 JP 2014077351 W JP2014077351 W JP 2014077351W WO 2015056675 A1 WO2015056675 A1 WO 2015056675A1
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- Prior art keywords
- stress
- phosphocholine
- glycero
- depression
- induced
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
- A61K31/685—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23J—PROTEIN COMPOSITIONS FOR FOODSTUFFS; WORKING-UP PROTEINS FOR FOODSTUFFS; PHOSPHATIDE COMPOSITIONS FOR FOODSTUFFS
- A23J7/00—Phosphatide compositions for foodstuffs, e.g. lecithin
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- 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
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- 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
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
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- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
Definitions
- the present invention relates to an antidepressant concomitant agent, and more particularly, to a combination of two types of phosphatidylcholine for treatment of depression and improvement of cognitive function associated with depression.
- Depression is a common mental illness, but since the diagnosis is often overlooked and treatment is not performed, the morbidity is high and patients suffer from social psychological maladjustment. Depression is primarily a bipolar disorder with severe mood changes, major depression characterized by severe depression but no depression, and certain diagnostic criteria (eg, mood modulation) Can be categorized as more uncertain and mild bipolar disease and major depression.
- TCAs tricyclic antidepressants
- SSRI selective serotonin reuptake inhibitors
- MAOI monoamine oxidase inhibitors
- TCA has side effects and it is necessary to monitor EKG and plasma drug concentrations.
- SSRIs have been reported to have adverse effects on sexual function (mainly aorgasmia and delayed ejaculation).
- Other common side effects include extrapyramidal side effects such as sleep disturbances, yawning, weight changes, suicide aspirations, and dystonia reactions.
- phosphatidylcholine has an effect of improving cognitive function, and that a combination of two specific types of phosphatidylcholine is more effective for improving cognitive function (Patent Document 1). .
- Patent Document 1 it is not known that a combination of two specific types of phosphatidylcholine exhibits an excellent antidepressant action.
- the present invention aims to provide an antidepressant concomitant agent and the like.
- the inventor has found from previous studies that the combination of two specific types of phosphatidylcholines is more effective in improving cognitive function.
- two specific types of phosphatidylcholines namely 1,2-dilinoleoyl-sn-glycero-3-phosphocholine (DL-PC) and 1-palmitoyl-2-oleoyl -Sn-glycero-3-phosphocholine (PO-PC) combined use to improve stress-induced suppression of Akt activation (hereinafter referred to as stress-induced suppression of Akt activation), and stress-induced GSK-3 ⁇
- the present invention is completed by finding that it has an action to suppress activation (hereinafter stress-induced GSK-3 ⁇ activation), and also has an excellent antidepressant action and cognitive function improving action associated with depression.
- the present invention is as follows.
- An antidepressant combination agent comprising DL-PC and PO-PC.
- the agent according to (1) above which is a food.
- a stress-induced Akt activation suppression improving agent comprising DL-PC and PO-PC.
- a stress-induced GSK-3 ⁇ activation inhibitor comprising DL-PC and PO-PC.
- the agent according to (3) or (4) above which is a research reagent.
- a method for improving the suppression of stress-induced Akt activation characterized by treating cells / tissue with DL-PC and PO-PC.
- a method for suppressing stress-induced GSK-3 ⁇ activation which comprises treating cells / tissue with DL-PC and PO-PC.
- DL-PC and PO-PC has the effect of improving the suppression of stress-induced Akt activation and the effect of suppressing the stress-induced GSK-3 ⁇ activation, and various research reagents based on these effects ( Agent), and a combination agent for antidepressant and a cognitive function improving agent accompanying depression.
- DL- / PO-PC DL-PC and PO-PC
- FIG. 2 is a graph showing that combined administration of DL-PC and PO-PC improves stress-induced memory impairment.
- FIG. 3 is a graph showing that the combined administration of DL-PC and PO-PC does not affect the learning latency. After restraint stress was applied for 4 days, DL-PC and PO-PC, or polyethylene glycol (PEG) was orally administered for 3 days, and then a water maze test was performed.
- DL- / PO-PC DL-PC and PO-PC
- FIG. 4 is a graph showing that combined administration of DL-PC and PO-PC improves stress-induced dephosphorylation of GSK-3 ⁇ . A restraint stress was applied for 4 days, and DL-PC and PO-PC, or polyethylene glycol (PEG) was orally administered for 3 days, and then mice were subjected to a forced swimming test.
- DL- / PO-PC DL-PC and PO-PC
- the present invention is characterized in that two kinds of specific phosphatidylcholines are used in combination.
- the present invention in which two types of phosphatylcholines are used in combination is also referred to as the combination agent of the present invention for convenience.
- One phosphatidylcholine has the following formula:
- —C (O) R 1 and —C (O) R 2 are each a linoleic acid residue
- the other phosphatidylcholine has the following formula:
- Palmitoyl oleoyl phosphatidylcholine (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine; PO-PC) represented by:
- DL-PC and PO-PC may be derivatized in view of their activity and safety.
- Examples thereof include, but are not limited to, derivatization such as hydrogenation, hydroxylation, alkylation, and halogenation.
- DL-PC and PO-PC used in the present invention are those isolated and purified from animals (eg, egg yolk), plants (eg, soybean), fungi (yeast, mold), etc., and chemically synthesized, etc. There is no limit.
- the DL-PC and PO-PC used in the present invention can be used without particular limitation as long as they are purified to such an extent that they can be used as pharmaceuticals. Moreover, what is marketed can also be used.
- the amounts of DL-PC and PO-PC in the concomitant drug of the present invention are the administration form of the concomitant drug (described later), the severity of the disease, the animal species to be administered, the drug acceptability of the administrable object, the body weight, respectively. Depends on age, etc. Usually, 50-500 mg, preferably 100-300 mg of DL-PC, and 50-500 mg, preferably 100-300 mg of PO-PC are administered to a subject per adult day.
- the intake ratio between DL-PC and PO-PC is preferably about 1: 1. When DL-PC and PO-PC are used in combination, a smaller dose can be achieved than when each is used alone.
- the administration form of the concomitant drug of the present invention is not particularly limited, and DL-PC and PO-PC may be combined at the time of administration.
- Such dosage forms include, for example, (1) Administration as a single preparation obtained by simultaneously formulating DL-PC and PO-PC, (2) Simultaneous administration by the same route of administration of two preparations obtained by separately formulating DL-PC and PO-PC, (3) Administration of two types of preparations obtained by separately formulating DL-PC and PO-PC with a time difference in the same administration route, (4) Co-administration of two preparations obtained by separately formulating DL-PC and PO-PC by different administration routes, (5) Administration of two types of preparations obtained by separately preparing DL-PC and PO-PC with different administration routes with a time difference. From the viewpoint of convenience, administration as a single preparation or simultaneous administration of two preparations by the same route is preferable.
- formulation a single formulation obtained by formulating DL-PC and PO-PC simultaneously, and a formulation obtained by separately formulating DL-PC and PO-PC separately.
- formulation a single formulation obtained by formulating DL-PC and PO-PC simultaneously, and a formulation obtained by separately formulating DL-PC and PO-PC separately.
- the concomitant agent of the present invention can contain an optional additive such as a pharmaceutically acceptable carrier in addition to the active ingredients DL-PC and PO-PC.
- a pharmaceutically acceptable carrier include sucrose, starch, mannitol, sorbit, lactose, glucose, cellulose, talc, calcium phosphate, calcium carbonate and other excipients, cellulose, methylcellulose, hydroxypropylcellulose, polypropylpyrrolidone.
- the combination agent of the present invention can be formulated as a preparation suitable for oral administration.
- Preparations suitable for oral administration include solutions in which an effective amount of a substance is dissolved in a diluent such as water or physiological saline, capsules, granules, powders or tablets containing the effective amount of the substance as solids or granules.
- a suspension in which an effective amount of a substance is suspended in an appropriate dispersion medium an emulsion in which a solution in which an effective amount of a substance is dissolved is dispersed in an appropriate dispersion medium, and the like.
- the combination of the present invention can be formulated as a preparation suitable for parenteral administration.
- Formulations suitable for parenteral administration include aqueous and non-aqueous isotonic sterile injection solutions, which include antioxidants, Buffers, antibacterial agents, isotonic agents and the like may be included.
- Aqueous and non-aqueous sterile suspensions are also included, which may contain suspending agents, solubilizers, thickeners, stabilizers, preservatives and the like.
- the preparation can be enclosed in a container in unit doses or multiple doses like ampoules and vials.
- the active ingredient and a pharmaceutically acceptable carrier can be lyophilized and stored in a state that may be dissolved or suspended in a suitable sterile vehicle immediately before use.
- the combination of the present invention containing DL-PC and PO-PC as active ingredients is effective against mammals (eg, mice, rats, hamsters, rabbits, cats, dogs, cows, sheep, monkeys, humans, etc.).
- mammals eg, mice, rats, hamsters, rabbits, cats, dogs, cows, sheep, monkeys, humans, etc.
- the combination agent of the present invention having an effect of improving depression and cognitive function associated with depression, and thus containing DL-PC and PO-PC, is associated with the treatment of depression (concomitant drug for antidepressant) and depression It is useful as an agent for improving cognitive dysfunction, and is provided as a pharmaceutical (hereinafter also referred to simply as the pharmaceutical of the present invention).
- the present invention provides a method for preventing, improving and / or treating depression (hereinafter also simply referred to as the method of the present invention) by such pharmacological action by the combined use of DL-PC and PO-PC as active ingredients. Can do.
- treatment means that a subject (subject) exhibiting depressive symptoms is alleviated or prevented from worsening or delayed.
- “Improvement” means that in a subject (subject) exhibiting cognitive impairment associated with depression, the symptoms are alleviated, preferably to such an extent that they do not interfere with daily life.
- prevention means preventing the manifestation of the symptom in a subject (subject) that does not exhibit depressive symptoms.
- the concomitant drug of the present invention can be provided as food.
- the combination of the present invention containing DL-PC and PO-PC as active ingredients is effective against mammals (eg, mice, rats, hamsters, rabbits, cats, dogs, cows, sheep, monkeys, humans, etc.).
- the concomitant drug of the present invention which has an action of improving depression and cognitive function associated with depression, and therefore contains DL-PC and PO-PC as active ingredients, is useful for the prevention and improvement of cognitive impairment associated with depression and depression. It is effective.
- it can be provided as a functional food effective in the prevention and improvement of depression and cognitive impairment associated with depression.
- “food” means all foods and drinks other than drugs and quasi drugs. Examples include, but are not limited to, foods for specified health use, nutritional functional foods, and so-called supplements.
- the concomitant agent of the present invention When used as a food, examples of the food include general foods (for example, bread, dairy products (eg, milk, yogurt), confectionery, candy, rice cake, chocolate, cake, pudding, jelly, Soft drinks, noodles), health foods, dietary supplements, and foods for specified health use and nutritional function foods as defined in the Health Function Food System of the Ministry of Health, Labor and Welfare.
- the food may be in any form such as a liquid (water-soluble or insoluble), a solid such as a powder, a granule, a tablet or a capsule, or a semi-solid such as a jelly.
- the concomitant agent of the present invention can be used by dissolving in water or a predetermined aqueous solution.
- the combination agent of the present invention may contain a solubilizer (eg, linoleic acid) and a stabilizer.
- the amount of intake thereof is the form used (eg, liquid, solid, semi-solid), DL-PC and PO-PC content, and DL-PC and PO-
- the total amount of DL-PC and PO-PC in food is preferably 30% or more, more preferably 90% or more It is included in the ratio.
- ingredients other than DL-PC and PO-PC in food the above-mentioned optional additives can be mentioned.
- the concomitant drug of the present invention is one in which the unit intake of the concomitant drug or a divided amount thereof is individually packaged or filled, or a plurality of unit intakes or divided amounts thereof are comprehensively packaged or filled. obtain.
- the unit intake of the concomitant drug or a divided amount thereof is the unit intake of both DL-PC and PO-PC, that is, the total phosphatidylcholine. Or the division amount.
- the unit intake of the concomitant drug or the divided amount thereof is determined by dividing the DL-PC unit intake or divided amount with the PO-PC It is a combination of unit intake or its divided amount.
- a unit intake or its divided amount thereof is converted into a normal package (for example, a PTP (press through packaging) sheet, a paper container, What was packed or filled separately in a film (for example, plastic film) container, a glass container, a plastic container) is mentioned.
- a normal package for example, a PTP (press through packaging) sheet, a paper container, What was packed or filled separately in a film (for example, plastic film) container, a glass container, a plastic container
- Such individually packaged or filled pharmaceuticals or foods can be further combined and packaged together in one container (eg, paper container, film (eg, plastic film) container, glass container, plastic container). It may be filled.
- a medicine or food in which a large number of unit intakes or divided amounts thereof are comprehensively packaged or filled for example, a single container (eg, paper container, film (eg, , Plastic film) containers, glass containers, plastic containers) or the like packed or filled.
- the pharmaceutical product or food of the present invention can also contain a unit intake or a divided amount thereof in a sufficient number for long-term intake.
- a unit intake or a divided amount thereof in a sufficient number for long-term intake.
- it is 3 days or more, preferably 7 days, 10 days, It may be included in numbers sufficient for ingestion for 14 days or 21 days or more, 1 month, 2 months, 3 months or more.
- the concomitant drug of the present invention includes one or more compounds that can treat or ameliorate cognitive impairment associated with depression or depression. Also good.
- Examples of the pharmacological action provided by the combined use of DL-PC and PO-PC revealed in the present invention include the following.
- (1) Action to suppress stress-induced GSK-3 ⁇ activation Many reports have shown that inhibition of GSK-3 ⁇ (GSK-3 ⁇ phosphorylation) exhibits antidepressant action (references). The suppression of GSK-3 ⁇ phosphorylation due to stress such as restraint stress is as shown in the Examples below, but the combined use of DL-PC and PO-PC only inhibits the suppression of such phosphorylation. Therefore, phosphorylation can be promoted. It can be said that the combined use of DL-PC and PO-PC is useful as an antidepressant because an antidepressant action can be expected by suppressing stress-induced activation of GSK-3 ⁇ .
- Akt also referred to as protein kinase B
- protein kinase B is a kind of serine threonine kinase, and threonine 308 group (Thr308) and serine 473 are used for its activation. It is believed that phosphorylation of two amino acids of the group (Ser473) is essential.
- Akt has a function of specifically phosphorylating serine or threonine residues of intracellular proteins. For example, activated Akt is inactivated by phosphorylating GSK-3 ⁇ . As shown in the examples described later, the phosphorylation of Akt is suppressed by stress such as restraint stress (that is, the activation of Akt is inhibited).
- the combination agent of the present invention containing DL-PC and PO-PC as active ingredients stresses mammals (eg, mice, rats, hamsters, rabbits, cats, dogs, cows, sheep, monkeys, humans, etc.)
- the combination of the present invention containing DL-PC and PO-PC has the effect of improving the suppression of Akt activation induced by ATP and the effect of suppressing GSK3 ⁇ activation induced by stress. It is useful as an agent that suppresses or suppresses active Akt activation and as a stress-inducible GSK-3 ⁇ activation inhibitor, and is provided as a reagent (hereinafter also referred to as the agent of the present invention).
- the cell / tissue to be treated with the agent of the present invention is not particularly limited as long as it is a cell / tissue capable of expressing active Akt or active GSK-3 ⁇ , but preferably the above-mentioned brain-derived neuron, PC A neuronal model cell line such as a -12 cell line (a pheochromocytoma derived from the adrenal medulla) or a brain tissue derived from a mammal.
- “treatment” refers to bringing the cells / tissues into contact with the agent of the present invention for a necessary and sufficient time, and the time varies depending on the desired effect and the type of cells used, but usually from 1 minute to One hour, preferably about 3 to 30 minutes. Conveniently, it is carried out by incubating in a solution (eg, culture medium) containing the agent of the present invention.
- a solution eg, culture medium
- Depression Model Currently, studies of depression using behavior of laboratory animals mainly utilize the efficacy of antidepressants and the response to stress on both sides of depression. Depression models mainly use methods that induce depression in animals by applying stress such as isolation, electric shock, forced water, and changes in the surrounding environment and temperature. In this experimental example, an animal model of restraint stress was used. The stress corresponding to the experimental animals was confined in a narrow space where they could not move to induce symptoms corresponding to depression, and whether or not there was an antidepressant effect when the test compound was administered was examined. Male C57BL / 6J mice were obtained from Japan SLC Inc. (Shizuoka. Japan) at the age of 8 weeks. The mice were trapped in a 11.5 cm plastic cylinder (diameter, 2.7 cm) for 3 hours a day, and subjected to stress for 4 consecutive days.
- stress such as isolation, electric shock, forced water, and changes in the surrounding environment and temperature.
- an animal model of restraint stress was used. The stress corresponding to the experimental animals was
- the forced swim test is a behavioral test used to screen for antidepressant effects of compounds. Also in this experimental example, restraint stress was applied for 4 days, followed by oral administration of DL-PC and PO-PC, or polyethylene glycol (PEG) for 3 days, and then a forced swimming test was performed according to a previous report (Porsolt RD, Le Pichon). M, Jalfre M. Depression: a new animal model sensitive to antidepressant treatments. Nature 1977; 266: 730-732.). The mouse was placed in a plastic cylinder (height: 25 cm, diameter: 10 cm) filled with water to a height of 15 cm and left at 23 ° C. for 6 minutes. The time of floating without moving the hind limbs or swimming observed during the latter 4 minutes was measured as the immobility time and used as an indicator of depression.
- the rat was released from one of five randomly selected locations facing the aquarium wall, and the time taken to retreat onto the platform (acquisition latency) was measured. If the evacuation was successful, the rat was allowed to stay on the platform for 10 seconds. If the platform could not be found within 90 seconds, the test was stopped and the mouse was allowed to stay on the platform for 10 seconds. The test was conducted 4 times a day at 2-minute intervals for 4 consecutive days. After 7 days, the platform was removed, and the time to reach the place where the platform was (retention latency, maximum 30 seconds) was measured.
- Anti-phospho-threonine 308-Akt (pThr308) antibody (Cell Signaling, Beverly, MA, USA) Anti-phospho-serine 473-Akt (pSer473) antibody (Cell Signaling, Beverly, MA, USA) Anti-Akt antibody (Cell Signaling, Beverly, MA, USA) Anti-phospho-GSK-3 ⁇ (pSer9) antibody (Cell Signaling, Beverly, MA, USA) Anti-GSK-3 ⁇ antibody (Cell Signaling, Beverly, MA, USA)
- the membrane was reacted with horseradish peroxidase conjugated goat anti-rabbit IgG antibody or goat anti-mouse IgG antibody.
- Immunoreactivity was detected using an ECL kit (Invitrogen, Carlsbad, CA, USA) and visualized using a chemiluminescent detection system (GE Healthcare, Piscataway, NJ, USA). Signal density was measured with ImageQuant software (GE Healthcare).
- DL-PC and PO-PC were orally administered once daily every day to mice given restraint stress and mice not given restraint stress using an oral sonde.
- Administration protocol Combination of DL-PC and PO-PC [DL-PC (0.05 mg / kg) + PO-PC (0.05 mg / kg), 0.1 mg / kg as PC] The results are shown in FIG.
- GSK-3 ⁇ is dephosphorylated (ie, GSK-3 ⁇ is activated)
- the combined use of DL-PC and PO-PC improves the dephosphorylation (ie, GSK-3 ⁇ is inactivated) Confirmed to do.
- DL-PC and PO-PC improves stress-induced Akt dephosphorylation at Ser473 (improves suppression of stress-induced Akt activation).
- DL-PC and PO-PC, or polyethylene glycol (PEG) was orally administered to mice that were depressed by 4-day restraint stress for 3 days, and after performing a forced swimming test, the hypothalamus was isolated and a sample was prepared Then, the state of phosphorylation of Akt was examined by Western blotting. Mice not subjected to restraint stress were used as positive controls, and PEG was used as negative controls.
- DL-PC and PO-PC were orally administered once daily every day to mice given restraint stress and mice not given restraint stress using an oral sonde.
- DL-PC and PO-PC has an improving effect on the suppression of stress-induced Akt activation, an inhibitory effect on stress-induced GSK-3 ⁇ activation, and various research reagents (agents) based on these effects, It is useful as a cognitive function improving agent accompanying depression and depression.
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Abstract
Description
このように、既存の薬剤の有害な副作用を示さずに、効果が向上した新しいうつ病の治療薬の開発が望まれている。
(1)DL-PC及びPO-PCを含有することを特徴とする、抗うつ用併用剤。
(2)食品である、上記(1)記載の剤。
(3)DL-PC及びPO-PCを含有することを特徴とする、ストレス誘導Akt活性化抑制改善剤。
(4)DL-PC及びPO-PCを含有することを特徴とする、ストレス誘導GSK-3β活性化抑制剤。
(5)研究用試薬である、上記(3)又は(4)に記載の剤。
(6)有効量のDL-PC及び有効量のPO-PCを、それを必要とする対象に併用して投与することを特徴とする、うつを予防、改善及び/又は治療する方法。
(7)DL-PC及びPO-PCで細胞・組織を処理することを特徴とする、ストレス誘導性Akt活性化抑制を改善する方法。
(8)DL-PC及びPO-PCで細胞・組織を処理することを特徴とする、ストレス誘導性GSK-3β活性化を抑制する方法。
本発明は2種類の特定のホスファチジルコリンを併用することに特徴がある。本明細書中、2種類のホスファチルコリンを併用する本発明を、便宜上、本発明の併用剤とも称する。
一方のホスファチジルコリンは、下記式
で表される、ジリノレオイルホスファチジルコリン(1,2-ジリノレオイル-sn-グリセロ-3-ホスホコリン;DL-PC)である。
もう一方のホスファチジルコリンは、下記式
で表される、パルミトイルオレオイルホスファチジルコリン(1-パルミトイル-2-オレオイル-sn-グリセロ-3-ホスホコリン;PO-PC)である。
(1)DL-PCとPO-PCとを同時に製剤化して得られる単一の製剤としての投与、
(2)DL-PCとPO-PCとを別々に製剤化して得られる2種の製剤の同一投与経路での同時投与、
(3)DL-PCとPO-PCとを別々に製剤化して得られる2種の製剤の同一投与経路での時間差をおいての投与、
(4)DL-PCとPO-PCとを別々に製剤化して得られる2種の製剤の異なる投与経路での同時投与、
(5)DL-PCとPO-PCとを別々に製剤化して得られる2種の製剤の異なる投与経路での時間差をおいての投与
等が挙げられる。
簡便性の観点から、単一の製剤としての投与、又は2種の製剤の同一経路での同時投与が好ましい。
本発明の併用剤が、単一の製剤として提供される場合には、該併用剤の単位摂取量又はその分割量は、DL-PC及びPO-PC両方の、即ち、ホスファチジルコリン全体の単位摂取量又はその分割量である。本発明の併用剤が、2種の製剤の併用として提供される場合には、該併用剤の単位摂取量又はその分割量は、DL-PCの単位摂取量又は分割量と、PO-PCの単位摂取量又はその分割量との組み合わせである。
(1)ストレス誘導性GSK-3β活性化を抑制する作用
GSK-3βの抑制(GSK-3βリン酸化)が抗うつ作用を示すことが数多く報告されている(参考文献)。拘束ストレス等のストレスによってGSK-3βのリン酸化が抑制されることは後述の実施例に示す通りであるが、DL-PCとPO-PCとの併用はかかるリン酸化の抑制を阻害するのみならず、リン酸化を促進することができる。
DL-PCとPO-PCとの併用はストレス誘導性のGSK-3β活性化を抑制することで抗うつ作用が期待できるので抗うつ剤として有用であると言える。
(参考文献)
Latapy C, RiouxV, Guitton MJ, Beaulieu JM. Selective deletion of forebrain glycogen synthase kinase 3β reveals a central role in serotonin-sensitive anxiety and social behaviour. Philos Trans R Soc Lond B BiolSci 2012;367(1601):2460-2474.
Akt(プロテインキナーゼBとも称される)はセリンスレオニンリン酸化酵素の1種であり、その活性化にはスレオニン308基(Thr308)、セリン473基(Ser473)の2つのアミノ酸のリン酸化が必須であると考えられている。Aktは、細胞内タンパク質のセリン又はスレオニン残基を特異的にリン酸化する機能を有している。例えば、活性化されたAktはGSK-3βをリン酸化することで不活性化させる。
拘束ストレス等のストレスによってAktのリン酸化が抑制される(すなわちAkt活性化が抑制される)ことは後述の実施例に示す通りであるが、DL-PCとPO-PCとの併用はかかるリン酸化の抑制を阻害するのみならず、リン酸化を促進することができる。
DL-PCとPO-PCとの併用はストレス誘導性のAkt活性化抑制を改善することでGSK-3βの活性化を抑制することが考えられる(参考文献)。従って、DL-PCとPO-PCとの併用は抗うつ作用が期待できるので抗うつ剤として有用であると言える。
(参考文献)
1. LeibrockC, Ackermann TF, Hierlmeier M, Lang F, Borgwardt S, Lang UE. Akt2 deficiency is associated with anxiety and depressive behavior in mice. Cell PhysiolBiochem 2013;32:766-777.
2. Marsden WN. Synaptic plasticity in depression: molecular, cellular and functional correlates. Prog Neuropsychopharmacol Biol Psychiatry 2013;43:168-184.
本発明の剤で処理する対象となる細胞・組織は、活性型Aktや活性型GSK-3βを発現し得る細胞・組織であれば特に限定されないが、好ましくは上記哺乳動物由来の脳神経細胞、PC-12細胞株(副腎髄質由来の褐色細胞腫)等の神経細胞モデル細胞株あるいは哺乳動物由来の脳組織である。ここで「処理」とは、上記細胞・組織と本発明の剤とを必要十分な時間接触させることであり、その時間は所望される効果や用いる細胞の種類によっても異なるが、通常1分~1時間、好ましくは3~30分程度である。簡便には、本発明の剤を含有する溶液(例、培養液)中でインキュベートすることによって実施される。
動物に関する取扱い
全ての手法は兵庫医科大学動物実験委員会の認可を受け、NIH(国立衛生研究所)の実験動物の管理と使用に関する指針に準拠している。
現在、実験動物の行動を用いたうつ病の研究では、うつ病の両側面である抗うつ剤の効能とストレスに対する反応が主に利用される。うつ病のモデルでは、主に孤立、電気ショック、強制的に水につけること、周辺環境や温度変化などのストレスを加えることにより、動物にうつ病を誘発する方法を使用している。本実験例では、拘束ストレス(restraint stress)の動物モデルを使用した。動けない狭い空間に実験動物を閉じ込めるストレスを加えて、うつ病に相当する症状を誘発し、試験化合物を投与した時、抗うつ効果があるか否かを調べた。雄性C57BL/6Jマウスを8週齢の時点でJapan SLC Inc. (Shizuoka. Japan)から入手した。マウスを11.5cmのプラスチック製のシリンダー(直径,2.7cm)に1日3時間閉じ込め、それを4日間連続して行いストレスを与えた。
強制水泳試験は、化合物の抗うつ効果をスクリーニングするために用いられる行動学的な試験である。本実験例においても、拘束ストレスを4日間与え、その後DL-PC及びPO-PC、あるいはポリエチレングリコール(PEG)を3日間経口投与した後に、強制水泳試験を既報に従って行なった(Porsolt RD, Le Pichon M, Jalfre M. Depression: a new animal model sensitive to antidepressant treatments. Nature 1977;266:730-732.)。マウスを、15cmの高さまで水を満たしたプラスチック製のシリンダー(高さ:25cm、直径:10cm)に入れ23℃で6分間放置した。後半の4分間の間に観察される、後肢を動かすことも泳ぐこともせず浮いている時間を、無動時間として測定し、うつ状態の指標とした。
雄性ウィスターラット(7週)を水迷路試験に用いた。円形のプラスチック製の水槽(直径90cm、深さ36cm)を用いた。水槽の内側は全て黒色に塗り、底から20cmまで墨汁で濁った水を満たした(22℃)。黒色に塗ったプラットホーム(直径11cm)を水中に置き、水面下0.5cm水没するようにした。水槽は試験室に置き、ラットが水槽から見られる目印を幾つか設けた。試験を行っている間は、目印の位置は変えずにおいた。プラットホームを水槽の中央と端から等距離のところにある一定の位置、すなわち、4分円の一つの中心に設けた。無作為に選択した5箇所のうちの一つに水槽の壁に向き合わせてラットを放し、プラットホーム上に退避するまでの時間(習得潜時:acquisition latency)を測定した。うまく退避できれば、ラットをそのままプラットホーム上で10秒間滞在させた。90秒以内にプラットホームを見つけることができなければ、試験は中止しプラットホーム上にマウスを10秒間滞在させた。2分間隔で1日4回、連続して4日間試験を行なった。7日後、プラットホームを除去し、プラットホームがあった場所に到達するまでの時間(滞納潜時:retention latency、最大で30秒)を測定した。
細胞質画分、細胞膜画分及び全ライセートの蛋白質を1% (w/v)ドデシル硫酸ナトリウム(SDS)で溶解した。タンパク質をTGXゲル(BioRad, Hercules, CA, USA)を用いたSDS-ポリアクリルアミドゲル電気泳道で分離し、ポリビニリデンフルオライド膜に転写した。ブロッティング膜は5% (w/v)BSAを含むTBS-T[150 mMNaCl, 0.1% (v/v) Tween20及び20 mM Tris, pH7.5]でブロッキングし、続いて、以下の抗体とそれぞれ反応させた。
抗ホスホ-スレオニン308-Akt(pThr308)抗体(Cell Signaling, Beverly, MA, USA)
抗ホスホ-セリン473-Akt(pSer473)抗体(Cell Signaling, Beverly, MA, USA)
抗Akt抗体(Cell Signaling, Beverly, MA, USA)
抗ホスホ-GSK-3β(pSer9)抗体(Cell Signaling, Beverly, MA, USA)
抗-GSK-3β抗体(Cell Signaling, Beverly, MA, USA)
洗浄後、膜をホースラディッシュペルオキシダーゼコンジュゲートヤギ抗ウサギIgG抗体あるいはヤギ抗マウスIgG抗体と反応させた。免疫反応性は、ECLキット(Invitrogen, Carlsbad, CA, USA)を用いて検出し、化学発光検出システム(GE Healthcare, Piscataway, NJ, USA)を用いて可視化した。シグナル密度をImageQuant ソフトウェア(GE Healthcare)で測定した。
実験例1:DL-PC及びPO-PCの併用は用量依存的にうつ状態を改善する。
4日間の拘束ストレスによりうつ状態にしたマウスにDL-PC及びPO-PC、あるいはポリエチレングリコール(PEG)を3日間経口投与した後に、強制水泳試験を行い、無動時間を測定することによってDL-PC及びPO-PCの併用の抗うつ効果を調べた。ポジティブコントロールとしては拘束ストレスを与えていないマウスを用い、ネガティブコントロールとしてはPEGを用いた。
拘束ストレスを与えたマウス及び拘束ストレスを与えていないマウスに下記(i)~(vi)のプロトコルに従って、DL-PC及び/又はPO-PCを経口ゾンデを用いて、ストレスモデル作成後から試験終了まで、1日1回経口投与した。
[投与プロトコル]
(i) DL-PC及びPO-PCの併用 [DL-PC (0.05 mg/kg) + PO-PC (0.05 mg/kg), PCとして0.1 mg/kg]
(ii) DL-PC及びPO-PCの併用 [DL-PC (0.25 mg/kg) + PO-PC (0.25 mg/kg), PCとして0.5 mg/kg]
(iii) DL-PC及びPO-PCの併用 [DL-PC (0.5 mg/kg) + PO-PC (0.5 mg/kg), PCとして1 mg/kg]
(iv) DL-PC及びPO-PCの併用 [DL-PC (2.5 mg/kg) + PO-PC (2.5 mg/kg), PCとして5 mg/kg]
(v) DL-PC単独 [1 mg/kg]
(vi) PO-PC単独 [1 mg/kg]
結果を図1に示す[(i)~(iv)の結果:図1A、(v)~(vi)の結果:図1B]。DL-PC及びPO-PCを併用して投与することにより拘束ストレスによるうつ状態を改善できることがわかった。
4日間の拘束ストレスによりうつ状態にしたマウスにDL-PC及びPO-PC、あるいはポリエチレングリコール(PEG)を3日間経口投与した後に、水迷路試験を行い、滞納潜時を測定することによってDL-PC及びPO-PCの併用の記憶障害改善作用を調べた。ポジティブコントロールとしては拘束ストレスを与えていないマウスを用い、ネガティブコントロールとしてはPEGを用いた。マウスにはPEGあるいはDL-PC及びPO-PCを、経口ゾンデを用いて投与した。
結果を図2に示す。ストレスにより滞納潜時が有意に延長した。この結果は、ストレスにより記憶障害(うつに伴う記憶障害)が誘導されることを示している。DL-PC及びPO-PCの併用は、有意にストレス誘導性の滞納潜時の延長を改善した。この結果は、DL-PC及びPO-PCの併用がストレス誘導性の記憶障害(うつに伴う記憶障害)を改善させる作用があることを意味する。
DL-PC及びPO-PCの併用は、ストレスを与えていない(即ちうつ状態ではない)場合の記憶機能に対しては影響を与えなかった。
一方、ストレスは習得潜時には影響を与えず、DL-PC及びPO-PCの併用もストレスの有無にかかわらず習得潜時に影響を与えなかった(図3)。
4日間の拘束ストレスによりうつ状態にしたマウスにDL-PC及びPO-PC、あるいはポリエチレングリコール(PEG)を3日間経口投与し、強制水泳試験を行った後、視床下部を単離し、試料を調製してウエスタンブロッティングによりGsk-3βのリン酸化の状態を調べた。ポジティブコントロールとしては拘束ストレスを与えていないマウスを用い、ネガティブコントロールとしてはPEGを用いた。
拘束ストレスを与えたマウス及び拘束ストレスを与えていないマウスにDL-PC及びPO-PCを経口ゾンデを用いて、毎日1日1回経口投与した。
[投与プロトコル]
DL-PC及びPO-PCの併用 [DL-PC (0.05 mg/kg) + PO-PC (0.05 mg/kg), PCとして0.1 mg/kg]
結果を図4に示す。拘束ストレスを与えることによりGSK-3βが脱リン酸化(即ちGSK-3βが活性化)され、DL-PC及びPO-PCの併用は当該脱リン酸化を改善(即ちGSK-3βが非活性化)することが確認された。この結果は、ストレスによってGSK-3βが脱リン酸化(GSK-3βの活性化)し、DL-PC及びPO-PCの併用はそのGSK-3βの脱リン酸化を改善する(GSK-3βの非活性化)ことを示している。GSK-3βの活性化はうつ状態を悪化させると考えられており、DCP-LAはGSK-3βの非活性化によりうつ病を改善する可能性を示唆している。
4日間の拘束ストレスによりうつ状態にしたマウスにDL-PC及びPO-PC、あるいはポリエチレングリコール(PEG)を3日間経口投与し、強制水泳試験を行った後、視床下部を単離し、試料を調製してウエスタンブロッティングによりAktのリン酸化の状態を調べた。ポジティブコントロールとしては拘束ストレスを与えていないマウスを用い、ネガティブコントロールとしてはPEGを用いた。
拘束ストレスを与えたマウス及び拘束ストレスを与えていないマウスにDL-PC及びPO-PCを経口ゾンデを用いて、毎日1日1回経口投与した。
[投与プロトコル]
DL-PC及びPO-PCの併用 [DL-PC (0.05 mg/kg) + PO-PC (0.05 mg/kg), PCとして0.1 mg/kg]
結果を図5に示す。pT308あるいはpS473のシグナル強度は全Aktについての強度で標準化した。
拘束ストレスを与えることによりAktが脱リン酸化(即ちAkt活性化の抑制)されるが、DL-PC及びPO-PCの併用は当該脱リン酸化を改善(即ちAkt活性化抑制を改善)することが確認された。AktはGSK-3βをリン酸化することで不活性化させることが知られているので、DL-PC及びPO-PCの併用により、Akt活性化抑制を改善してGSK-3βのリン酸化(GSK-3βの非活性化)に寄与することが考えられる。
Claims (8)
- 1,2-ジリノレオイル-sn-グリセロ-3-ホスホコリン及び1-パルミトイル-2-オレオイル-sn-グリセロ-3-ホスホコリンを含有することを特徴とする、抗うつ用併用剤。
- 食品である、請求項1記載の剤。
- 1,2-ジリノレオイル-sn-グリセロ-3-ホスホコリン及び1-パルミトイル-2-オレオイル-sn-グリセロ-3-ホスホコリンを含有することを特徴とする、ストレス誘導Akt活性化抑制改善剤。
- 1,2-ジリノレオイル-sn-グリセロ-3-ホスホコリン及び1-パルミトイル-2-オレオイル-sn-グリセロ-3-ホスホコリンを含有することを特徴とする、ストレス誘導GSK-3β活性化抑制剤。
- 研究用試薬である、請求項3又は4に記載の剤。
- 有効量の1,2-ジリノレオイル-sn-グリセロ-3-ホスホコリン及び有効量の1-パルミトイル-2-オレオイル-sn-グリセロ-3-ホスホコリンを、それを必要とする対象に併用して投与することを特徴とする、うつを予防、改善及び/又は治療する方法。
- 1,2-ジリノレオイル-sn-グリセロ-3-ホスホコリン及び1-パルミトイル-2-オレオイル-sn-グリセロ-3-ホスホコリンで細胞・組織を処理することを特徴とする、ストレス誘導性Akt活性化抑制を改善する方法。
- 1,2-ジリノレオイル-sn-グリセロ-3-ホスホコリン及び1-パルミトイル-2-オレオイル-sn-グリセロ-3-ホスホコリンで細胞・組織を処理することを特徴とする、ストレス誘導性GSK-3β活性化を抑制する方法。
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JP6372929B2 (ja) | 2018-08-15 |
EP3072516A4 (en) | 2017-06-07 |
EP3072516A1 (en) | 2016-09-28 |
JPWO2015056675A1 (ja) | 2017-03-09 |
US9655911B2 (en) | 2017-05-23 |
US20160235773A1 (en) | 2016-08-18 |
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