WO2010086972A1

WO2010086972A1 - Antistress agent

Info

Publication number: WO2010086972A1
Application number: PCT/JP2009/051372
Authority: WO
Inventors: 敦生関山
Original assignee: Sekiyama Atsuo
Priority date: 2009-01-28
Filing date: 2009-01-28
Publication date: 2010-08-05

Abstract

Provided is a safe and effective antistress agent which relieves responses in vivo caused by stress loading. An antistress agent or an antagonist or reliever against physical and mental disorders caused by loads in vivo, characterized by comprising a ω-methylsulfinylalkyl isothiocyanate (wherein the alkyl group has from 4 to 8 carbon atoms) as the active ingredient and inhibiting the secretion of ACTH and/or an increase in a cytokine or a chemokine after stress loading. As the ω-methylsulfinylalkyl isothiocyanate, 6-methylsulfinylhexyl isothiocyanate can be in particular suitably used.

Description

Anti-stress agent

The present invention has an action of suppressing the secretion of ACTH (adrenocorticotropic hormone) after stress loading and / or the action of suppressing increase of inflammatory cytokines after stress loading, and is used as a drug, food, etc. The present invention relates to an agent, and an antagonist and a relieving agent for a mechanism in which a load on a living body causes mental and physical disorders.

Mental and / or physical stress affects host defense including nerves, endocrine and immune systems (Non-Patent Documents 1 and 2). When stress is applied, blood levels of various inflammatory cytokines (eg, IL-18, IL-1β, IL-6, TNF-α, etc.) increase (Non-patent Document 3) and disturb the immune and biological defense systems. It is known to do (Non-Patent Document 4). Further, the present inventor has reported that an increase in inflammatory cytokines caused by stress load is caused by active oxygen molecules (Non-patent Document 5).

In recent studies, it has been reported that IL-18 mRNA is expressed in the adrenal gland in response to adrenocorticotropic hormone (ACTH) and cold stress (Non-patent Document 6). In addition, it has been reported that the adrenal gland and immune cells use different promoters for IL-18 mRNA (Non-patent Document 7). However, induction of mature IL-18 has not been shown in both studies. On the other hand, elevation of IL-18 in plasma has been reported in psychiatric patients (Non-patent Document 8).

In modern society, human beings are working and living under various stresses. In general, there are individual differences in how stress is felt, and there is no clear indicator of the presence or absence or strength of stress. The present inventor has found that stress has caused an increase in cytokines such as IL-18 through previous studies, and has clarified the flow of information transmission using IL-18 as the apex of the stress cascade, thereby objectively applying stress. Evaluation was made possible (Patent Document 1, Non-Patent Documents 9 and 10).

6-Methylsulfinylhexyl isothiocyanate is a kind of coconut oil contained in the wasabi (Wasabia Japonica) rhizome. It is detoxifying, improving blood flow, antioxidant (Patent Document 2), cell cycle arrest (Patent) Document 3), glutathione-S-transferase activity-inducing action (Patent Document 4), elastase activity inhibitory action (Patent Document 5) and the like are known. The present inventor suggests in Patent Document 1 that the antioxidants including the isothiocyanate may relieve mental stress by inhibiting the signal transduction of the stress cascade. It remains unknown whether it is more effective.
International Publication No. 2006/003927 Pamphlet JP 2006-069982 A JP 2006-089394 A JP 2001-064253 A JP 2006-008562 A Dugue, B. et al., Scand. J. Clin. Invest. 53, 555-561 (1993) Kiecolt-Glaser, J. K. et al., Proc. Natl. Acad. Sci. USA 93, 3043-3047 (1996) Dugue, B. et al. Scand. J. Clin. Invest. 53, 555-561 (1993) Sekiyama, A. et al. J Med Invest. 52, 236-239 (2005) Sekiyama, A. et al. Immunity 22 (6), 669-677 (2005) Conti, B. et al. J. Biol. Chem. 272, 2035-2037 (1997) Sugama, S. et al. J. Immunol. 165, 6287-6292 (2000) Kokai, M. et al. J. Immunother. 25, 68-71 (2002) Sekiyama, A. et al. Immunity 22 (6), 669-677 (2005) Sekiyama, A. et al. J Neuroimmunol. 171 (1-2), 38-44 (2006)

An object of the present invention is to provide a safe and effective anti-stress agent that alleviates in-vivo response due to stress load on a living body.

As a result of diligent research to solve the above-mentioned problems, the present inventors have found that 6-methylsulfinylhexyl isothiocyanate contained in a lot of wasabi rhizomes is excellent in anti-stress action, thereby completing the present invention. It came.
That is, the present invention provides the following.
[1] It contains ω-methylsulfinylalkylisothiocyanate (wherein the alkyl group has 4 to 8 carbon atoms) as an active ingredient, and suppresses the secretion of ACTH and / or increase in cytokine or chemokine after stress loading An anti-stress agent or an antagonist or alleviating agent against a physical and mental disorder caused by a biological load.
[2] In [1], ω-methylsulfinylalkyl isothiocyanate is horseradish, horseradish, cabbage, watercress, brussels sprouts, cauliflower, radish, tangle radish, rapeseed, broccoli, Takana, mustard, turnip, and Chinese cabbage rape. The agent according to [1] above, which is obtained from one or more species selected from the family plant family.
[3] The agent according to the above [2], wherein the ω-methylsulfinylalkyl isothiocyanate is obtained by physical means of crushing or grinding cruciferous plants, extraction means with a solvent, drying means, or a combination thereof.
[4] The agent according to [2] or [3], wherein the cruciferous plant is Wasabi.
[5] The agent according to [4], wherein, in [4], the wasabi is a wasabi leaf or a wasabi rhizome.
[6] Cytokines are IL-1β, IL-1ra, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL -11, IL-12, IL-13, IL-15, IL-17, IL-18, Eotaxin, FGF basic, G-CSF, GM-CSF, IFN-γ, IFN-α, IP-10, MCP- 1, MIP-1α, MIP-1β, PDGF-BB, RANTES, TNF-α, VEGF, CSF-2, TGF-β, neurotrophin 5, MCP-3, β-2-microglobulin, angiotensin II, CSF- 3, CXC chemokine ligand 1, CXC chemokine ligand 5, HGF, IL-1α, IL-2ra, IL-16, CTACK, GRO-α, ICAM-1, IFN-α2, LIF, MCP-3, M-CSF, The agent according to any one of [1] to [5], which is selected from the group consisting of MIF, MIG, β-NGF, SCF, SCGF-β, SDF1a, TNF-β, and VCAM-1.
[7] The agent according to [6] above, wherein the cytokine is IL-18.
[8] containing ω-methylsulfinylalkyl isothiocyanate (wherein the alkyl group has 4 to 8 carbon atoms) as an active ingredient,
IL-1β, IL-1ra, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL- 12, IL-13, IL-15, IL-17, IL-18, Eotaxin, FGF basic, G-CSF, GM-CSF, IFN-γ, IFN-α, IP-10, MCP-1, MIP-1α , MIP-1β, PDGF-BB, RANTES, TNF-α, VEGF, CSF-2, TGF-β, neurotrophin 5, MCP-3, β-2-microglobulin, angiotensin II, CSF-3, CXC chemokine ligand 1, CXC chemokine ligand 5, HGF, IL-1α, IL-2ra, IL-16, CTACK, GRO-α, ICAM-1, IFN-α2, LIF, MCP-3, M-CSF, MIF, MIG, β -An anti-stress agent or biological load characterized by regulating in vivo the amount of stress factor or fatigue factor selected from the group consisting of NGF, SCF, SCGF-β, SDF1a, TNF-β and VCAM-1 Antagonists or mitigators against physical and mental disorders.
[9] The agent according to any one of [1] to [8] above, wherein the ω-methylsulfinylalkyl isothiocyanate is 6-methylsulfinylhexyl isothiocyanate.
[10] A pharmaceutical comprising the agent according to any one of [1] to [9].
[11] A food containing the agent according to any one of [1] to [9].
[12] The food according to [11] above, which is a health functional food or a dietary supplement.
[13] The food according to [12], wherein the health functional food is a food for specified health use or a food with a nutritional function.
[14] including a step of administering an effective amount of ω-methylsulfinylalkylisothiocyanate (wherein the alkyl group has 4 to 8 carbon atoms) to a subject in need thereof, whereby the adrenal gland after stress loading A method of antagonizing or alleviating stress or biological load causing psychosomatic disorders, wherein secretion of cortical stimulating hormone and / or increase in cytokine or chemokine is suppressed.
[15] In the above [14], ω-methylsulfinylalkyl isothiocyanate is horseradish, horseradish, cabbage, watercress, brussels sprouts, cauliflower, radish, leach radish, rapeseed, broccoli, Takana, mustard, turnip, and Chinese cabbage rape. The method according to [14] above, wherein the method is obtained from one or more species selected from the family plant family.
[16] The method according to [15] above, wherein the ω-methylsulfinylalkylisothiocyanate is obtained by physical means of crushing or grading cruciferous plants, extraction means with a solvent, drying means, or a combination thereof.
[17] The method according to [15] or [16] above, wherein the cruciferous plant is Wasabi.
[18] The method according to [17] above, wherein, in [17], the wasabi is a wasabi leaf or a wasabi rhizome.
[19] Cytokines are IL-1β, IL-1ra, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL -11, IL-12, IL-13, IL-15, IL-17, IL-18, Eotaxin, FGF basic, G-CSF, GM-CSF, IFN-γ, IFN-α, IP-10, MCP- 1, MIP-1α, MIP-1β, PDGF-BB, RANTES, TNF-α, VEGF, CSF-2, TGF-β, neurotrophin 5, MCP-3, β-2-microglobulin, angiotensin II, CSF- 3, CXC chemokine ligand 1, CXC chemokine ligand 5, HGF, IL-1α, IL-2ra, IL-16, CTACK, GRO-α, ICAM-1, IFN-α2, LIF, MCP-3, M-CSF, The method according to any one of [14] to [18] above, which is selected from the group consisting of MIF, MIG, β-NGF, SCF, SCGF-β, SDF1a, TNF-β and VCAM-1.
[20] The method described in [19] above, wherein the cytokine is IL-18.
[21] comprising administering an effective amount of ω-methylsulfinylalkyl isothiocyanate (wherein the alkyl group has 4 to 8 carbon atoms) to a subject in need thereof, thereby
IL-1β, IL-1ra, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL- 12, IL-13, IL-15, IL-17, IL-18, Eotaxin, FGF basic, G-CSF, GM-CSF, IFN-γ, IFN-α, IP-10, MCP-1, MIP-1α , MIP-1β, PDGF-BB, RANTES, TNF-α, VEGF, CSF-2, TGF-β, neurotrophin 5, MCP-3, β-2-microglobulin, angiotensin II, CSF-3, CXC chemokine ligand 1, CXC chemokine ligand 5, HGF, IL-1α, IL-2ra, IL-16, CTACK, GRO-α, ICAM-1, IFN-α2, LIF, MCP-3, M-CSF, MIF, MIG, β -The stress or fatigue load in the body of the stress factor or fatigue factor selected from the group consisting of NGF, SCF, SCGF-β, SDF1a, TNF-β and VCAM-1 is regulated. Antagonistic or mitigating methods.
[22] The method according to any one of [14] to [21] above, wherein the ω-methylsulfinylalkyl isothiocyanate is 6-methylsulfinylhexyl isothiocyanate.

The anti-stress agent of the present invention contains ω-methylsulfinylalkylisothiocyanate as an active ingredient, and by ingesting this as a food or a medicine, secretion of ACTH and glucocorticoid after stress loading on the living body and / or There is an effect of suppressing an increase in cytokine or chemokine after stress loading and reducing an excessive reaction of a living body. The anti-stress agent of the present invention also acts as an antagonist or alleviating agent against a physical load causing mental and physical disorders. Since an excessive reaction of a living body is associated with various diseases, the present invention can be applied to prevention or treatment of diseases caused by stress.

It is a figure which shows the effect with respect to stress-related ACTH rise of 6-MSITC (trademark) 1 week administration. It is a figure which shows the effect with respect to stress-related IL-18 rise of 6-MSITC (trademark) 1 week administration. It is a figure which shows the effect with respect to stress-related ACTH raise of 6-MSITC (trademark) 2 week administration. It is a figure which shows the effect with respect to stress-related IL-18 rise of 6-MSITC (trademark) 2 week administration. It is the figure which showed collapse of the healthy pattern of cytokine and chemokine by night shift stress. It is a figure which shows the avoidance and suppression effect with respect to collapse of the healthy pattern of the cytokine and chemokine by night shift stress of 6-MSITC or placebo administration. A healthy pattern is maintained in the 6-MSITC administration group. It is the figure which showed collapse of the healthy pattern of cytokine and chemokine by the exercise stress in humans. It is a figure which shows the effect with respect to the decay | disruption of the healthy pattern of the cytokine and chemokine by the exercise stress in a human by 6-MSITC or placebo administration. A healthy pattern is maintained in the 6-MSITC administration group. It is the figure which showed collapse of the healthy pattern of cytokine and chemokine by the mental workload stress in humans. FIG. 6 is a graph showing the effect of administration of 6-MSITC or placebo on disruption of healthy patterns of cytokines and chemokines due to mental workload stress in humans. A healthy pattern is maintained in the 6-MSITC administration group. It is a figure which shows the recovery | restoration by rest after collapse of the healthy pattern of cytokine and chemokine by the exercise stress in humans. It is a figure which shows the effect which it has on the recovery | restoration by rest after the collapse of the healthy pattern of the cytokine and chemokine by the exercise stress in the human by 6-MSITC or placebo administration. The recovery effect is remarkable in the 6-MSITC administration group. It is a figure which shows the recovery | restoration by rest after collapse of the healthy pattern of cytokine and chemokine by the mental workload stress in humans. FIG. 6 is a graph showing the effect of 6-MSITC or placebo administration on recovery by rest after disruption of the normal pattern of cytokines and chemokines due to mental workload stress in humans. The recovery effect is remarkable in the 6-MSITC administration group.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention provides an anti-stress agent, an antagonist or mitigation agent (hereinafter referred to as “the agent of the present invention”) against a physical and psychological disorder caused by biological stress.

In the present invention, the term “stress” means various responses of the living body due to the extraordinary chemical, physical, mental, verbal or exertional stress on the mental and physical body (stress load). . Further, “stress” also means various responses of the living body due to the application of a constant load from inside the living body (stress load).

Specific examples of “stress” to be alleviated by the present invention include physical stress caused by high temperature, low temperature, high pressure, low pressure, noise, radiation, ultraviolet rays, chemistry caused by harmful chemical substances such as oxygen deficiency, heavy metals, and arsenic. Mental stress due to physical stress, anger, anxiety, fear, tension, restraint, and labor stress due to labor and work can be exemplified, but in the present invention, physical stress, chemical stress, labor stress, and mental stress are preferable. As the mental stress, restraint stress is more preferable, and long-term restraint stress is particularly preferable. Here, the long time cannot be generally described due to living organisms or individual differences, but in the case of animals, 6 hours or more are exemplified. As physical stress, stress due to ultraviolet irradiation is preferable, and as chemical stress, stress due to exposure to harmful chemical substances is preferable.

Stress loading activates the hypothalamic-pituitary-adrenal (HPA) axis to induce the secretion of ACTH (adrenocorticotropic hormone), induces glucocorticoids, while induces cytokines and chemokines such as IL-18 To do. In addition, increases in vivo cytokines represented by IL18 cause further secretion of ACTH and glucocorticoid. Therefore, in the present invention, “stress” specifically refers to the secretion of ACTH and / or the increase of cytokines and chemokines in vivo (preferably an increase in blood concentration). It is also meant to include the disease caused by it.

In the present invention, “anti-stress” specifically refers to suppression of ACTH secretion after stress loading and / or suppression of in vivo cytokine increase (preferably an increase in blood concentration), and the excess of the living body associated therewith. It also includes the reduction of response as well as the prevention or treatment of diseases resulting therefrom.

In the present invention, cytokine and chemokine are IL-1β, IL-1ra, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL. -10, IL-11, IL-12, IL-13, IL-15, IL-17, IL-18, Eotaxin, FGF basic, G-CSF, GM-CSF, IFN-γ, IFN-α, IP- 10, MCP-1, MIP-1α, MIP-1β, PDGF-BB, RANTES, TNF-α, VEGF, CSF-2, TGF-β, Neurotrophin 5, MCP-3, β-2-microglobulin, Angiotensin II, CSF-3, CXC chemokine ligand 1, CXC chemokine ligand 5, HGF, IL-1α, IL-2ra, IL-16, CTACK, GRO-α, ICAM-1, IFN-α2, LIF, MCP-3, Examples include M-CSF, MIF, MIG, β-NGF, SCF, SCGF-β, SDF1a, TNF-β, and VCAM-1. Particularly preferably, the cytokine is TNF-α, Eotaxin and IL-18.

Ω-methylsulfinylalkyl isothiocyanate may be a chemically synthesized substance or a natural product as an extract obtained from a cruciferous plant. Specific examples of these substances include 5-methylsulfinylpentyl isothiocyanate, 6-methylsulfinyl hexyl isothiocyanate, 7-methylsulfinyl heptyl isothiocyanate, and 8-methylsulfinyl octyl isothiocyanate. In particular, 6-methylsulfinylhexyl isothiocyanate is preferable.

In the case of natural products, ω-methylsulfinylalkyl isothiocyanate is a group of cruciferous plants such as Japanese horseradish, horseradish, cabbage, watercress, Brussels sprouts, cauliflower, radish, radish, rapeseed, broccoli, Takana, mustard, turnip, Chinese cabbage, etc. Those obtained from one or more selected from the above are preferred. Among these, Japanese wasabi (Wasabia が Japonica) having a high content of 6-methylsulfinylhexyl isothiocyanate is more preferable, and either Japanese wasabi leaves or Japanese wasabi rhizome may be used. Particularly preferred.

The method for synthesizing ω-methylsulfinylalkylisothiocyanate will be described as follows.

In principle, the method of Kiaer et al. Is followed (Kiaer et al. Acta chem. Scand, 11, 1298, 1957). Ω-Chloroalkenol is used as a starting material and refluxed with CH ₃ -SNa to give ω-methylthioalkenol, which is reacted with SOCl ₂ to give ω-chloroalkenol methylsulfide.

Next, an amino group is introduced using the Gabriel method to produce N- (ω-methylthioalkyl) -phthalimide, and hydrazine hydrate is added thereto to reflux to obtain ω-methylthioalkylamine. Further, according to the method of Li et al. (Li et al. J. Org. Chem., 62, 4539, 1997), ω-methylthioalkylisothiocyanate obtained via thiuram disulfide was oxidized with mCPBA to oxidize the methylthio group. Obtain methylsulfinylalkylisothiocyanate.

In extracting ω-methylsulfinylalkylisothiocyanate from Brassicaceae plants, the plant body is subjected to extraction pretreatment by physical means such as grinding or grated water, methanol, ethanol, acetone, acetone, ethyl acetate, diethyl ether, Extraction with an organic solvent such as dichloromethane or dichloroethane, or extraction with a distillation method such as steam distillation or molecular distillation is preferred, but it is not particularly limited to these methods.

For example, the specific extraction method of this wasabi with an organic solvent is as follows. After the rhizome of this wasabi is grated, it is extracted with an ethyl acetate solvent, and this extract is dehydrated with anhydrous sodium sulfate and then concentrated with an evaporator. Ω-methylsulfinylalkylisothiocyanate is obtained. This method is particularly suitable for the extraction of 6-methylsulfinylhexyl isothiocyanate. Commercially available 6-methylsulfinylhexyl isothiocyanate may be used, and examples thereof include Wasabi sulfinyl (registered trademark) (6-MSITC (registered trademark)) manufactured by Kinshi Co., Ltd.

In the case of extraction from watercress of ω-methylsulfinylalkylisothiocyanate, it is extracted in the same manner as this wasabi. For example, the watercress are ground and then extracted with an ethyl acetate solvent. The extract is dehydrated with anhydrous sodium sulfate and then concentrated with an evaporator to obtain ω-methylsulfinylalkylisothiocyanate. This method is particularly suitable for the extraction of 7-methylsulfinyl heptyl isothiocyanate and 8-methylsulfinyl octyl isothiocyanate.

The above-mentioned extract is extracted and concentrated, and then purified by an arbitrary method such as a liquid-liquid distribution method, chromatography, molecular distillation, or rectification. Before and after the purification means, drying means such as hot air drying and freeze drying may be combined.

In addition to ω-methylsulfinylalkylisothiocyanate, flavonoids such as apigenin, luteolin and kaempferol, glycosides or multimers thereof, and phenylpropanoids such as ferulic acid and sinapinic acid as active ingredients of the antistress agent of the present invention Or their glycosides or multimers, other isothiocyanates, or other polyphenols. These components may be used alone or in combination of two or more.

Specific examples of the other isothiocyanates include allyl isothiocyanate, secondary butyl isothiocyanate, 3-butenyl isothiocyanate, 4-pentenyl isothiocyanate, 5-hexenyl isothiocyanate, 5-methylthiopentyl isothiocyanate, Examples include 6-methylthiohexyl isothiocyanate, 7-methylthioheptyl isothiocyanate, and 8-methylthiooctyl isothiocyanate.

Active ingredients other than ω-methylsulfinylalkylisothiocyanate may be synthesized by various chemical synthesis methods in addition to extraction from plants by the above-described method. Those skilled in the art can synthesize these active ingredients by methods well known in the art.

The agent of the present invention is useful as a medicine, food, and the like, and examples of its administration include mammals (eg, humans, mice, rats, hamsters, rabbits, cats, dogs, cows, sheep, monkeys, etc.). It is done. In addition, when adapted to mammals other than humans, the intake of the agent of the present invention may be appropriately adjusted according to the body weight or size of the animal.

When the agent of the present invention is a medicine, it generally contains an active ingredient and a carrier. The carrier is not particularly limited as long as it is a pharmaceutically acceptable carrier, and examples thereof include a substance for formulation described below (eg, excipient, solvent, etc.).
Here, the administration form of the medicament of the present invention is not particularly limited, but can be performed through general administration routes such as oral administration, rectal administration, injection, administration by infusion. Oral dosage forms include granules, fine granules, powders, coated tablets, tablets, suppositories, powders, (micro) capsules, chewables, syrups, juices, liquids, suspensions, emulsions, etc. In addition, general dosage forms of pharmaceutical preparations such as direct intravenous injection, infusion administration, and preparations that prolong the release of active substances can be adopted as injections.

These drugs can be formulated by conventional methods. Various pharmacologically acceptable substances for preparation (as adjuvants and the like) can be blended as necessary in the preparation. The substance for the preparation can be appropriately selected depending on the dosage form of the preparation. For example, the excipient, the diluent, the additive, the disintegrant, the binder, the coating agent, the lubricant, the lubricant, the lubricant, and the flavoring agent. , Sweeteners, solubilizers, solvents and the like. Furthermore, specific examples of the pharmaceutical substance include magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, milk protein, gelatin, starch, cellulose and derivatives thereof, animal and vegetable oils, polyethylene glycol, and solvents, Examples include sterilized water and mono- or polyhydric alcohols such as glycerol.

In the case of oral administration, the dose of the active ingredient in the medicament of the present invention varies depending on the symptoms, age, and administration method of the patient to be administered, but the daily dose of the active ingredient for an adult (with a body weight of 60 kg) is usually 10 pg. About 5 g, preferably about 100 ng to 10 mg, more preferably about 0.5 mg to 3 mg. For example, when the active ingredient is 6-methylsulfinylhexyl isothiocyanate, the daily dose of 6-methylsulfinylhexyl isothiocyanate is usually about 10 pg to 5 g, preferably about 100 ng to 10 mg, more preferably 0.5 mg to About 3 mg. Usually, the above-mentioned amount is administered in 1 to 3 divided doses per day.
In addition, the dose of the active ingredient in the case of parenteral administration (intake), such as infusion administration, injection administration (intravenous administration), etc., is 10 to 20 minutes within the preferable dose (intake amount) range for oral administration. About 1 can be administered. Usually, the above-mentioned amount is administered in 1 to 3 divided doses per day.

In addition, the medicament of the present invention may be combined (contained) with other drugs. Examples of such drugs include other anti-stress agents, vitamins, hormones, nutrients, peptic ulcers, steroids, Examples include tumor agents, antiviral agents, antibacterial agents, antidepressants, antipsychotics, and tranquilizers. These can use together (contain) 1 type, or 2 or more types.

The agent of the present invention suppresses the secretion of ACTH and / or the increase of inflammatory cytokines after stress loading. Increases in inflammatory cytokines after stress loading are closely associated with various diseases by causing excessive responses in the body. Therefore, the agent of the present invention is also useful for preventing or treating diseases caused by stress. Diseases caused by stress include diseases that develop, worsen, or recur due to the involvement of cytokines such as IL-18. Examples of these diseases include depression, PTSD, anxiety, obsessive-compulsive disorder, schizophrenia, psychosomatic disease, appendicitis, peptic ulcer, gastric ulcer, duodenal ulcer, peritonitis, pancreatitis, ulcerative, pseudomembranous, acute And ischemic colitis, diverticulitis, epiglottitis, achalasia, cholangitis, cholecystitis, hepatitis, Crohn's disease, enteritis, Whipple disease, (bronchial) asthma, allergy, anaphylactic shock, immune complex disease, organ ischemia Reperfusion injury, organ necrosis, hay fever, sepsis, sepsis, endotoxin shock, cachexia, hyperthermia, eosinophilic granulomas, granulomatosis, sarcoidosis, septic abortion, epididymis, vagina Inflammation, prostatitis, urethritis, bronchitis, emphysema, pulmonary edema, rhinitis, cystic fibrosis, pneumonia, pneumoconiosis, alveolitis, bronchiolitis, pharyngitis, pleurisy, sinusitis, influenza, respiratory organs Endoplasmic reticulum virus infection, herpes infection, HIV infection, hepatitis B virus infection, hepatitis C virus infection, disseminated bacteremia, dengue fever, candidiasis, malaria, filariasis, amoebiasis, hydatid cyst, burn, dermatitis, Dermatomyositis, sunburn, hives, warts, wheal, vasculitis, vasculitis, endocarditis, arteritis, atherosclerosis, thrombophlebitis, epicarditis, myocarditis, myocardial ischemia , Periarteritis nodosa, rheumatic fever, Alzheimer's disease, celiac disease, congestive heart failure, adult respiratory distress syndrome, meningitis, encephalitis, multiple sclerosis, cerebral infarction, stroke, Guillain-Barre syndrome, neuritis, neuralgia Spinal cord injury, paralysis, uveitis, arthritis, arthralgia, osteomyelitis, fasciitis, Paget's disease, gout, periodontal disease, rheumatoid arthritis, synovitis, myasthenia gravis, amyotrophic lateral cord Sclerosis, thyroiditis, all Systemic lupus erythematosus (SLE), Goodpasture syndrome, Behcet's syndrome, allograft rejection, graft-versus-host disease, type I diabetes, ankylosing spondylitis, Burger disease, type II diabetes, Reiter's syndrome, Hodgkin's disease, cirrhosis, kidney Failure, allergic asthma, nephritis, myocardial infarction, Sjogren's syndrome, contact dermatitis, atopic dermatitis, depression, eating disorders, dysphagia, taste disorders, acne vulgaris, pemphigus, ichthyosis, psoriasis, burns , Photosensitivity, ultraviolet skin disorder, or radioactive disorder, carbon monoxide poisoning, hypoxia or secondary disorders thereof.

Furthermore, the agent of the present invention may be contained in food. When contained in food, any form may be used as long as it is a general meal form containing the active ingredient of the present invention. For example, drinks such as soft drinks and powdered drinks can be prepared by adding an appropriate flavor. Specifically, for example, it can be mixed with juice, milk, confectionery, jelly, yogurt, rice cake, etc. to eat and drink.
It is also possible to provide such foods as health functional foods or dietary supplements. This health functional food includes food for specified health use and food with nutritional function. The food for specific health is a food that can indicate that a specific health purpose can be expected, for example, prevention or reduction of stress. In addition, nutritional functional foods are foods that can display the function of nutritional components when the amount of nutritional components included in the daily intake standard amount conforms to the standards for the upper and lower limits established by the national government. It is. Dietary supplements include so-called nutritional supplements or health supplements. In the present invention, the food for specified health use is a food with a label indicating that it is used for applications such as prevention or reduction of stress, and further a document (so-called notation) describing that it is used for such applications. Foods that include the above as a package are also included.
Furthermore, the agent of the present invention can be used as a concentrated liquid food or a food supplement. When used as a food supplement, it can be prepared in the form of tablets, capsules, powders, granules, suspensions, chewables, syrups and the like. The food supplement in the present invention refers to those taken for the purpose of supplementing nutrition in addition to those taken as food, and also includes nutritional supplements and supplements.
For example, when the active ingredient is 6-methylsulfinylhexyl isothiocyanate, the daily dose of 6-methylsulfinylhexyl isothiocyanate is usually about 10 pg to 5 g, preferably about 100 ng to 10 mg, more preferably 0.5 mg to About 3 mg.

When taking as food, the intake varies depending on the symptom, age, weight, dosage form, method of intake, etc. of the subject of intake, but the daily dose is from 1 pg / kg body weight to 800 mg / kg body weight as an active ingredient. For example, when the active ingredient is 6-methylsulfinyl hexyl isothiocyanate, preferably, 6-methylsulfinyl hexyl isothiocyanate 15 ng / kg body weight to 1.5 mg / kg body weight, more preferably 10 ng / kg body weight per adult day About 50 ng / kg body weight is preferred. In the food of the present invention, the amount per day can be taken at once or divided into several times. The intake period is not particularly limited.

The food of the present invention suppresses the secretion of ACTH and / or the increase of inflammatory cytokines after stress loading. Increases in inflammatory cytokines after stress loading are closely associated with various diseases by causing excessive responses in the body. Therefore, the food of the present invention is also useful for preventing or ameliorating a disease caused by stress. Examples of the disease caused by stress include those described above.

In the present invention, the agent containing ω-methylsulfinylalkylisothiocyanate as an active ingredient includes a description that can be used or should be used for prevention or reduction of stress, etc. Commercial packages are also included.

The contents of all publications, including patents and patent application specifications cited in this specification, are hereby incorporated by reference herein to the same extent as if all were explicitly stated. Is.

Hereinafter, the present invention will be described in detail using examples, but the present invention is not limited to the following examples.

Example 1
(Method)
Male C57 / B6 mice (10 weeks old; purchased from Seac Yoshitomi) were bred with free drinking of 0.5 ng% by weight of 6-MSITC (registered trademark) (manufactured by Kinshi Co., Ltd.). At 1 and 2 weeks after the start of 6-MSITC® administration, the mice were fixed in a restraint (27 mm diameter round plastic tube) and restraint stress was applied for up to 6 hours.
Immediately after release from restraint stress, blood was collected from the heart, and the serum was separated by centrifugation at 2500 rpm for 10 minutes at 4 ° C., and the ACTH and IL-18 concentrations in the serum were measured. ACTH concentration was measured by SRL for measurement by RIA method, and IL-18 concentration was measured by ELISA using Quantikine ^™ immunoassay kit (R & D Systems).

(result)
1 and 3, the increase in serum ACTH after restraint stress loading was suppressed in mice that received 6-MSITC (registered trademark) compared to mice that did not. From FIG. 3, in the 2-week administration group, the ACTH increase (phase 2) reaction after long-time (6 hours) stress was also strongly suppressed. It was found that the inhibitory action of ACTH by 6-MSITC (registered trademark) acts only on the increase of ACTH due to stress and does not affect the steady-state ACTH concentration.
2 and 4, the increase in serum IL-18 after restraint stress load was suppressed in the mice that received 6-MSITC (registered trademark) compared to the mice that did not.
The inhibitory action of these 6-MSITC® was more strongly observed in the 2-week administration group (FIG. 4) than in the 1-week administration group (FIG. 2).
Furthermore, mice that received 6-MSITC (registered trademark) were less quarreled during breeding and were mild during stress.
(Discussion)
It was revealed that 6-MSITC (registered trademark) has an effect of suppressing acute stress response. 6-MSITC® has been shown not only to prevent exacerbations of inflammation due to stress, but also to reduce the load on the hypothalamic-pituitary adrenal system related to obesity and diabetes.
In the future, by clarifying the suppression mechanism of inflammatory cytokines and ACTH elevation, health food, therapeutic diet, anti-inflammatory analgesic, tranquilizer, antidepressant, antipsychotic, anxiolytic, antidementia, endocrine There is a possibility that it can be used as a component such as a regulator or an anti-inflammatory agent.

Example 2
Anti-fatigue effect verification protocol for humans Ingestion for 4 weeks, 2 cross-over studies (subjects)
Tests were conducted on doctors and nurses working night shifts. This study was conducted with full informed consent after a thorough explanation of the study.
(Number of subjects)
42 people (21 people per group)
(Method)
Test meal: Soft capsule containing 50 ng of 6-MSITC extracted from natural wasabi The following tests were conducted for 7 days before and after night shift before taking the test meal (or placebo). One group received the test meal every day between 20-21 o'clock for 4 weeks, and the other group received a placebo on a similar intake schedule. The following examinations were similarly conducted for 14 days after taking the test meal (or placebo) for 4 weeks and before and after night shift. The test meal or placebo start date was defined as day 0.
(Subject management during study period)
・ Record of daily life log (sleeping time, alcohol, medicine) during the whole test period ・ Record of meal (morning, noon, evening) during test meal (or placebo) intake period ・ Steps by pedometer (registered trademark) Record (inspection)
1) Evaluation of personality and subjective symptoms TEG (Tokyo University egogram) (-1 week only)
CMI, SDS, MAS (0, 4, 6 weeks)
Every blood collection: GHQ, subjective research (Occupational Health Research Institute)
Those who were subject to Kraepelin performed the Kraepelin test at the time when they should end the night shift at 0 points.
2) Quantitative analysis of fatigue VAS (Visual Analogue Scale): Every blood sampling Fatigue questionnaire: -1, 0, 4, 6 weeks 3) Physical examination Blood pressure, pulse, body weight, height, body fat percentage, steps ( Commercial pedometer (registered trademark) use)
Blood pressure and pulse are around -1, 0, 4, 6 weeks.
Otherwise, after working at -1, 0, 4, 6 weeks.
4) Life record (survey)
(Meal content and alcohol consumption) Sleeping hours, working hours, (Questionnaire survey on the effects of test meals at the end of the study)
5) Blood test (-1, 0, 4, 6 weeks)
General biochemical peripheral blood general examination, leukocyte fractionation, TP, ALB, γ-GTP, AST (GOT), ALT (GPT), ALP, CPK, LDH, UN, Cre, UA, TG, Tcho, HDL-cho, Optional for comprehensive measurement () items for LDL-cho, Na, K, Cl, free fatty acids, blood glucose, cytokines
Special items Citric acid, lactic acid, pyruvic acid, ketone body fraction, vitamin C, vitamin E, cortisol, ACTH, (glutathione, cysteine, d-ROMs, carnitine fraction, DHEA, DHEAS, CoQ redox ratio), IL- 1β, IL-1ra, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-15, IL-17, IL-18, Eotaxin, FGF basic, G-CSF, GM-CSF, IFN-γ, IFN-α, IP-10, MCP-1, MIP-1α, MIP -1β, PDGF-BB, RANTES, TNF-α, VEGF, CSF-2, TGF-β, neurotrophin 5, MCP-3, β-2-microglobulin, angiotensin II, CSF-3, CXC chemokine ligand 1, CXC chemokine ligand 5, HGF, IL-1α, IL-2ra, IL-16, CTACK, GRO-α, ICAM-1, IFN-α2, LIF, MCP-3, M-CSF, MIF, MIG, β-NGF , SCF, SCGF-β, SDF1a, TNF-β and VCAM-1
6) Saliva test Cortisol, amylase 7) Physiological test In some subjects, a night-time Kraepelin test was performed.

The results are shown in Figs. In humans exposed to night shift stress, exercise stress and mental workload stress, it was found that the 6-MSITC administration group has an effect of avoiding or suppressing the disruption of healthy patterns of cytokines and chemokines.

The anti-stress agent of the present invention suppresses the secretion of ACTH and glucocorticoid after stress loading on the living body and / or the increase in cytokine or chemokine after stress loading by ingesting as a food or a pharmaceutical, Reduce. The anti-stress agent of the present invention also acts as an antagonist or alleviating agent against a physical load causing mental and physical disorders. Since an excessive reaction of a living body is associated with various diseases, the present invention can be applied to prevention or treatment of diseases caused by stress.

Claims

Contains ω-methylsulfinylalkylisothiocyanate (wherein the alkyl group has 4 to 8 carbon atoms) as an active ingredient, and suppresses secretion of corticotropin and / or increase in cytokine or chemokine after stress An anti-stress agent or an antagonist or alleviating agent against a physical and mental disorder caused by a biological load.
The ω-methylsulfinylalkyl isothiocyanate according to claim 1, wherein the ω-methylsulfinylalkyl isothiocyanate is from a group of wasabi, horseradish, cabbage, watercress, Brussels sprouts, cauliflower, radish, radish, rapeseed, broccoli, Takana, mustard, turnip, and Chinese cabbage. The agent of Claim 1 which is obtained from the 1 type or multiple types selected.
The agent according to claim 2, wherein the ω-methylsulfinylalkyl isothiocyanate is obtained by physical means of crushing or grinding cruciferous plants, extraction means using a solvent, drying means, or a combination thereof.
The agent according to claim 2 or 3, wherein the cruciferous plant is this wasabi.
5. The agent according to claim 4, wherein the wasabi is a wasabi leaf or a wasabi rhizome.
Cytokines are IL-1β, IL-1ra, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-15, IL-17, IL-18, Eotaxin, FGF basic, G-CSF, GM-CSF, IFN-γ, IFN-α, IP-10, MCP-1, MIP -1α, MIP-1β, PDGF-BB, RANTES, TNF-α, VEGF, CSF-2, TGF-β, Neurotrophin 5, MCP-3, β-2-microglobulin, Angiotensin II, CSF-3, CXC Chemokine ligand 1, CXC chemokine ligand 5, HGF, IL-1α, IL-2ra, IL-16, CTACK, GRO-α, ICAM-1, IFN-α2, LIF, MCP-3, M-CSF, MIF, MIG , Β-NGF, SCF, SCGF-β, SDF1a, TNF-β and an agent according to any one of claims 1 to 5 selected from the group of VCAM-1.
The agent according to claim 6, wherein the cytokine is IL-18.
ω-methylsulfinylalkyl isothiocyanate (wherein the alkyl group has 4 to 8 carbon atoms) as an active ingredient,
IL-1β, IL-1ra, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL- 12, IL-13, IL-15, IL-17, IL-18, Eotaxin, FGF basic, G-CSF, GM-CSF, IFN-γ, IFN-α, IP-10, MCP-1, MIP-1α , MIP-1β, PDGF-BB, RANTES, TNF-α, VEGF, CSF-2, TGF-β, neurotrophin 5, MCP-3, β-2-microglobulin, angiotensin II, CSF-3, CXC chemokine ligand 1, CXC chemokine ligand 5, HGF, IL-1α, IL-2ra, IL-16, CTACK, GRO-α, ICAM-1, IFN-α2, LIF, MCP-3, M-CSF, MIF, MIG, β -An anti-stress agent or biological load characterized by regulating in vivo the amount of stress factor or fatigue factor selected from the group consisting of NGF, SCF, SCGF-β, SDF1a, TNF-β and VCAM-1 Antagonists or mitigators against physical and mental disorders.
The agent according to any one of claims 1 to 8, wherein the ω-methylsulfinylalkyl isothiocyanate is 6-methylsulfinylhexyl isothiocyanate.
A pharmaceutical comprising the agent according to any one of claims 1 to 9.
A food containing the agent according to any one of claims 1 to 9.
The food according to claim 11, which is a health functional food or a dietary supplement.
The food according to claim 12, wherein the health functional food is a food for specified health use or a food with a nutritional function.
Administration of an effective amount of ω-methylsulfinylalkylisothiocyanate (wherein the alkyl group has 4 to 8 carbon atoms) to a subject in need thereof, thereby causing adrenocorticotropic hormone after stress loading Secretion or / and increase in cytokines or chemokines is suppressed, stress or biological stress is antagonizing or alleviating a physical or mental disorder.
The ω-methylsulfinylalkyl isothiocyanate according to claim 14, wherein the ω-methylsulfinylalkyl isothiocyanate is from the wasabi, horseradish, cabbage, watercress, Brussels sprouts, cauliflower, radish, radish, rapeseed, broccoli, takana, mustard, turnip, and Chinese cabbage The method according to claim 14, which is obtained from one or more selected.
The method according to claim 15, wherein the ω-methylsulfinylalkyl isothiocyanate is obtained by physical means of crushing or scouring cruciferous plants, extraction means by a solvent, drying means, or a combination thereof.
The method according to claim 15 or 16, wherein the cruciferous plant is Wasabi.
The method according to claim 17, wherein the wasabi is a wasabi leaf or a wasabi rhizome.
Cytokines are IL-1β, IL-1ra, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-15, IL-17, IL-18, Eotaxin, FGF basic, G-CSF, GM-CSF, IFN-γ, IFN-α, IP-10, MCP-1, MIP -1α, MIP-1β, PDGF-BB, RANTES, TNF-α, VEGF, CSF-2, TGF-β, Neurotrophin 5, MCP-3, β-2-microglobulin, Angiotensin II, CSF-3, CXC Chemokine ligand 1, CXC chemokine ligand 5, HGF, IL-1α, IL-2ra, IL-16, CTACK, GRO-α, ICAM-1, IFN-α2, LIF, MCP-3, M-CSF, MIF, MIG The method according to any one of claims 14 to 18, wherein the method is selected from the group of β-NGF, SCF, SCGF-β, SDF1a, TNF-β and VCAM-1.
The method according to claim 19, wherein the cytokine is IL-18.
Administering an effective amount of an ω-methylsulfinylalkylisothiocyanate (wherein the alkyl group has 4 to 8 carbon atoms) to a subject in need thereof, whereby
IL-1β, IL-1ra, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL- 12, IL-13, IL-15, IL-17, IL-18, Eotaxin, FGF basic, G-CSF, GM-CSF, IFN-γ, IFN-α, IP-10, MCP-1, MIP-1α , MIP-1β, PDGF-BB, RANTES, TNF-α, VEGF, CSF-2, TGF-β, neurotrophin 5, MCP-3, β-2-microglobulin, angiotensin II, CSF-3, CXC chemokine ligand 1, CXC chemokine ligand 5, HGF, IL-1α, IL-2ra, IL-16, CTACK, GRO-α, ICAM-1, IFN-α2, LIF, MCP-3, M-CSF, MIF, MIG, β -The stress or fatigue load in the body of the stress factor or fatigue factor selected from the group consisting of NGF, SCF, SCGF-β, SDF1a, TNF-β and VCAM-1 is regulated. Antagonistic or mitigating methods.
The method according to any one of claims 14 to 21, wherein the ω-methylsulfinylalkyl isothiocyanate is 6-methylsulfinylhexyl isothiocyanate.