WO2017141966A1 - Procédé d'évaluation de stress - Google Patents

Procédé d'évaluation de stress Download PDF

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Publication number
WO2017141966A1
WO2017141966A1 PCT/JP2017/005527 JP2017005527W WO2017141966A1 WO 2017141966 A1 WO2017141966 A1 WO 2017141966A1 JP 2017005527 W JP2017005527 W JP 2017005527W WO 2017141966 A1 WO2017141966 A1 WO 2017141966A1
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WIPO (PCT)
Prior art keywords
stress
mice
tci
acute
room
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PCT/JP2017/005527
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English (en)
Japanese (ja)
Inventor
仁範 船上
淳 多賀
邦子 三田村
成志 市田
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Kindai University
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Kindai University
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Priority to JP2018500156A priority Critical patent/JP6757037B2/ja
Publication of WO2017141966A1 publication Critical patent/WO2017141966A1/fr
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing

Definitions

  • the present invention relates to a method for evaluating stress felt by humans and animals, and a method using 1,2,3,4-tetrahydrocyclopenta [b] indole as a stress marker.
  • Patent Document 1 mentions the degree of stress relief felt during massage. Here, the point which uses cortisol as a stress marker is disclosed.
  • Patent Document 2 discloses that dehydroandrosterone sulfate, 17-ketosteroid sulfate, and dehydroepiandrosterone can be stress markers as stress markers.
  • cortisol has an anti-stress factor that counteracts stress, and therefore, it has been pointed out as a problem that it is difficult to use as a quantitative index in a unified manner.
  • Patent Document 3 discloses that dehydroepiandrosterone is used as an index as a stress marker.
  • Patent Document 4 discloses a method for stably measuring cortisol as an index of stress because stress evaluation with cortisol is unstable.
  • Patent Document 5 discloses that chromogranin A, which is known as a tumor marker, can be used as a stress marker, and the coffee bean extract has an effect of suppressing the secretion of chromogranin A.
  • cortisol which is known as a stress marker, may not have a constant expression during stress, and is unstable as an index. In addition, acute stress and chronic stress could not be distinguished.
  • the stress evaluation method according to the present invention is characterized by using 1,2,3,4-tetrahydrocyclopenta [b] indole represented by formula (1) as an index.
  • 1,2,3,4-tetrahydrocyclopenta [b] indole is always expressed when acute stress is applied, the stress state can be reliably grasped. In addition, when the stress becomes steady, the expression becomes zero. Therefore, it can be determined that the patient is in a chronic stress state using as an index that it does not appear at all.
  • TCI 1,2,3,4-tetrahydrocyclopenta [b] indole
  • TCI When animals (at least mammals) feel stress, they produce TCI, which is observed in the blood.
  • an analyzer such as GC / HPLC or GCMS / HPLC-MS which can qualitatively determine the target component.
  • the behavioral abnormality is an official standard in the case of humans (“International Classification of Diseases” (ICD-10) of WHO (World Health Organization) or “DSM-IV” of the American Psychiatric Association). ).
  • ICD-10 International Classification of Diseases
  • DSM-IV the American Psychiatric Association
  • the evaluation may be performed by a test such as an elevated plus maze test.
  • an acute stress state is a state that falls immediately after a stress is applied and that disappears within a short time when the stress is eliminated.
  • Chronic stress is a condition that occurs due to repeated or continuous stress for a certain period of time, and it does not recover even if the stress is relieved with any indefinite complaints to the body (at least for a certain period of time) Even if there is no sign of recovery).
  • description will be made based on examples.
  • mice As an example, an experiment using a mouse was performed.
  • a mouse a ddY male mouse (purchased from Nippon SLC Co., Ltd.) having a body weight of about 20-25 g (4 weeks old) was used. Normal breeding of mice was performed at a room temperature of 24 ⁇ 1 ° C. under a light / dark cycle every 12 hours (from 7 am to 7 pm, lighting), and 8 mice / gauge were used. Feed (MF (trade name), oriental yeast) and water were ingested freely.
  • MF trade name
  • mice were subjected to Specific Alternation of Rhythm in temperature (SART) to be in a chronic stress state.
  • SART Specific Alternation of Rhythm in temperature
  • a mouse breeding cage is prepared in both a breeding room at room temperature of 24 ° C. (hereinafter “room temperature breeding room”) and an animal breeding chamber having a temperature of 4 ° C. (hereinafter referred to as “cold breeding room”).
  • room temperature breeding room a breeding room temperature breeding room
  • an animal breeding chamber having a temperature of 4 ° C. hereinafter referred to as “cold breeding room”.
  • mice were moved between the cages every hour, and stress was applied by exposure to changes in environmental temperature for 7 days from 16:00 to 9:00 in the next morning in a 4 ° C chamber. added.
  • the room temperature room and the room temperature room were switched according to the SART stress loading method until 11:00 in the morning of the experiment.
  • Figure 1 shows the progress of the SART stress loading method.
  • Room A is a room-temperature breeding room and Room B is a cold room.
  • the mouse is moved between both chambers for each cage.
  • the line in the figure represents the movement of the rearing cage.
  • the number written at the turning point of the line is the time.
  • Mice that are switched between room temperature room (Room A) and cold room room (Room B) every hour from 9:00 to 16:00 every day are left in the cold room (Room B) from 16:00 to 9:00 the next morning. Is done.
  • Chronic stress is created by exposure to such temperature changes for 7 days (SART stress). Mice subjected to SART stress are called “chronic stress mice”.
  • Non-stressed mice Mice that did not give stress are called “non-stressed mice”. In addition, some non-stressed mice were given acute stress by being left in the low temperature breeding room Room B of FIG. 1 for 1 hour. Such a mouse subjected to acute stress is referred to as “acute stress mouse”. Non-stressed mice moved between gauges on the same schedule as the SART stress in order to remove the stress element accompanying the movement. Of course, this movement was designed not to cause stress due to temperature.
  • a silica monolith (diameter: 2.9 mm, length: 10 mm, containing an adsorbent, GL Sciences Inc.) for chronic stress mice, acute stress mice, and non-stress mice, and GC / MS / TD (Shimadzu Corporation: GC-2010, GCMS-Q2010Plus, OPTIC-4) was used for analysis.
  • Figure 2 shows the results.
  • the horizontal axis is time (minute: min), and the vertical axis is intensity (no unit).
  • cold1-1, cold2-1, and cold3-1 are acute stress mice.
  • control2-1, control2-2, control3-1, and control1-2 are all non-stressed mice.
  • cortisol When stress is applied, cortisol is expressed in humans, but mice have few enzymes necessary for biosynthesis of cortisol. Therefore, when stress is applied, cholesterol (Cholest-5-en-3-ol) that should become cortisol is expressed.
  • FIG. 3 is an enlarged view of a part of FIG. A peak equivalent to 156 mz in this portion (indicated by an arrow in FIG. 3) was expressed in all three mice in the acute stress mice (cold1-1, cold2-1, cold3-1), and non-stressed mice The substance which did not express was confirmed. And it was confirmed that TCI corresponds to this part.
  • TCI is a substance that is reliably expressed in acute stress mice, it can be used as a stress marker.
  • TCI can be detected from saliva, it is easy to observe in time series how much stress is caused by the applied load.
  • FIG. 4 shows the results of analyzing blood of acute stress mice and chronic stress mice.
  • TCI is observed at a peak portion of 156 mz surrounded by a square.
  • Acute stress mice expressed TCI, but chronic stress mice did not express TCI.
  • mice loaded with SART stress are in a chronic stress state and their behavioral pattern is clearly different from non-stressed mice ("Anxiety-Like Behavior in Eleveed Plus-Maze Test in Repeated Cold-Stressed Mice") , Taeko Hata et al, Jpn. J. Pharmacol. 85, 189-196 (2001)).
  • the stress evaluation method using this will be explained more specifically.
  • the stress marker (TCI) according to the present invention can also be used for humans. However, it is more suitable to know the animal's stress state.
  • This step can be said to be a step of examining the presence or absence of behavioral abnormalities to be examined.
  • the body fluid to be examined blood is desirable if blood can be collected
  • the expression of TCI is examined by GC / MS. This step may be referred to as a step of checking whether or not TCI is expressed in the test object.
  • an anti-TCI antibody (a monoclonal antibody or a polyclonal antibody) may be used, and ELISA (Enzyme-Linked Immuno) may be used. (Sorbent Assay) may be used. Moreover, EIA (Enzyme immunoassay) and RIA (Radioimmunoassay) can be used.
  • the anti-TCI antibody can be obtained by a known ordinary method. In addition, a method that can specifically detect TCI may be used.
  • TCI expression is observed without any behavioral abnormality, it is determined that the patient is in an acute stress state. Further, when no abnormal behavior is observed and no TCI expression is observed, it can be determined that the subject is not particularly stressed, that is, is in a relaxed state.
  • the stress evaluation method using the stress marker (TCI) according to the present invention can be used as a guideline for determining whether or not there is an acute stress and whether or not the patient is in a chronic stress state.
  • the stress evaluation method according to the present invention is extremely objective to determine whether a stress-free state, an acute stress state, or a chronic stress state using the presence / absence of behavioral abnormality and the presence / absence of expression of a stress marker TCI. Therefore, it is possible to objectively evaluate the stress state of a strange animal. Of course, the human stress state can also be objectively evaluated.

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  • Life Sciences & Earth Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Molecular Biology (AREA)
  • Biomedical Technology (AREA)
  • Chemical & Material Sciences (AREA)
  • Hematology (AREA)
  • Immunology (AREA)
  • Urology & Nephrology (AREA)
  • Cell Biology (AREA)
  • Microbiology (AREA)
  • Biotechnology (AREA)
  • Food Science & Technology (AREA)
  • Medicinal Chemistry (AREA)
  • Physics & Mathematics (AREA)
  • Analytical Chemistry (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • General Physics & Mathematics (AREA)
  • Pathology (AREA)
  • Investigating Or Analysing Biological Materials (AREA)

Abstract

Le cortisol est traditionnellement connu comme marqueur de stress, mais il y a des cas où son expression pendant le stress n'est pas constante, le cortisol est donc un indicateur instable. En outre, le cortisol ne permet pas de distinguer le stress aigu du stress chronique. Ce procédé d'évaluation de stress est caractérisé en ce qu'un état de stress aigu chez le sujet d'essai est déterminé lorsque 1,2,3,4-tétrahydrocyclopenta[b]indole présenté dans l'expression (1) est exprimé.
PCT/JP2017/005527 2016-02-15 2017-02-15 Procédé d'évaluation de stress Ceased WO2017141966A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP2018500156A JP6757037B2 (ja) 2016-02-15 2017-02-15 ストレス評価方法

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2016026406 2016-02-15
JP2016-026406 2016-02-15

Publications (1)

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WO2017141966A1 true WO2017141966A1 (fr) 2017-08-24

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2010523556A (ja) * 2007-04-05 2010-07-15 アンドレイ・アレクサンドロビッチ・イワシェンコ 置換された２，３，４，５−テトラヒドロ−１ｈ−ピリド［４，３−ｂ］インドール、その製造のための方法及び使用
WO2014177680A1 (fr) * 2013-05-03 2014-11-06 Salion Gmbh Procédé in vitro de détection précoce d'une inflammation potentielle, associée en particulier à un rejet d'une greffe, un trouble neurodégénératif ou une dépression
US20150266821A1 (en) * 2010-02-04 2015-09-24 Radius Health, Inc. Selective androgen receptor modulators

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2010523556A (ja) * 2007-04-05 2010-07-15 アンドレイ・アレクサンドロビッチ・イワシェンコ 置換された２，３，４，５−テトラヒドロ−１ｈ−ピリド［４，３−ｂ］インドール、その製造のための方法及び使用
US20150266821A1 (en) * 2010-02-04 2015-09-24 Radius Health, Inc. Selective androgen receptor modulators
WO2014177680A1 (fr) * 2013-05-03 2014-11-06 Salion Gmbh Procédé in vitro de détection précoce d'une inflammation potentielle, associée en particulier à un rejet d'une greffe, un trouble neurodégénératif ou une dépression

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
FUNAKAMI, YOSHINORI ET AL.: "Effect of the alphal-adrenoceptor Agonist Phenylephrine on SART Stress-induced Orthostatic Hypotension in Rats", BIOPSYCHOSOCIAL MEDICINE, vol. 4, no. 13, 2010, pages 1 - 9, XP021082041 *
JIN-HYUNG ET AL.: "Roles of Indole as an Interspecies and terkingdom Signaling Molecule", TRENDS IN MICROBIOLOGY, vol. 11, 23 January 2015 (2015-01-23), pages 707 - 718, XP055542300 *

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JP6757037B2 (ja) 2020-09-16

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